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Opdivo

Generic name: nivolumab
Dosage form: injection
Drug class: Anti-PD-1 monoclonal antibodies

Medically reviewed by Drugs.com. Last updated on Sep 1, 2021.

Indications and Usage for Opdivo

Unresectable or Metastatic Melanoma

Opdivo, as a single agent or in combination with ipilimumab, is indicated for the treatment of patients with unresectable or metastatic melanoma.

Adjuvant Treatment of Melanoma

Opdivo is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection.

Metastatic Non-Small Cell Lung Cancer

Opdivo, in combination with ipilimumab, is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (≥1%) as determined by an FDA-approved test [see Dosage and Administration (2.1)], with no EGFR or ALK genomic tumor aberrations.
Opdivo, in combination with ipilimumab and 2 cycles of platinum-doublet chemotherapy, is indicated for the first-line treatment of adult patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.
Opdivo is indicated for the treatment of patients with metastatic NSCLC with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving Opdivo.

Malignant Pleural Mesothelioma

Opdivo, in combination with ipilimumab, is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma.

Advanced Renal Cell Carcinoma

Opdivo, in combination with ipilimumab, is indicated for the first-line treatment of patients with intermediate or poor risk advanced RCC.
Opdivo, in combination with cabozantinib, is indicated for the first-line treatment of patients with advanced RCC.
Opdivo as a single agent is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

Classical Hodgkin Lymphoma

Opdivo is indicated for the treatment of adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after:

autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin, or
3 or more lines of systemic therapy that includes autologous HSCT.

This indication is approved under accelerated approval based on overall response rate [see Clinical Studies (14.6)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Squamous Cell Carcinoma of the Head and Neck

Opdivo is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

Urothelial Carcinoma

Opdivo is indicated for the adjuvant treatment of patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC [see Clinical Studies (14.8)].

Opdivo is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who:

have disease progression during or following platinum-containing chemotherapy
have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Microsatellite Instability-High or Mismatch Repair Deficient Metastatic Colorectal Cancer

Opdivo, as a single agent or in combination with ipilimumab, is indicated for the treatment of adult and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.9)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Hepatocellular Carcinoma

Opdivo, in combination with ipilimumab, is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.10)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

Opdivo is indicated for the adjuvant treatment of completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease in patients who have received neoadjuvant chemoradiotherapy (CRT).
Opdivo is indicated for the treatment of patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy.

Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma

Opdivo, in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the treatment of patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma.

Opdivo Dosage and Administration

Patient Selection

Select patients with metastatic NSCLC for treatment with Opdivo in combination with ipilimumab based on PD-L1 expression [see Clinical Studies (14.3)].

Information on FDA-approved tests for the determination of PD-L1 expression in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics.

Recommended Dosage

The recommended dosages of Opdivo as a single agent are presented in Table 1.

Table 1: Recommended Dosages for Opdivo as a Single Agent

Indication

Recommended Opdivo Dosage

Duration of Therapy

Unresectable or metastatic melanoma

240 mg every 2 weeks

(30-minute intravenous infusion)

or

480 mg every 4 weeks

(30-minute intravenous infusion)

Until disease progression or unacceptable toxicity

Metastatic non-small cell lung cancer

Advanced renal cell carcinoma

Classical Hodgkin lymphoma

Squamous cell carcinoma of the head and neck

Locally advanced or metastatic urothelial carcinoma

Esophageal squamous cell carcinoma

Adjuvant treatment of melanoma

240 mg every 2 weeks

(30-minute intravenous infusion)

or

480 mg every 4 weeks

(30-minute intravenous infusion)

Until disease recurrence or unacceptable toxicity for up to 1 year

Adjuvant treatment of urothelial carcinoma (UC)

Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer

Adult patients and pediatric patients age 12 years and older and weighing 40 kg or more:

240 mg every 2 weeks

(30-minute intravenous infusion)

or

480 mg every 4 weeks

(30-minute intravenous infusion)

Until disease progression or unacceptable toxicity

Pediatric patients age 12 years and older and weighing less than 40 kg:

3 mg/kg every 2 weeks

(30-minute intravenous infusion)

Adjuvant treatment of resected esophageal or gastroesophageal junction cancer

240 mg every 2 weeks

(30-minute intravenous infusion)

or

480 mg every 4 weeks

(30-minute intravenous infusion)

Until disease progression or unacceptable toxicity for a total treatment duration of 1 year

The recommended dosages of Opdivo in combination with other therapeutic agents are presented in Table 2. Refer to the respective Prescribing Information for each therapeutic agent administered in combination with Opdivo for the recommended dosage information, as appropriate.

Table 2: Recommended Dosages of Opdivo in Combination with Other Therapeutic Agents

Indication

Recommended Opdivo Dosage

Duration of Therapy

Unresectable or metastatic melanoma

1 mg/kg every 3 weeks

(30-minute intravenous infusion)

with ipilimumab 3 mg/kg intravenously

over 90 minutes on the same day

In combination with ipilimumab for a maximum of 4 doses or until unacceptable toxicity, whichever occurs earlier

240 mg every 2 weeks

(30-minute intravenous infusion)

or

480 mg every 4 weeks

(30-minute intravenous infusion)

After completing 4 doses of combination therapy, administer as single agent until disease progression or unacceptable toxicity

Metastatic non-small cell lung cancer expressing PD-L1

3 mg/kg every 2 weeks

(30-minute intravenous infusion)

with ipilimumab 1 mg/kg every 6 weeks

(30-minute intravenous infusion)

In combination with ipilimumab until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression

Metastatic or recurrent non-small cell lung cancer

360 mg every 3 weeks

(30-minute intravenous infusion)

with ipilimumab 1 mg/kg every 6 weeks

(30-minute intravenous infusion)

and histology-based platinum

doublet chemotherapy every 3 weeks

In combination with ipilimumab until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression

2 cycles of histology-based platinum-doublet chemotherapy

Malignant pleural mesothelioma

360 mg every 3 weeks

(30-minute intravenous infusion)

with ipilimumab 1 mg/kg every 6 weeks

(30-minute intravenous infusion)

In combination with ipilimumab until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression

Advanced renal cell carcinoma

3 mg/kg every 3 weeks

(30-minute intravenous infusion)

with ipilimumab 1 mg/kg intravenously

over 30 minutes on the same day

In combination with ipilimumab
for 4 doses

240 mg every 2 weeks

(30-minute intravenous infusion)

or

480 mg every 4 weeks

(30-minute intravenous infusion)

Administer Opdivo in combination with cabozantinib 40 mg orally once daily without food

Opdivo: Until disease progression, unacceptable toxicity, or up to 2 years

Cabozantinib: Until disease progression or unacceptable toxicity

240 mg every 2 weeks

(30-minute intravenous infusion)

or

480 mg every 4 weeks

(30-minute intravenous infusion)

After completing 4 doses of combination therapy with ipilimumab, administer as single agent until disease progression or unacceptable toxicity

Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer

3 mg/kg every 3 weeks

(30-minute intravenous infusion)

with ipilimumab 1 mg/kg intravenously

over 30 minutes on the same day

In combination with ipilimumab
for 4 doses

Adult patients and pediatric patients age 12 years and older and weighing 40 kg or more:

240 mg every 2 weeks

(30-minute intravenous infusion)

or

480 mg every 4 weeks

(30-minute intravenous infusion)

After completing 4 doses of combination therapy, administer as single agent until disease progression or unacceptable toxicity

Pediatric patients age 12 years and older and weighing less than 40 kg:

3 mg/kg every 2 weeks

(30-minute intravenous infusion)

Hepatocellular carcinoma

1 mg/kg every 3 weeks

(30-minute intravenous infusion)

with ipilimumab 3 mg/kg intravenously

over 30 minutes on the same day

In combination with ipilimumab
for 4 doses

240 mg every 2 weeks

(30-minute intravenous infusion)

or

480 mg every 4 weeks

(30-minute intravenous infusion)

After completing 4 doses of combination therapy, administer as single agent until disease progression or unacceptable toxicity

Gastric cancer, Gastroesophageal junction cancer, and Esophageal adenocarcinoma

240 mg every 2 weeks

(30-minute intravenous infusion)

with fluoropyrimidine- and platinum-containing chemotherapy every 2 weeks

or

360 mg every 3 weeks

(30-minute intravenous infusion)

with fluoropyrimidine- and platinum-containing chemotherapy every 3 weeks

Until disease progression, unacceptable toxicity, or up to 2 years

Dose Modifications

No dose reduction for Opdivo is recommended. In general, withhold Opdivo for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue Opdivo for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating steroids.

Dosage modifications for Opdivo or Opdivo in combination for adverse reactions that require management different from these general guidelines are summarized in Table 3 and Table 4.

When Opdivo is administered in combination with ipilimumab, withhold or permanently discontinue both ipilimumab and Opdivo for an adverse reaction meeting these dose modification guidelines.

Table 3: Recommended Dosage Modifications for Adverse Reactions
a Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg per day (or equivalent) or less within 12 weeks of initiating steroids.
b If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue Opdivo based on recommendations for hepatitis with no liver involvement.
c Depending on clinical severity, consider withholding for Grade 2 endocrinopathy until symptom improvement with hormone replacement. Resume once acute symptoms have resolved.
ALT = alanine aminotransferase, AST = aspartate aminotransferase, DRESS = Drug Rash with Eosinophilia and Systemic Symptoms, SJS = Stevens Johnson Syndrome, TEN = toxic epidermal necrolysis, ULN = upper limit normal

Adverse Reaction

Severity

Dosage Modification

Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)]

Pneumonitis

Grade 2

Withholda

Grades 3 or 4

Permanently discontinue

Colitis

For colitis in patients treated with combination therapy with ipilimumab, see Table 4.

Grade 2 or 3

Withholda

Grade 4

Permanently discontinue

Hepatitis with no tumor involvement of the liver

For liver enzyme elevations in patients treated with combination therapy with ipilimumab, see Table 4.

AST/ALT increases to >3 and ≤8 times ULN

or

Total bilirubin increases to >1.5 and ≤3 times ULN.

Withholda

AST or ALT increases to >8 times ULN

or

Total bilirubin increases to >3 times ULN.

Permanently discontinue

Hepatitis with tumor involvement of the liverb

For liver enzyme elevations in patients treated with combination therapy with ipilimumab, see Table 4.

Baseline AST/ALT is >1 and ≤3 times ULN and increases to >5 and ≤10 times ULN

or

Baseline AST/ALT is >3 and ≤5 times ULN and increases to >8 and ≤10 times ULN.

Withholda

AST/ALT increases to >10 times ULN

or

Total bilirubin increases to >3 times ULN.

Permanently discontinue

Endocrinopathiesc

Grade 3 or 4

Withhold until clinically stable or permanently discontinue depending on severity

Nephritis with Renal Dysfunction

Grade 2 or 3 increased blood creatinine

Withholda

Grade 4 increased blood creatinine

Permanently discontinue

Exfoliative Dermatologic Conditions

Suspected SJS, TEN, or DRESS

Withhold

Confirmed SJS, TEN, or DRESS

Permanently discontinue

Myocarditis

Grades 2, 3, or 4

Permanently discontinue

Neurological Toxicities

Grade 2

Withholda

Grade 3 or 4

Permanently discontinue

Other Adverse Reactions

Infusion-Related Reactions

[see Warnings and Precautions (5.2)]

Grade 1 or 2

Interrupt or slow the rate of infusion

Grade 3 or 4

Permanently discontinue

Table 4: Recommended Dosage Modifications for Adverse Reactions in Patients Treated with Combination Therapy
a Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg per day (or equivalent) or less within 12 weeks of initiating steroids.
b If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue Opdivo in combination with ipilimumab based on recommendations for hepatitis with no liver involvement.
c Consider corticosteroid therapy for hepatic adverse reactions if Opdivo is withheld or discontinued when administered in combination with cabozantinib.
d After recovery, rechallenge with one or both of Opdivo and cabozantinib may be considered. If rechallenging with cabozantinib with or without Opdivo, refer to cabozantinib Prescribing Information.

Treatment

Adverse Reaction

Severity

Dosage Modification

Opdivo in combination with ipilimumab

Colitis

Grade 2

Withholda

Grade 3 or 4

Permanently discontinue

Hepatitis with no tumor involvement of the liver

or

Hepatitis with tumor involvement of the liver/non-HCC

AST/ALT increases to >3 times ULN and ≤5 times ULN

or

Total bilirubin increases to ≥1.5 and ≤3 times ULN.

Withholda

AST or ALT >5 times ULN or

Total bilirubin >3 times ULN.

Permanently discontinue

Hepatitis with tumor involvement of the liverb/HCC

Baseline AST/ALT is >1 and ≤3 times ULN and increases to >5 and ≤10 times ULN

or

Baseline AST/ALT is >3 and ≤5 times ULN and increases to >8 and ≤10 times ULN.

Withholda

AST/ALT increases to >10 times ULN

or

Total bilirubin increases to >3 times ULN.

Permanently discontinue

Opdivo in combination with cabozantinib

Liver enzyme elevations

ALT or AST >3 times ULN but ≤10 times ULN with concurrent total bilirubin <2 times ULN

Withholdc both Opdivo and cabozantinib until adverse reactions recoverd to Grades 0-1

ALT or AST >10 times ULN

or >3 times ULN with concurrent total bilirubin ≥2 times ULN

Permanently discontinuec both Opdivo and cabozantinib

Preparation and Administration

Visually inspect for particulate matter and discoloration. Opdivo is a clear to opalescent, colorless to pale-yellow solution. Discard if cloudy, discolored, or contains extraneous particulate matter other than a few translucent-to-white, proteinaceous particles. Do not shake.

Preparation
Withdraw the required volume of Opdivo and transfer into an intravenous container.
Dilute Opdivo with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepare an infusion with a final concentration ranging from 1 mg/mL to 10 mg/mL. The total volume of infusion must not exceed 160 mL.
• For adult and pediatric patients with body weight ≥40 kg, do not exceed a total volume of infusion of 160 mL.
• For adult and pediatric patients with body weight <40 kg, do not exceed a total volume of infusion of 4 mL/kg of body weight.
Mix diluted solution by gentle inversion. Do not shake.
Discard partially used vials or empty vials of Opdivo.
The product does not contain a preservative.

After preparation, store the diluted solution either:
• at room temperature and room light for no more than 8 hours from the time of preparation to end of the infusion. Discard diluted solution if not used within 8 hours from the time of preparation; or
• under refrigeration at 2°C to 8°C (36°F to 46°F) and protected from light for no more than 7 days from the time of preparation to end of infusion. Discard diluted solution if not used within 7 days from the time of preparation.
Do not freeze.
Administration
Administer the infusion over 30 minutes through an intravenous line containing a sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer to 1.2 micrometer).
Administer Opdivo in combination with other therapeutic agents as follows:
o
With ipilimumab: administer Opdivo first followed by ipilimumab on the same day.
o
With platinum-doublet chemotherapy: administer Opdivo first followed by platinum-doublet chemotherapy on the same day
o
With ipilimumab and platinum-doublet chemotherapy: administer Opdivo first followed by ipilimumab and then platinum-doublet chemotherapy on the same day.
o
With fluoropyrimidine- and platinum-containing chemotherapy: administer Opdivo first followed by fluoropyrimidine- and platinum-containing chemotherapy on the same day.
Use separate infusion bags and filters for each infusion.
Flush the intravenous line at end of infusion.
Do not co-administer other drugs through the same intravenous line.

Dosage Forms and Strengths

Injection: 40 mg/4 mL (10 mg/mL), 100 mg/10 mL (10 mg/mL), 120 mg/12 mL (10 mg/mL), and 240 mg/24 mL (10 mg/mL) clear to opalescent, colorless to pale-yellow solution in a single-dose vial.

Contraindications

None.

Warnings and Precautions

Severe and Fatal Immune-Mediated Adverse Reactions

Opdivo is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment with a PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies.

Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue Opdivo depending on severity [see Dosage and Administration (2.2)]. In general, if Opdivo requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.

Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis

Opdivo can cause immune-mediated pneumonitis, which is defined as requiring use of steroids and no clear alternate etiology. In patients treated with other PD-1/PD-L1 blocking antibodies, the incidence of pneumonitis is higher in patients who have received prior thoracic radiation.

Opdivo as a Single Agent

Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients receiving Opdivo as a single agent, including Grade 4 (<0.1%), Grade 3 (0.9%), and Grade 2 (2.1%) adverse reactions. Pneumonitis led to permanent discontinuation of Opdivo in 1.1% and withholding of Opdivo in 0.8% of patients.

Systemic corticosteroids were required in 100% (61/61) of patients with pneumonitis. Pneumonitis resolved in 84% of the 61 patients. Of the 15 patients in whom Opdivo was withheld for pneumonitis, 14 reinitiated Opdivo after symptom improvement; of these, 4 (29%) had recurrence of pneumonitis.

Opdivo with Ipilimumab

Opdivo 3 mg/kg with Ipilimumab 1 mg/kg: In NSCLC, immune-mediated pneumonitis occurred in 9% (50/576) of patients receiving Opdivo 3 mg/kg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks, including Grade 4 (0.5%), Grade 3 (3.5%), and Grade 2 (4.0%) immune-mediated pneumonitis. Four patients (0.7%) died due to pneumonitis. Immune-mediated pneumonitis led to permanent discontinuation of Opdivo with ipilimumab in 5% of patients and withholding of Opdivo with ipilimumab in 3.6% of patients.

Systemic corticosteroids were required in 100% of patients with pneumonitis. Pneumonitis resolved in 72% of the patients. Approximately 13% (2/16) of patients had recurrence of pneumonitis after reinitiation of Opdivo with ipilimumab.

Immune-Mediated Colitis

Opdivo can cause immune-mediated colitis, defined as requiring use of corticosteroids and no clear alternate etiology. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.

Opdivo as a Single Agent

Immune-mediated colitis occurred in 2.9% (58/1994) of patients receiving Opdivo as a single agent, including Grade 3 (1.7%) and Grade 2 (1%) adverse reactions. Colitis led to permanent discontinuation of Opdivo in 0.7% and withholding of Opdivo in 0.9% of patients.

Systemic corticosteroids were required in 100% (58/58) of patients with colitis. Four patients required addition of infliximab to high-dose corticosteroids. Colitis resolved in 86% of the 58 patients. Of the 18 patients in whom Opdivo was withheld for colitis, 16 reinitiated Opdivo after symptom improvement; of these, 12 (75%) had recurrence of colitis.

Opdivo with Ipilimumab

Opdivo 1 mg/kg with Ipilimumab 3 mg/kg: Immune-mediated colitis occurred in 25% (115/456) of patients with melanoma or HCC receiving Opdivo 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 4 (0.4%), Grade 3 (14%), and Grade 2 (8%) adverse reactions. Colitis led to permanent discontinuation of Opdivo with ipilimumab in 14% and withholding of Opdivo with ipilimumab in 4.4% of patients.

Systemic corticosteroids were required in 100% (115/115) of patients with colitis. Approximately 23% of patients required addition of infliximab to high-dose corticosteroids. Colitis resolved in 93% of the 115 patients. Of the 20 patients in whom Opdivo with ipilimumab was withheld for colitis, 16 reinitiated treatment after symptom improvement; of these, 9 (56%) had recurrence of colitis.

Opdivo 3 mg/kg with Ipilimumab 1 mg/kg: Immune-mediated colitis occurred in 9% (60/666) of patients with RCC or CRC receiving Opdivo 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 3 (4.4%) and Grade 2 (3.7%) adverse reactions. Colitis led to permanent discontinuation of Opdivo with ipilimumab in 3.2% and withholding of Opdivo with ipilimumab in 2.7% of patients with RCC or CRC.

Systemic corticosteroids were required in 100% (60/60) of patients with colitis. Approximately 23% of patients with immune-mediated colitis required addition of infliximab to high-dose corticosteroids. Colitis resolved in 95% of the 60 patients. Of the 18 patients in whom Opdivo with ipilimumab was withheld for colitis, 16 reinitiated treatment after symptom improvement; of these, 10 (63%) had recurrence of colitis.

Immune-Mediated Hepatitis and Hepatotoxicity

Opdivo can cause immune-mediated hepatitis, defined as requiring the use of corticosteroids and no clear alternate etiology.

Opdivo as a Single Agent

Immune-mediated hepatitis occurred in 1.8% (35/1994) of patients receiving Opdivo as a single agent, including Grade 4 (0.2%), Grade 3 (1.3%), and Grade 2 (0.4%) adverse reactions. Hepatitis led to permanent discontinuation of Opdivo in 0.7% and withholding of Opdivo in 0.6% of patients.

Systemic corticosteroids were required in 100% (35/35) of patients with hepatitis. Two patients required the addition of mycophenolic acid to high-dose corticosteroids. Hepatitis resolved in 91% of the 35 patients. Of the 12 patients in whom Opdivo was withheld for hepatitis, 11 reinitiated Opdivo after symptom improvement; of these, 9 (82%) had recurrence of hepatitis.

Opdivo with Ipilimumab

Opdivo 1 mg/kg with Ipilimumab 3 mg/kg: Immune-mediated hepatitis occurred in 15% (70/456) of patients with melanoma or HCC receiving Opdivo 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 4 (2.4%), Grade 3 (11%), and Grade 2 (1.8%) adverse reactions. Immune-mediated hepatitis led to permanent discontinuation of Opdivo with ipilimumab in 8% or withholding of Opdivo with ipilimumab in 3.5% of patients.

Systemic corticosteroids were required in 100% (70/70) of patients with hepatitis. Approximately 9% of patients with immune-mediated hepatitis required the addition mycophenolic acid to high-dose corticosteroids. Hepatitis resolved in 91% of the 70 patients. Of the 16 patients in whom Opdivo with ipilimumab was withheld for hepatitis, 14 reinitiated treatment after symptom improvement; of these, 8 (57%) had recurrence of hepatitis.

Opdivo 3 mg/kg with Ipilimumab 1 mg/kg: Immune-mediated hepatitis occurred in 7% (48/666) of patients with RCC or CRC receiving Opdivo 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 4 (1.2%), Grade 3 (4.9%), and Grade 2 (0.4%) adverse reactions. Immune-mediated hepatitis led to permanent discontinuation of Opdivo with ipilimumab in 3.6% and withholding of Opdivo with ipilimumab in 2.6% of patients with RCC or CRC.

Systemic corticosteroids were required in 100% (48/48) of patients with hepatitis. Approximately 19% of patients with immune-mediated hepatitis required addition of mycophenolic acid to high-dose corticosteroids. Hepatitis resolved in 88% of the 48 patients. Of the 17 patients in whom Opdivo with ipilimumab was withheld for hepatitis, 14 reinitiated treatment after symptom improvement; of these, 10 (71%) had recurrence of hepatitis.

Opdivo with Cabozantinib

Opdivo in combination with cabozantinib can cause hepatic toxicity with higher frequencies of Grade 3 and 4 ALT and AST elevations compared to Opdivo alone. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt Opdivo and cabozantinib and consider administering corticosteroids [see Dosage and Administration (2.3)].

With the combination of Opdivo and cabozantinib, Grades 3 and 4 increased ALT or AST were seen in 11% of patients [see Adverse Reactions (6.1)]. ALT or AST >3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either Opdivo (n=11) or cabozantinib (n=9) administered as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving Opdivo, 2 patients receiving cabozantinib, and 7 patients receiving both Opdivo and cabozantinib.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

Opdivo can cause primary or secondary adrenal insufficiency. For grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold Opdivo depending on severity [see Dosage and Administration (2.2)].

Opdivo as a Single Agent

Adrenal insufficiency occurred in 1% (20/1994) of patients receiving Opdivo as a single agent, including Grade 3 (0.4%) and Grade 2 (0.6%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of Opdivo in 0.1% and withholding of Opdivo in 0.4% of patients.

Approximately 85% of patients with adrenal insufficiency received hormone replacement therapy. Systemic corticosteroids were required in 90% (18/20) of patients with adrenal insufficiency. Adrenal insufficiency resolved in 35% of the 20 patients. Of the 8 patients in whom Opdivo was withheld for adrenal insufficiency, 4 reinitiated Opdivo after symptom improvement and all required hormone replacement therapy for their ongoing adrenal insufficiency.

Opdivo with Ipilimumab

Opdivo 1 mg/kg with Ipilimumab 3 mg/kg: Adrenal insufficiency occurred in 8% (35/456) of patients with melanoma or HCC receiving Opdivo 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of Opdivo with ipilimumab in 0.4% and withholding of Opdivo with ipilimumab in 2.0% of patients.

Approximately 71% (25/35) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 37% of the 35 patients. Of the 9 patients in whom Opdivo with ipilimumab was withheld for adrenal insufficiency, 7 reinitiated treatment after symptom improvement and all required hormone replacement therapy for their ongoing adrenal insufficiency.

Opdivo 3 mg/kg with Ipilimumab 1 mg/kg: Adrenal insufficiency occurred in 7% (48/666) of patients with RCC or CRC who received Opdivo 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 4 (0.3%), Grade 3 (2.5%), and Grade 2 (4.1%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of Opdivo with ipilimumab in 1.2% and withholding of Opdivo with ipilimumab in 2.1% of patients with RCC or CRC.

Approximately 94% (45/48) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 29% of the 48 patients. Of the 14 patients in whom Opdivo with ipilimumab was withheld for adrenal insufficiency, 11 reinitiated treatment after symptom improvement; of these, all received hormone replacement therapy and 2 (18%) had recurrence of adrenal insufficiency.

Opdivo with Cabozantinib

Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received Opdivo with cabozantinib, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of Opdivo and cabozantinib in 0.9% and withholding of Opdivo and cabozantinib in 2.8% of patients with RCC.

Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom Opdivo with cabozantinib was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.

Hypophysitis

Opdivo can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as clinically indicated. Withhold or permanently discontinue Opdivo depending on severity [see Dosage and Administration (2.2)].

Opdivo as a Single Agent

Hypophysitis occurred in 0.6% (12/1994) of patients receiving Opdivo as a single agent, including Grade 3 (0.2%) and Grade 2 (0.3%) adverse reactions. Hypophysitis led to permanent discontinuation of Opdivo in <0.1% and withholding of Opdivo in 0.2% of patients.

Approximately 67% (8/12) of patients with hypophysitis received hormone replacement therapy, including systemic corticosteroids. Hypophysitis resolved in 42% of the 12 patients. Of the 3 patients in whom Opdivo was withheld for hypophysitis, 2 reinitiated Opdivo after symptom improvement; of these, none had recurrence of hypophysitis.

Opdivo with Ipilimumab

Opdivo 1 mg/kg with Ipilimumab 3 mg/kg: Hypophysitis occurred in 9% (42/456) of patients with melanoma or HCC receiving Opdivo 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 3 (2.4%) and Grade 2 (6%) adverse reactions. Hypophysitis led to permanent discontinuation of Opdivo with ipilimumab in 0.9% and withholding of Opdivo with ipilimumab in 4.2% of patients.

Approximately 86% of patients with hypophysitis received hormone replacement therapy. Systemic corticosteroids were required in 88% (37/42) of patients with hypophysitis. Hypophysitis resolved in 38% of the 42 patients. Of the 19 patients in whom Opdivo with ipilimumab was withheld for hypophysitis, 9 reinitiated treatment after symptom improvement; of these, 1 (11%) had recurrence of hypophysitis.

Opdivo 3 mg/kg with Ipilimumab 1 mg/kg: Hypophysitis occurred in 4.4% (29/666) of patients with RCC or CRC receiving Opdivo 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 4 (0.3%), Grade 3 (2.4%), and Grade 2 (0.9%) adverse reactions. Hypophysitis led to permanent discontinuation of Opdivo with ipilimumab in 1.2% and withholding of Opdivo with ipilimumab in 2.1% of patients with RCC or CRC.

Approximately 72% (21/29) of patients with hypophysitis received hormone replacement therapy, including systemic corticosteroids. Hypophysitis resolved in 59% of the 29 patients. Of the 14 patients in whom Opdivo with ipilimumab was withheld for hypophysitis, 11 reinitiated treatment after symptom improvement; of these, 2 (18%) had recurrence of hypophysitis.

Thyroid Disorders

Opdivo can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement or medical management as clinically indicated. Withhold or permanently discontinue Opdivo depending on severity [see Dosage and Administration (2.2)].

Thyroiditis

Opdivo as a Single Agent

Thyroiditis occurred in 0.6% (12/1994) of patients receiving Opdivo as a single agent, including Grade 2 (0.2%) adverse reactions. Thyroiditis led to permanent discontinuation of Opdivo in no patients and withholding of Opdivo in 0.2% of patients.

Systemic corticosteroids were required in 17% (2/12) of patients with thyroiditis. Thyroiditis resolved in 58% of the 12 patients. Of the 3 patients in whom Opdivo was withheld for thyroiditis, 1 reinitiated Opdivo after symptom improvement without recurrence of thyroiditis.

Hyperthyroidism

Opdivo as a Single Agent

Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving Opdivo as a single agent, including Grade 3 (<0.1%) and Grade 2 (1.2%) adverse reactions. Hyperthyroidism led to the permanent discontinuation of Opdivo in no patients and withholding of Opdivo in 0.4% of patients.

Approximately 19% of patients with hyperthyroidism received methimazole, 7% received carbimazole, and 4% received propylthiouracil. Systemic corticosteroids were required in 9% (5/54) of patients. Hyperthyroidism resolved in 76% of the 54 patients. Of the 7 patients in whom Opdivo was withheld for hyperthyroidism, 4 reinitiated Opdivo after symptom improvement; of these, none had recurrence of hyperthyroidism.

Opdivo with Ipilimumab

Opdivo 1 mg/kg with Ipilimumab 3 mg/kg: Hyperthyroidism occurred in 9% (42/456) of patients with melanoma or HCC who received Opdivo 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 3 (0.9%) and Grade 2 (4.2%) adverse reactions. Hyperthyroidism led to the permanent discontinuation of Opdivo with ipilimumab in no patients and withholding of Opdivo with ipilimumab in 2.4% of patients.

Approximately 26% of patients with hyperthyroidism received methimazole and 21% received carbimazole. Systemic corticosteroids were required in 17% (7/42) of patients. Hyperthyroidism resolved in 91% of the 42 patients. Of the 11 patients in whom Opdivo with ipilimumab was withheld for hyperthyroidism, 8 reinitiated treatment after symptom improvement; of these, 1 (13%) had recurrence of hyperthyroidism.

Opdivo 3 mg/kg with Ipilimumab 1 mg/kg: Hyperthyroidism occurred in 12% (80/666) of patients with RCC or CRC who received Opdivo 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 3 (0.6%) and Grade 2 (4.5%) adverse reactions. Hyperthyroidism led to permanent discontinuation of Opdivo with ipilimumab in no patients and withholding of Opdivo with ipilimumab in 2.3% of patients with RCC or CRC.

Of the 80 patients with RCC or CRC who developed hyperthyroidism, approximately 16% received methimazole and 3% received carbimazole. Systemic corticosteroids were required in 20% (16/80) of patients with hyperthyroidism. Hyperthyroidism resolved in 85% of the 80 patients. Of the 15 patients in whom Opdivo with ipilimumab was withheld for hyperthyroidism, 11 reinitiated treatment after symptom improvement; of these, 3 (27%) had recurrence of hyperthyroidism.

Hypothyroidism

Opdivo as a Single Agent

Hypothyroidism occurred in 8% (163/1994) of patients receiving Opdivo as a single agent, including Grade 3 (0.2%) and Grade 2 (4.8%) adverse reactions. Hypothyroidism led to the permanent discontinuation of Opdivo in no patients and withholding of Opdivo in 0.5% of patients.

Approximately 79% of patients with hypothyroidism received levothyroxine. Systemic corticosteroids were required in 3.1% (5/163) of patients with hypothyroidism. Hypothyroidism resolved in 35% of the 163 patients. Of the 9 patients in whom Opdivo was withheld for hypothyroidism, 3 reinitiated Opdivo after symptom improvement; of these, 1 (33%) had recurrence of hypothyroidism.

Opdivo with Ipilimumab

Opdivo 1 mg/kg with Ipilimumab 3 mg/kg: Hypothyroidism occurred in 20% (91/456) of patients with melanoma or HCC receiving Opdivo 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 3 (0.4%) and Grade 2 (11%) adverse reactions. Hypothyroidism led to the permanent discontinuation of Opdivo with ipilimumab in 0.9% and withholding of Opdivo with ipilimumab in 0.9% of patients.

Approximately 89% of patients with hypothyroidism received levothyroxine. Systemic corticosteroids were required in 2.2% (2/91) of patients with hypothyroidism. Hypothyroidism resolved in 41% of the 91 patients. Of the 4 patients in whom Opdivo with ipilimumab was withheld for hypothyroidism, 2 reinitiated treatment after symptom improvement; of these, none had recurrence of hypothyroidism.

Opdivo 3 mg/kg with Ipilimumab 1 mg/kg: Hypothyroidism occurred in 18% (122/666) of patients with RCC or CRC who received Opdivo 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks, including Grade 3 (0.6%) and Grade 2 (11%) adverse reactions. Hypothyroidism led to permanent discontinuation of Opdivo with ipilimumab in 0.2% and withholding of Opdivo with ipilimumab in 1.4% of patients with RCC or CRC.

Of the 122 patients with RCC or CRC who developed hypothyroidism, approximately 82% received levothyroxine. Systemic corticosteroids were required in 7% (9/122) of patients with hypothyroidism. Hypothyroidism resolved in 27% of the 122 patients. Of the 9 patients in whom Opdivo with ipilimumab was withheld for hypothyroidism, 5 reinitiated treatment after symptom improvement; of these, 1 (20%) had recurrence of hypothyroidism.

Type 1 Diabetes Mellitus, which can present with Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold Opdivo depending on severity [see Dosage and Administration (2.2)].

Opdivo as a Single Agent

Diabetes occurred in 0.9% (17/1994) of patients receiving Opdivo as a single agent, including Grade 3 (0.4%) and Grade 2 (0.3%) adverse reactions, and two cases of diabetic ketoacidosis. Diabetes led to the permanent discontinuation of Opdivo in no patients and withholding of Opdivo in 0.1% of patients.

No patients (0/17) with diabetes required systemic corticosteroids. Diabetes resolved in 29% of the 17 patients. Of the 2 patients in whom Opdivo was withheld for diabetes, both reinitiated Opdivo after symptom improvement; of these, neither had recurrence of diabetes.

Immune-Mediated Nephritis with Renal Dysfunction

Opdivo can cause immune-mediated nephritis, which is defined as requiring use of steroids and no clear alternate etiology.

Opdivo as a Single Agent

Immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients receiving Opdivo as a single agent, including Grade 4 (<0.1%), Grade 3 (0.5%), and Grade 2 (0.6%) adverse reactions. Immune-mediated nephritis and renal dysfunction led to permanent discontinuation of Opdivo in 0.3% and withholding of Opdivo in 0.4% of patients.

Systemic corticosteroids were required in 100% (23/23) of patients with nephritis and renal dysfunction. Nephritis and renal dysfunction resolved in 78% of the 23 patients. Of the 7 patients in whom Opdivo was withheld for nephritis or renal dysfunction, 7 reinitiated Opdivo after symptom improvement; of these, 1 (14%) had recurrence of nephritis or renal dysfunction.

Immune-Mediated Dermatologic Adverse Reactions

Opdivo can cause immune-mediated rash or dermatitis, defined as requiring the use of steroids and no clear alternate etiology. Exfoliative dermatitis, including Stevens-Johnson Syndrome, toxic epidermal necrolysis (TEN), and DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) has occurred with PD-1/L-1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue Opdivo depending on severity [see Dosage and Administration (2.2)].

Opdivo as a Single Agent

Immune-mediated rash occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and Grade 2 (2.2%) adverse reactions. Immune-mediated rash led to permanent discontinuation of Opdivo in 0.3% and withholding of Opdivo in 0.5% of patients.

Systemic corticosteroids were required in 100% (171/171) of patients with immune-mediated rash. Rash resolved in 72% of the 171 patients. Of the 10 patients in whom Opdivo was withheld for immune-mediated rash, 9 reinitiated Opdivo after symptom improvement; of these, 3 (33%) had recurrence of immune-mediated rash.

Opdivo with Ipilimumab

Opdivo 1 mg/kg with Ipilimumab 3 mg/kg: Immune-mediated rash occurred in 28% (127/456) of patients with melanoma or HCC receiving Opdivo 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 3 (4.8%) and Grade 2 (10%) adverse reactions. Immune-mediated rash led to permanent discontinuation of Opdivo with ipilimumab in 0.4% and withholding of Opdivo with ipilimumab in 3.9% of patients.

Systemic corticosteroids were required in 100% (127/127) of patients with immune-mediated rash. Rash resolved in 84% of the 127 patients. Of the 18 patients in whom Opdivo with ipilimumab was withheld for immune-mediated rash, 15 reinitiated treatment after symptom improvement; of these, 8 (53%) had recurrence of immune-mediated rash.

Opdivo 3 mg/kg with Ipilimumab 1 mg/kg: Immune-mediated rash occurred in 16% (108/666) of patients with RCC or CRC who received Opdivo 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 3 (3.5%) and Grade 2 (4.2%) adverse reactions. Immune-mediated rash led to permanent discontinuation of Opdivo with ipilimumab in 0.5% of patients and withholding of Opdivo with ipilimumab in 2.0% of patients with RCC or CRC.

Systemic corticosteroids were required in 100% (108/108) of patients with immune-mediated rash. Rash resolved in 75% of the 108 patients. Of the 13 patients in whom Opdivo with ipilimumab was withheld for immune-mediated rash, 11 reinitiated treatment after symptom improvement; of these, 5 (46%) had recurrence of immune-mediated rash.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received Opdivo or Opdivo in combination with ipilimumab, or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions.

Cardiac/Vascular: Myocarditis, pericarditis, vasculitis

Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barre syndrome, nerve paresis, autoimmune neuropathy

Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss

Gastrointestinal: Pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis

Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis, and associated sequelae including renal failure, arthritis, polymyalgia rheumatic

Endocrine: Hypoparathyroidism

Other (Hematologic/Immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection

Infusion-Related Reactions

Opdivo can cause severe infusion-related reactions, which have been reported in <1.0% of patients in clinical trials. Discontinue Opdivo in patients with severe or life-threatening infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild or moderate infusion-related reactions [see Dosage and Administration (2.3)].

Opdivo as a Single Agent

In patients who received Opdivo as a 60-minute intravenous infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients.

In a trial assessing the pharmacokinetics and safety of a more rapid infusion, in which patients received Opdivo as a 60-minute intravenous infusion or a 30-minute intravenous infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation, or withholding of Opdivo.

Opdivo with Ipilimumab

Opdivo 1 mg/kg with Ipilimumab 3 mg/kg

Infusion-related reactions occurred in 2.5% (10/407) of patients with melanoma and in 8% (4/49) of patients with HCC who received Opdivo 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks.

Opdivo 3 mg/kg with Ipilimumab 1 mg/kg

Infusion-related reactions occurred in 5.1% (28/547) of patients with RCC and 4.2% (5/119) of patients with CRC who received Opdivo 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, respectively. Infusion-related reactions occurred in 12% (37/300) of patients with malignant pleural mesothelioma who received Opdivo 3 mg/kg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1 receptor blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause) [see Adverse Reactions (6.1)]. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1 receptor blocking antibody prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

Based on its mechanism of action and data from animal studies, Opdivo can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Opdivo and for at least 5 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

Increased Mortality in Patients with Multiple Myeloma when Opdivo Is Added to a Thalidomide Analogue and Dexamethasone

In randomized clinical trials in patients with multiple myeloma, the addition of a PD-1 blocking antibody, including Opdivo, to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Adverse Reactions

The following clinically significant adverse reactions are described elsewhere in the labeling.

Severe and Fatal Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)]
Infusion-Related Reactions [see Warnings and Precautions (5.2)]
Complications of Allogeneic HSCT [see Warnings and Precautions (5.3)]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data in WARNINGS AND PRECAUTIONS reflect exposure to Opdivo as a single agent in 1994 patients enrolled in CHECKMATE-037, CHECKMATE-017, CHECKMATE-057, CHECKMATE-066, CHECKMATE-025, CHECKMATE-067, CHECKMATE-205, CHECKMATE-039 or a single-arm trial in NSCLC (n=117); Opdivo 1 mg/kg with ipilimumab 3 mg/kg in patients enrolled in CHECKMATE-067 (n=313), CHECKMATE-040 (n=49), or another randomized trial (n=94); Opdivo 3 mg/kg administered with ipilimumab 1 mg/kg (n=666) in patients enrolled in CHECKMATE-214 or CHECKMATE-142; Opdivo 3 mg/kg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks in patients enrolled in CHECKMATE-227 (n=576) or CHECKMATE-743 (n=300); Opdivo 360 mg with ipilimumab 1 mg/kg and 2 cycles of platinum-doublet chemotherapy in CHECKMATE-9LA (n=361); and Opdivo 240 mg with cabozantinib 40 mg in patients enrolled in CHECKMATE-9ER (n=320).

Unresectable or Metastatic Melanoma

Previously Treated Metastatic Melanoma

The safety of Opdivo was evaluated in CHECKMATE-037, a randomized, open-label trial in 370 patients with unresectable or metastatic melanoma [see Clinical Studies (14.1)]. Patients had documented disease progression following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. The trial excluded patients with autoimmune disease, prior ipilimumab-related Grade 4 adverse reactions (except for endocrinopathies) or Grade 3 ipilimumab-related adverse reactions that had not resolved or were inadequately controlled within 12 weeks of the initiating event, patients with a condition requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications, a positive test for hepatitis B or C, and a history of HIV. Patients received Opdivo 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=268) or investigator’s choice of chemotherapy (n=102): dacarbazine 1000 mg/m2 intravenously every 3 weeks or carboplatin AUC 6 mg/mL/min and paclitaxel 175 mg/m2 intravenously every 3 weeks. The median duration of exposure was 5.3 months (range: 1 day to 13.8+ months) in Opdivo-treated patients and was 2 months (range: 1 day to 9.6+ months) in chemotherapy-treated patients. In this ongoing trial, 24% of patients received Opdivo for >6 months and 3% of patients received Opdivo for >1 year.

The population characteristics in the Opdivo group and the chemotherapy group were similar: 66% male, median age 59.5 years, 98% White, baseline Eastern Cooperative Oncology Group (ECOG) performance status 0 (59%) or 1 (41%), 74% with M1c stage disease, 73% with cutaneous melanoma, 11% with mucosal melanoma, 73% received two or more prior therapies for advanced or metastatic disease, and 18% had brain metastasis. There were more patients in the Opdivo group with elevated lactate dehydrogenase (LDH) at baseline (51% vs. 38%).

Serious adverse reactions occurred in 41% of patients receiving Opdivo. Opdivo was discontinued for adverse reactions in 9% of patients. Twenty-six percent of patients receiving Opdivo had a dose interruption for an adverse reaction. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving Opdivo. The most frequent Grade 3 and 4 adverse reactions reported in 2% to <5% of patients receiving Opdivo were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. The most common adverse reaction (reported in ≥20% of patients) was rash.

Tables 5 and 6 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-037.

Table 5: Adverse Reactions Occurring in ≥10% of Opdivo-Treated Patients and at a Higher Incidence than in the Chemotherapy Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-037
Toxicity was graded per NCI CTCAE v4.
a Includes maculopapular rash, erythematous rash, pruritic rash, follicular rash, macular rash, papular rash, pustular rash, vesicular rash, and acneiform dermatitis.
b Includes rhinitis, pharyngitis, and nasopharyngitis.

Adverse Reaction

Opdivo
(n=268)

Chemotherapy
(n=102)

All Grades (%)

Grades 3-4 (%)

All Grades (%)

Grades 3-4 (%)

Skin and Subcutaneous Tissue

Rasha

21

0.4

7

0

Pruritus

19

0

3.9

0

Respiratory, Thoracic and Mediastinal

Cough

17

0

6

0

Infections

Upper respiratory tract infectionb

11

0

2.0

0

General

Peripheral edema

10

0

5

0

Clinically important adverse reactions in <10% of patients who received Opdivo were:

Cardiac Disorders: ventricular arrhythmia

Eye Disorders: iridocyclitis

General Disorders and Administration Site Conditions: infusion-related reactions

Investigations: increased amylase, increased lipase

Nervous System Disorders: dizziness, peripheral and sensory neuropathy

Skin and Subcutaneous Tissue Disorders: exfoliative dermatitis, erythema multiforme, vitiligo, psoriasis

Table 6: Laboratory Abnormalities Worsening from Baselinea Occurring in ≥10% of Opdivo-Treated Patients and at a Higher Incidence than in the Chemotherapy Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-037
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Opdivo group (range: 252 to 256 patients) and chemotherapy group (range: 94 to 96 patients).

Laboratory Abnormality

Opdivo

Chemotherapy

All Grades (%)

Grades 3-4 (%)

All Grades (%)

Grades 3-4 (%)

Increased AST

28

2.4

12

1.0

Hyponatremia

25

5

18

1.1

Increased alkaline phosphatase

22

2.4

13

1.1

Increased ALT

16

1.6

5

0

Hyperkalemia

15

2.0

6

0

Previously Untreated Metastatic Melanoma

CHECKMATE-066

The safety of Opdivo was also evaluated in CHECKMATE-066, a randomized, double-blind, active-controlled trial in 411 previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma [see Clinical Studies (14.1)]. The trial excluded patients with autoimmune disease and patients requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications. Patients received Opdivo 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=206) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=205). The median duration of exposure was 6.5 months (range: 1 day to 16.6 months) in Opdivo-treated patients. In this trial, 47% of patients received Opdivo for >6 months and 12% of patients received Opdivo for >1 year.

The trial population characteristics in the Opdivo group and dacarbazine group: 59% male, median age 65 years, 99.5% White, 61% with M1c stage disease, 74% with cutaneous melanoma, 11% with mucosal melanoma, 4% with brain metastasis, and 37% with elevated LDH at baseline. There were more patients in the Opdivo group with ECOG performance status 0 (71% vs. 59%).

Serious adverse reactions occurred in 36% of patients receiving Opdivo. Adverse reactions led to permanent discontinuation of Opdivo in 7% of patients and dose interruption in 26% of patients; no single type of adverse reaction accounted for the majority of Opdivo discontinuations. Grade 3 and 4 adverse reactions occurred in 41% of patients receiving Opdivo.

The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving Opdivo were increased gamma-glutamyltransferase (3.9%) and diarrhea (3.4%). The most common adverse reactions (reported in ≥20% of patients and at a higher incidence than in the dacarbazine arm) were fatigue, musculoskeletal pain, rash, and pruritus.

Tables 7 and 8 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-066.

Table 7: Adverse Reactions Occurring in ≥10% of Opdivo-Treated Patients and at a Higher Incidence than in the Dacarbazine Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-066
Toxicity was graded per NCI CTCAE v4.
a Includes periorbital edema, face edema, generalized edema, gravitational edema, localized edema, peripheral edema, pulmonary edema, and lymphedema.
b Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, pain in jaw, and spinal pain.
c Includes maculopapular rash, erythematous rash, pruritic rash, follicular rash, macular rash, papular rash, pustular rash, vesicular rash, dermatitis, allergic dermatitis, exfoliative dermatitis, acneiform dermatitis, drug eruption, and skin reaction.
d Includes rhinitis, viral rhinitis, pharyngitis, and nasopharyngitis.

Adverse Reaction

Opdivo
(n=206)

Dacarbazine
(n=205)

All Grades (%)

Grades 3-4 (%)

All Grades (%)

Grades 3-4 (%)

General

Fatigue

49

1.9

39

3.4

Edemaa

12

1.5

4.9

0

Musculoskeletal and Connective Tissue

Musculoskeletal painb

32

2.9

25

2.4

Skin and Subcutaneous Tissue

Rashc

28

1.5

12

0

Pruritus

23

0.5

12

0

Vitiligo

11

0

0.5

0

Erythema

10

0

2.9

0

Infections

Upper respiratory tract infectiond

17

0

6

0

Clinically important adverse reactions in <10% of patients who received Opdivo were:

Nervous System Disorders: peripheral neuropathy

Table 8: Laboratory Abnormalities Worsening from Baselinea Occurring in ≥10% of Opdivo-Treated Patients and at a Higher Incidence than in the Dacarbazine Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-066
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Opdivo group (range: 194 to 197 patients) and dacarbazine group (range: 186 to 193 patients).

Laboratory Abnormality

Opdivo

Dacarbazine

All Grades (%)

Grades 3-4 (%)

All Grades (%)

Grades 3-4 (%)

Increased ALT

25

3.0

19

0.5

Increased AST

24

3.6

19

0.5

Increased alkaline phosphatase

21

2.6

14

1.6

Increased bilirubin

13

3.1

6

0

CHECKMATE-067

The safety of Opdivo, administered with ipilimumab or as a single agent, was evaluated in CHECKMATE-067, a randomized (1:1:1), double-blind trial in 937 patients with previously untreated, unresectable or metastatic melanoma [see Clinical Studies (14.1)]. The trial excluded patients with autoimmune disease, a medical condition requiring systemic treatment with corticosteroids (more than 10 mg daily prednisone equivalent) or other immunosuppressive medication within 14 days of the start of study therapy, a positive test result for hepatitis B or C, or a history of HIV.

Patients were randomized to receive:

Opdivo 1 mg/kg over 60 minutes with ipilimumab 3 mg/kg by intravenous infusion every 3 weeks for 4 doses followed by Opdivo as a single agent at a dose of 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (Opdivo and ipilimumab arm; n=313), or
Opdivo 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (Opdivo arm; n=313), or
Ipilimumab 3 mg/kg by intravenous infusion every 3 weeks for up to 4 doses (ipilimumab arm; n=311).

The median duration of exposure to Opdivo was 2.8 months (range: 1 day to 36.4 months) for the Opdivo and ipilimumab arm and 6.6 months (range: 1 day to 36.0 months) for the Opdivo arm. In the Opdivo and ipilimumab arm, 39% were exposed to Opdivo for ≥6 months and 30% exposed for >1 year. In the Opdivo arm, 53% were exposed for ≥6 months and 40% for >1 year.

The population characteristics were: 65% male, median age 61 years, 97% White, baseline ECOG performance status 0 (73%) or 1 (27%), 93% with American Joint Committee on Cancer (AJCC) Stage IV disease, 58% with M1c stage disease; 36% with elevated LDH at baseline, 4% with a history of brain metastasis, and 22% had received adjuvant therapy.

Serious adverse reactions (74% and 44%), adverse reactions leading to permanent discontinuation (47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4 adverse reactions (72% and 51%) all occurred more frequently in the Opdivo and ipilimumab arm relative to the Opdivo arm.

The most frequent (≥10%) serious adverse reactions in the Opdivo and ipilimumab arm and the Opdivo arm, respectively, were diarrhea (13% and 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1.0%). The most frequent adverse reactions leading to discontinuation of both drugs in the Opdivo and ipilimumab arm and of Opdivo in the Opdivo arm, respectively, were colitis (10% and 0.6%), diarrhea (8% and 2.2%), increased ALT (4.8% and 1.0%), increased AST (4.5% and 0.6%), and pneumonitis (1.9% and 0.3%).

The most common (≥20%) adverse reactions in the Opdivo and ipilimumab arm were fatigue, diarrhea, rash, nausea, pyrexia, pruritus, musculoskeletal pain, vomiting, decreased appetite, cough, headache, dyspnea, upper respiratory tract infection, arthralgia, and increased transaminases. The most common (≥20%) adverse reactions in the Opdivo arm were fatigue, rash, musculoskeletal pain, diarrhea, nausea, cough, pruritus, upper respiratory tract infection, decreased appetite, headache, constipation, arthralgia, and vomiting.

Tables 9 and 10 summarize the incidence of adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-067.

Table 9: Adverse Reactions Occurring in ≥10% of Patients on the Opdivo and Ipilimumab Arm or the Opdivo Arm and at a Higher Incidence than in the Ipilimumab Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-067
Toxicity was graded per NCI CTCAE v4.
a Includes asthenia and fatigue.
b Includes pustular rash, dermatitis, acneiform dermatitis, allergic dermatitis, atopic dermatitis, bullous dermatitis, exfoliative dermatitis, psoriasiform dermatitis, drug eruption, exfoliative rash, erythematous rash, generalized rash, macular rash, maculopapular rash, morbilliform rash, papular rash, papulosquamous rash, and pruritic rash.
c Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, and spinal pain.
d Includes upper respiratory tract infection, nasopharyngitis, pharyngitis, and rhinitis.
e Includes hypertension and blood pressure increased.

Adverse Reaction

Opdivo and Ipilimumab
(n=313)

Opdivo
(n=313)

Ipilimumab
(n=311)

All Grades (%)

Grades 3-4 (%)

All Grades (%)

Grades 3-4 (%)

All Grades (%)

Grades 3-4 (%)

General

Fatiguea

62

7

59

1.6

51

4.2

Pyrexia

40

1.6

16

0

18

0.6

Gastrointestinal

Diarrhea

54

11

36

5

47

7

Nausea

44

3.8

30

0.6

31

1.9

Vomiting

31

3.8

20

1.0

17

1.6

Skin and Subcutaneous Tissue

Rashb

53

6

40

1.9

42

3.5

Vitiligo

9

0

10

0.3

5

0

Musculoskeletal and Connective Tissue

Musculoskeletal painc

32

2.6

42

3.8

36

1.9

Arthralgia

21

0.3

21

1.0

16

0.3

Metabolism and Nutrition

Decreased appetite

29

1.9

22

0

24

1.3

Respiratory, Thoracic and Mediastinal

Cough/productive cough

27

0.3

28

0.6

22

0

Dyspnea/exertional dyspnea

24

2.9

18

1.3

17

0.6

Infections

Upper respiratory tract infectiond

23

0

22

0.3

17

0

Endocrine

Hypothyroidism

19

0.6

11

0

5

0

Hyperthyroidism

11

1.3

6

0

1

0

Investigations

Decreased weight

12

0

7

0

7

0.3

Vascular

Hypertensione

7

2.2

11

5

9

2.3

Clinically important adverse reactions in <10% of patients who received Opdivo with ipilimumab or Opdivo as a single agent were:

Gastrointestinal Disorders: stomatitis, intestinal perforation

Skin and Subcutaneous Tissue Disorders: vitiligo

Musculoskeletal and Connective Tissue Disorders: myopathy, Sjogren’s syndrome, spondyloarthropathy, myositis (including polymyositis)

Nervous System Disorders: neuritis, peroneal nerve palsy

Table 10: Laboratory Abnormalities Worsening from Baselinea Occurring in ≥20% of Patients Treated with Opdivo with Ipilimumab or Single-Agent Opdivo and at a Higher Incidence than in the Ipilimumab Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-067
Laboratory Abnormality Opdivo and Ipilimumab Opdivo Ipilimumab
All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%)
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Opdivo and ipilimumab (range: 75 to 297); Opdivo (range: 81 to 306); ipilimumab (range: 61 to 301).

Chemistry

Increased ALT

55

16

25

3.0

29

2.7

Hyperglycemia

53

5.3

46

7

26

0

Increased AST

52

13

29

3.7

29

1.7

Hyponatremia

45

10

22

3.3

26

7

Increased lipase

43

22

32

12

24

7

Increased alkaline phosphatase

41

6

27

2.0

23

2.0

Hypocalcemia

31

1.1

15

0.7

20

0.7

Increased amylase

27

10

19

2.7

15

1.6

Increased creatinine

26

2.7

19

0.7

17

1.3

Hematology

Anemia

52

2.7

41

2.6

41

6

Lymphopenia

39

5

41

4.9

29

4.0

Adjuvant Treatment of Melanoma

The safety of Opdivo as a single agent was evaluated in CHECKMATE-238, a randomized (1:1), double-blind trial in 905 patients with completely resected Stage IIIB/C or Stage IV melanoma received Opdivo 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=452) or ipilimumab 10 mg/kg by intravenous infusion every 3 weeks for 4 doses then every 12 weeks beginning at Week 24 for up to 1 year (n=453) [see Clinical Studies (14.2)]. The median duration of exposure was 11.5 months in Opdivo-treated patients and was 2.7 months in ipilimumab-treated patients. In this ongoing trial, 74% of patients received Opdivo for >6 months.

Serious adverse reactions occurred in 18% of Opdivo-treated patients. Study therapy was discontinued for adverse reactions in 9% of Opdivo-treated patients and 42% of ipilimumab-treated patients. Twenty-eight percent of Opdivo-treated patients had at least one omitted dose for an adverse reaction. Grade 3 or 4 adverse reactions occurred in 25% of Opdivo-treated patients.

The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of Opdivo-treated patients were diarrhea and increased lipase and amylase. The most common adverse reactions (at least 20%) were fatigue, diarrhea, rash, musculoskeletal pain, pruritus, headache, nausea, upper respiratory infection, and abdominal pain. The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%).

Tables 11 and 12 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-238.

Table 11: Adverse Reactions Occurring in ≥10% of Opdivo-Treated Patients - CHECKMATE-238
Adverse Reaction Opdivo
(n=452)
Ipilimumab 10 mg/kg
(n=453)
All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%)
Toxicity was graded per NCI CTCAE v4.
a Includes asthenia.
b Includes abdominal discomfort, lower abdominal pain, upper abdominal pain, and abdominal tenderness.
c Includes dermatitis described as acneiform, allergic, bullous, or exfoliative and rash described as generalized, erythematous, macular, papular, maculopapular, pruritic, pustular, vesicular, or butterfly, and drug eruption.
d Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, spinal pain, and pain in extremity.
e Includes postural dizziness and vertigo.
f Includes upper respiratory tract infection including viral respiratory tract infection, lower respiratory tract infection, rhinitis, pharyngitis, and nasopharyngitis.
g Includes secondary hypothyroidism and autoimmune hypothyroidism.

General

Fatiguea

57

0.9

55

2.4

Gastrointestinal

Diarrhea

37

2.4

55

11

Nausea

23

0.2

28

0

Abdominal painb

21

0.2

23

0.9

Constipation

10

0

9

0

Skin and Subcutaneous Tissue

Rashc

35

1.1

47

5.3

Pruritus

28

0

37

1.1

Musculoskeletal and Connective Tissue

Musculoskeletal paind

32

0.4

27

0.4

Arthralgia

19

0.4

13

0.4

Nervous System

Headache

23

0.4

31

2.0

Dizzinesse

11

0

8

0

Infections

Upper respiratory tract infectionf

22

0

15

0.2

Respiratory, Thoracic and Mediastinal

Cough/productive cough

19

0

19

0

Dyspnea/exertional dyspnea

10

0.4

10

0.2

Endocrine

Hypothyroidismg

12

0.2

7.5

0.4

Table 12: Laboratory Abnormalities Worsening from Baselinea Occurring in ≥10% of Opdivo-Treated Patients - CHECKMATE-238
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Opdivo group (range: 400 to 447 patients) and ipilimumab 10 mg/kg group (range: 392 to 443 patients).

Laboratory Abnormality

Opdivo

Ipilimumab 10 mg/kg

All Grades (%)

Grades 3-4 (%)

All Grades (%)

Grades 3-4 (%)

Hematology

Lymphopenia

27

0.4

12

0.9

Anemia

26

0

34

0.5

Leukopenia

14

0

2.7

0.2

Neutropenia

13

0

6

0.5

Chemistry

Increased Lipase

25

7

23

9

Increased ALT

25

1.8

40

12

Increased AST

24

1.3

33

9

Increased Amylase

17

3.3

13

3.1

Hyponatremia

16

1.1

22

3.2

Hyperkalemia

12

0.2

9

0.5

Increased Creatinine

12

0

13

0

Hypocalcemia

10

0.7

16

0.5

Metastatic Non-Small Cell Lung Cancer

First-line Treatment of Metastatic NSCLC: In Combination with Ipilimumab

The safety of Opdivo in combination with ipilimumab was evaluated in CHECKMATE-227, a randomized, multicenter, multi-cohort, open-label trial in patients with previously untreated metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations [see Clinical Studies (14.3)]. The trial excluded patients with untreated brain metastases, carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression. Patients received Opdivo 3 mg/kg by intravenous infusion over 30 minutes every 2 weeks and ipilimumab 1 mg/kg by intravenous infusion over 30 minutes every 6 weeks or platinum-doublet chemotherapy every 3 weeks for 4 cycles. The median duration of therapy in Opdivo and ipilimumab-treated patients was 4.2 months (range: 1 day to 25.5 months): 39% of patients received Opdivo and ipilimumab for >6 months and 23% of patients received Opdivo and ipilimumab for >1 year. The population characteristics were: median age 64 years (range: 26 to 87); 48% were ≥65 years of age, 76% White, and 67% male. Baseline ECOG performance status was 0 (35%) or 1 (65%), 85% were former/current smokers, 11% had brain metastases, 28% had squamous histology and 72% had non-squamous histology.

Serious adverse reactions occurred in 58% of patients. Opdivo and ipilimumab were discontinued for adverse reactions in 24% of patients and 53% had at least one dose withheld for an adverse reaction.

The most frequent (≥2%) serious adverse reactions were pneumonia, diarrhea/colitis, pneumonitis, hepatitis, pulmonary embolism, adrenal insufficiency, and hypophysitis. Fatal adverse reactions occurred in 1.7% of patients; these included events of pneumonitis (4 patients), myocarditis, acute kidney injury, shock, hyperglycemia, multi-system organ failure, and renal failure. The most common (≥20%) adverse reactions were fatigue, rash, decreased appetite, musculoskeletal pain, diarrhea/colitis, dyspnea, cough, hepatitis, nausea, and pruritus.

Tables 13 and 14 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-227.

Table 13: Adverse Reactions in ≥10% of Patients Receiving Opdivo and Ipilimumab - CHECKMATE-227
a Includes fatigue and asthenia.
b Includes eyelid edema, face edema, generalized edema, localized edema, edema, edema peripheral, and periorbital edema.
c Includes autoimmune dermatitis, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis atopic, dermatitis bullous, dermatitis contact, dermatitis exfoliative, dermatitis psoriasiform, granulomatous dermatitis, rash generalized, drug eruption, dyshidrotic eczema, eczema, exfoliative rash, nodular rash, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, toxic skin eruption.
d Includes pruritus and pruritus generalized.
e Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, and pain in extremity.
f Includes colitis, colitis microscopic, colitis ulcerative, diarrhea, enteritis infectious, enterocolitis, enterocolitis infectious, and enterocolitis viral.
g Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness.
h Includes dyspnea and dyspnea exertional.
i Includes cough and productive cough.
j Includes alanine aminotransferase increased, aspartate aminotransferase increased, autoimmune hepatitis, blood bilirubin increased, hepatic enzyme increased, hepatic failure, hepatic function abnormal, hepatitis, hepatitis E, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, immune-mediated hepatitis, liver function test abnormal, liver function test increased, transaminases increased.
k Includes autoimmune thyroiditis, blood thyroid stimulating hormone increased, hypothyroidism, primary hypothyroidism, thyroiditis, and tri-iodothyronine free decreased.
l Contains blood thyroid stimulating hormone decreased, hyperthyroidism, and tri-iodothyronine free increased.
m Includes lower respiratory tract infection, lower respiratory tract infection bacterial, lung infection, pneumonia, pneumonia adenoviral, pneumonia aspiration, pneumonia bacterial, pneumonia klebsiella, pneumonia influenzal, pneumonia viral, atypical pneumonia, organizing pneumonia.

Adverse Reaction

Opdivo and Ipilimumab
(n=576)

Platinum-doublet Chemotherapy
(n=570)

All Grades
(%)

Grades 3-4
(%)

All Grades
(%)

Grades 3-4
(%)

General

Fatiguea

44

6

42

4.4

Pyrexia

18

0.5

11

0.4

Edemab

14

0.2

12

0.5

Skin and Subcutaneous Tissue

Rashc

34

4.7

10

0.4

Pruritusd

21

0.5

3.3

0

Metabolism and Nutrition

Decreased appetite

31

2.3

26

1.4

Musculoskeletal and Connective Tissue

Musculoskeletal paine

27

1.9

16

0.7

Arthralgia

13

0.9

2.5

0.2

Gastrointestinal

Diarrhea/colitisf

26

3.6

16

0.9

Nausea

21

1.0

42

2.5

Constipation

18

0.3

27

0.5

Vomiting

13

1.0

18

2.3

Abdominal paing

10

0.2

9

0.7

Respiratory, Thoracic, and Mediastinal

Dyspneah

26

4.3

16

2.1

Coughi

23

0.2

13

0

Hepatobiliary

Hepatitisj

21

9

10

1.2

Endocrine

Hypothyroidismk

16

0.5

1.2

0

Hyperthyroidisml

10

0

0.5

0

Infections and Infestations

Pneumoniam

13

7

8

4.0

Nervous System

Headache

11

0.5

6

0

Other clinically important adverse reactions in CHECKMATE-227 were:

Skin and Subcutaneous Tissue: urticaria, alopecia, erythema multiforme, vitiligo

Gastrointestinal: stomatitis, pancreatitis, gastritis

Musculoskeletal and Connective Tissue: arthritis, polymyalgia rheumatica, rhabdomyolysis

Nervous System: peripheral neuropathy, autoimmune encephalitis

Blood and Lymphatic System: eosinophilia

Eye Disorders: blurred vision, uveitis

Cardiac: atrial fibrillation, myocarditis

Table 14: Laboratory Values Worsening from Baselinea Occurring in ≥20% of Patients on Opdivo and Ipilimumab - CHECKMATE-227
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Opdivo and ipilimumab group (range: 494 to 556 patients) and chemotherapy group (range: 469 to 542 patients).

Laboratory Abnormality

Opdivo and Ipilimumab

Platinum-doublet Chemotherapy

Grades 1-4
(%)

Grades 3-4
(%)

Grades 1-4
(%)

Grades 3-4
(%)

Hematology

Anemia

46

3.6

78

14

Lymphopenia

46

5

60

15

Chemistry

Hyponatremia

41

12

26

4.9

Increased AST

39

5

26

0.4

Increased ALT

36

7

27

0.7

Increased lipase

35

14

14

3.4

Increased alkaline phosphatase

34

3.8

20

0.2

Increased amylase

28

9

18

1.9

Hypocalcemia

28

1.7

17

1.3

Hyperkalemia

27

3.4

22

0.4

Increased creatinine

22

0.9

17

0.2

First-line Treatment of Metastatic or Recurrent NSCLC: In Combination with Ipilimumab and Platinum-Doublet Chemotherapy

The safety of Opdivo in combination with ipilimumab and platinum-doublet chemotherapy was evaluated in CHECKMATE-9LA [see Clinical Studies (14.3)]. Patients received either Opdivo 360 mg administered every 3 weeks in combination with ipilimumab 1 mg/kg administered every 6 weeks and platinum-doublet chemotherapy administered every 3 weeks for 2 cycles; or platinum-doublet chemotherapy administered every 3 weeks for 4 cycles. The median duration of therapy in Opdivo in combination with ipilimumab and platinum-doublet chemotherapy was 6 months (range: 1 day to 19 months): 50% of patients received Opdivo and ipilimumab for >6 months and 13% of patients received Opdivo and ipilimumab for >1 year.

Serious adverse reactions occurred in 57% of patients who were treated with Opdivo in combination with ipilimumab and platinum-doublet chemotherapy. The most frequent (>2%) serious adverse reactions were pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis, and respiratory failure. Fatal adverse reactions occurred in 7 (2%) patients, and included hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia.

Study therapy with Opdivo in combination with ipilimumab and platinum-doublet chemotherapy was permanently discontinued for adverse reactions in 24% of patients and 56% had at least one treatment withheld for an adverse reaction. The most common (>20%) adverse reactions were fatigue, musculoskeletal pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritus.

Tables 15 and 16 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9LA.

Table 15: Adverse Reactions in >10% of Patients Receiving Opdivo and Ipilimumab and Platinum-Doublet Chemotherapy - CHECKMATE-9LA
Adverse Reaction Opdivo and Ipilimumab and Platinum-Doublet Chemotherapy
(n=358)
Platinum-Doublet Chemotherapy
(n=349)
All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%)
Toxicity was graded per NCI CTCAE v4.
a Includes fatigue and asthenia
b Includes myalgia, back pain, pain in extremity, musculoskeletal pain, bone pain, flank pain, muscle spasms, musculoskeletal chest pain, musculoskeletal disorder, osteitis, musculoskeletal stiffness, non-cardiac chest pain, arthralgia, arthritis, arthropathy, joint effusion, psoriatic arthropathy, synovitis
c Includes colitis, ulcerative colitis, diarrhea, and enterocolitis
d Includes abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, and gastrointestinal pain
e Includes acne, dermatitis, acneiform dermatitis, allergic dermatitis, atopic dermatitis, bullous dermatitis, generalized exfoliative dermatitis, eczema, keratoderma blenorrhagica, palmar-plantar erythrodysaesthesia syndrome, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, morbilliform rash, papular rash, pruritic rash, skin exfoliation, skin reaction, skin toxicity, Stevens-Johnson syndrome, urticaria
f Includes pruritus and generalized pruritus
g Includes cough, productive cough, and upper-airway cough syndrome
h Includes dyspnea, dyspnea at rest, and exertional dyspnea
i Includes autoimmune thyroiditis, increased blood thyroid stimulating hormone, hypothyroidism, thyroiditis, and decreased free tri-iodothyronine
j Includes dizziness, vertigo and positional vertigo

General

Fatiguea

49

5

40

4.9

Pyrexia

14

0.6

10

0.6

Musculoskeletal and Connective Tissue

Musculoskeletal painb

39

4.5

27

2.0

Gastrointestinal

Nausea

32

1.7

41

0.9

Diarrheac

31

6

18

1.7

Constipation

21

0.6

23

0.6

Vomiting

18

2.0

17

1.4

Abdominal paind

12

0.6

11

0.9

Skin and Subcutaneous Tissue

Rashe

30

4.7

10

0.3

Pruritusf

21

0.8

2.9

0

Alopecia

11

0.8

10

0.6

Metabolism and Nutrition

Decreased appetite

28

2.0

22

1.7

Respiratory, Thoracic and Mediastinal

Coughg

19

0.6

15

0.9

Dyspneah

18

4.7

14

3.2

Endocrine

Hypothyroidismi

19

0.3

3.4

0

Nervous System

Headache

11

0.6

7

0

Dizzinessj

11

0.6

6

0

Table 16: Laboratory Values Worsening from Baselinea Occurring in >20% of Patients on Opdivo and Ipilimumab and Platinum-Doublet Chemotherapy - CHECKMATE-9LA
Laboratory Abnormality Opdivo and Ipilimumab and Platinum-Doublet Chemotherapy Platinum-Doublet Chemotherapy
Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%)
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Opdivo and ipilimumab and platinum-doublet chemotherapy group (range: 197 to 347 patients) and platinum-doublet chemotherapy group (range: 191 to 335 patients).

Hematology

Anemia

70

9

74

16

Lymphopenia

41

6

40

11

Neutropenia

40

15

42

15

Leukopenia

36

10

40

9

Thrombocytopenia

23

4.3

24

5

Chemistry

Hyperglycemia

45

7

42

2.6

Hyponatremia

37

10

27

7

Increased ALT

34

4.3

24

1.2

Increased lipase

31

12

10

2.2

Increased alkaline phosphatase

31

1.2

26

0.3

Increased amylase

30

7

19

1.3

Increased AST

30

3.5

22

0.3

Hypomagnesemia

29

1.2

33

0.6

Hypocalcemia

26

1.4

22

1.8

Increased creatinine

26

1.2

23

0.6

Hyperkalemia

22

1.7

21

2.1

Second-line Treatment of Metastatic NSCLC

The safety of Opdivo was evaluated in CHECKMATE-017, a randomized open-label, multicenter trial in patients with metastatic squamous NSCLC and progression on or after one prior platinum doublet-based chemotherapy regimen and in CHECKMATE-057, a randomized, open-label, multicenter trial in patients with metastatic non-squamous NSCLC and progression on or after one prior platinum doublet-based chemotherapy regimen [see Clinical Studies (14.3)]. These trials excluded patients with active autoimmune disease, medical conditions requiring systemic immunosuppression, or with symptomatic interstitial lung disease. Patients received Opdivo 3 mg/kg over 60 minutes by intravenous infusion every 2 weeks or docetaxel 75 mg/m2 intravenously every 3 weeks. The median duration of therapy in Opdivo-treated patients in CHECKMATE-017 was 3.3 months (range: 1 day to 21.7+ months) and in CHECKMATE-057 was 2.6 months (range: 0 to 24.0+ months). In CHECKMATE-017, 36% of patients received Opdivo for at least 6 months and 18% of patients received Opdivo for at least 1 year and in CHECKMATE-057, 30% of patients received Opdivo for >6 months and 20% of patients received Opdivo for >1 year.

Across both trials, the median age of Opdivo-treated patients was 61 years (range: 37 to 85); 38% were ≥65 years of age, 61% were male, and 91% were White. Ten percent of patients had brain metastases and ECOG performance status was 0 (26%) or 1 (74%).

In CHECKMATE-057, in the Opdivo arm, seven deaths were due to infection including one case of Pneumocystis jirovecii pneumonia, four were due to pulmonary embolism, and one death was due to limbic encephalitis. Serious adverse reactions occurred in 46% of patients receiving Opdivo. Opdivo was discontinued in 11% of patients and was delayed in 28% of patients for an adverse reaction.

The most frequent serious adverse reactions reported in ≥2% of patients receiving Opdivo were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. Across both trials, the most common adverse reactions (≥20%) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite.

Tables 17 and 18 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-057.

Table 17: Adverse Reactions Occurring in ≥10% of Opdivo-Treated Patients and at a Higher Incidence than Docetaxel (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-017 and CHECKMATE-057
Adverse Reaction Opdivo
(n=418)
Docetaxel
(n=397)
All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%)
Toxicity was graded per NCI CTCAE v4.

Respiratory, Thoracic and Mediastinal

Cough

31

0.7

24

0

Metabolism and Nutrition

Decreased appetite

28

1.4

23

1.5

Skin and Subcutaneous Tissue

Pruritus

10

0.2

2.0

0

Other clinically important adverse reactions observed in Opdivo-treated patients and which occurred at a similar incidence in docetaxel-treated patients and not listed elsewhere in section 6 include: fatigue/asthenia (48% all Grades, 5% Grade 3-4), musculoskeletal pain (33% all Grades), pleural effusion (4.5% all Grades), pulmonary embolism (3.3% all Grades).

Table 18: Laboratory Abnormalities Worsening from Baselinea Occurring in ≥10% of Opdivo-Treated Patients for all NCI CTCAE Grades and at a Higher Incidence than Docetaxel (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-017 and CHECKMATE-057
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Opdivo group (range: 405 to 417 patients) and docetaxel group (range: 372 to 390 patients), except for TSH: Opdivo group n=314 and docetaxel group n=297.
b Not graded per NCI CTCAE v4.

Laboratory Abnormality

Opdivo

Docetaxel

All Grades (%)

Grades 3-4 (%)

All Grades (%)

Grades 3-4 (%)

Chemistry

Hyponatremia

35

7

34

4.9

Increased AST

27

1.9

13

0.8

Increased alkaline phosphatase

26

0.7

18

0.8

Increased ALT

22

1.7

17

0.5

Increased creatinine

18

0

12

0.5

Increased TSHb

14

N/A

6

N/A

Malignant Pleural Mesothelioma

The safety of Opdivo in combination with ipilimumab was evaluated in CHECKMATE-743, a randomized, open-label trial in patients with previously untreated unresectable malignant pleural mesothelioma [see Clinical Studies (14.4)]. Patients received either Opdivo 3 mg/kg over 30 minutes by intravenous infusion every 2 weeks and ipilimumab 1 mg/kg over 30 minutes by intravenous infusion every 6 weeks for up to 2 years; or platinum-doublet chemotherapy for up to 6 cycles. The median duration of therapy in Opdivo and ipilimumab-treated patients was 5.6 months (range: 0 to 26.2 months); 48% of patients received Opdivo and ipilimumab for >6 months and 24% of patients received Opdivo and ipilimumab for >1 year.

Serious adverse reactions occurred in 54% of patients who were treated with Opdivo in combination with ipilimumab. The most frequent (≥2%) serious adverse reactions were pneumonia, pyrexia, diarrhea, pneumonitis, pleural effusion, dyspnea, acute kidney injury, infusion-related reaction, musculoskeletal pain, and pulmonary embolism. Fatal adverse reactions occurred in 4 (1.3%) patients and included pneumonitis, acute heart failure, sepsis and encephalitis.

Both Opdivo and ipilimumab were permanently discontinued due to adverse reactions in 23% of patients and 52% had at least one dose withheld due to an adverse reaction.

The most common (≥20%) adverse reactions were fatigue, musculoskeletal pain, rash, diarrhea, dyspnea, nausea, decreased appetite, cough, and pruritus.

Tables 19 and 20 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-743.

Table 19: Adverse Reactions in ≥10% of Patients Receiving Opdivo and Ipilimumab - CHECKMATE-743
a Includes fatigue and asthenia.
b Includes pyrexia and tumor-associated fever.
c Includes edema, generalized edema, peripheral edema, and peripheral swelling.
d Includes musculoskeletal pain, back pain, bone pain, flank pain, involuntary muscle contractions, muscle spasms, muscle twitching, musculoskeletal chest pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity, polymyalgia rheumatica, and spinal pain.
e Includes rash, acne, acneiform dermatitis, allergic dermatitis, atopic dermatitis, autoimmune dermatitis, bullous dermatitis, contact dermatitis, dermatitis, drug eruption, dyshidrotic eczema, eczema, erythematous rash, exfoliative rash, generalized exfoliative dermatitis, generalized rash, granulomatous dermatitis, keratoderma blenorrhagica, macular rash, maculopapular rash, morbilliform rash, nodular rash, papular rash, psoriasiform dermatitis, pruritic rash, pustular rash, skin exfoliation, skin reaction, skin toxicity, Stevens-Johnson syndrome, toxic skin eruption, and urticaria.
f Includes pruritus, allergic pruritus, and generalized pruritus.
g Includes diarrhea, colitis, enteritis, infectious enteritis, enterocolitis, infectious enterocolitis, microscopic colitis, ulcerative colitis, and viral enterocolitis.
h Includes abdominal pain, abdominal discomfort, abdominal tenderness, gastrointestinal pain, lower abdominal pain, and upper abdominal pain.
i Includes dyspnea, dyspnea at rest, and exertional dyspnea.
j Includes cough, productive cough, and upper-airway cough syndrome.
k Includes hypothyroidism, autoimmune thyroiditis, decreased free tri-iodothyronine, increased blood thyroid stimulating hormone, primary hypothyroidism, thyroiditis, and autoimmune hypothyroidism.
l Includes upper respiratory tract infection, nasopharyngitis, pharyngitis, and rhinitis.
m Includes pneumonia, lower respiratory tract infection, lung infection, aspiration pneumonia, and Pneumocystis jirovecii pneumonia.

Adverse Reaction

Opdivo and Ipilimumab
(n=300)

Chemotherapy
(n=284)

All Grades
(%)

Grades 3-4
(%)

All Grades
(%)

Grades 3-4
(%)

General

Fatiguea

43

4.3

45

6

Pyrexiab

18

1.3

4.6

0.7

Edemac

17

0

8

0

Musculoskeletal and Connective Tissue

Musculoskeletal paind

38

3.3

17

1.1

Arthralgia

13

1.0

1.1

0

Skin and Subcutaneous Tissue

Rashe

34

2.7

11

0.4

Pruritusf

21

1.0

1.4

0

Gastrointestinal

Diarrheag

32

6

12

1.1

Nausea

24

0.7

43

2.5

Constipation

19

0.3

30

0.7

Abdominal painh

15

1

10

0.7

Vomiting

14

0

18

2.1

Respiratory, Thoracic, and Mediastinal

Dyspneai

27

2.3

16

3.2

Coughj

23

0.7

9

0

Metabolism and Nutrition

Decreased appetite

24

1.0

25

1.4

Endocrine

Hypothyroidismk

15

0

1.4

0

Infections and Infestations

Upper respiratory tract infectionl

12

0.3

7

0

Pneumoniam

10

4.0

4.2

2.1

Table 20: Laboratory Values Worsening from Baselinea Occurring in ≥20% of Patients on Opdivo and Ipilimumab - CHECKMATE-743
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Opdivo and ipilimumab group (range: 109 to 297 patients) and chemotherapy group (range: 90 to 276 patients).

Laboratory Abnormality

Opdivo and Ipilimumab

Chemotherapy

Grades 1-4
(%)

Grades 3-4
(%)

Grades 1-4
(%)

Grades 3-4
(%)

Chemistry

Hyperglycemia

53

3.7

34

1.1

Increased AST

38

7

17

0

Increased ALT

37

7

15

0.4

Increased lipase

34

13

9

0.8

Hyponatremia

32

8

21

2.9

Increased alkaline phosphatase

31

3.1

12

0

Hyperkalemia

30

4.1

16

0.7

Hypocalcemia

28

0

16

0

Increased amylase

26

5

13

0.9

Increased creatinine

20

0.3

20

0.4

Hematology

Lymphopenia

43

8

57

14

Anemia

43

2.4

75

15

Advanced Renal Cell Carcinoma

First-line Renal Cell Carcinoma

CHECKMATE-214

The safety of Opdivo with ipilimumab was evaluated in CHECKMATE-214, a randomized open-label trial in 1082 patients with previously untreated advanced RCC received Opdivo 3 mg/kg over 60 minutes with ipilimumab 1 mg/kg intravenously every 3 weeks for 4 doses followed by Opdivo as a single agent at a dose of 3 mg/kg by intravenous infusion every 2 weeks (n=547) or sunitinib 50 mg orally daily for the first 4 weeks of a 6-week cycle (n=535) [see Clinical Studies (14.5)]. The median duration of treatment was 7.9 months (range: 1 day to 21.4+ months) in Opdivo and ipilimumab-treated patients and 7.8 months (range: 1 day to 20.2+ months) in sunitinib-treated patients. In this trial, 57% of patients in the Opdivo and ipilimumab arm were exposed to treatment for >6 months and 38% of patients were exposed to treatment for >1 year.

Serious adverse reactions occurred in 59% of patients receiving Opdivo and ipilimumab. Study therapy was discontinued for adverse reactions in 31% of Opdivo and ipilimumab patients. Fifty-four percent (54%) of patients receiving Opdivo and ipilimumab had a dose interruption for an adverse reaction.

The most frequent serious adverse reactions reported in ≥2% of patients treated with Opdivo and ipilimumab were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis; in patients treated with sunitinib, they were pneumonia, pleural effusion, and dyspnea. The most common adverse reactions (reported in ≥20% of patients) were fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, and decreased appetite. The most common laboratory abnormalities which have worsened compared to baseline in ≥30% of Opdivo and ipilimumab-treated patients include increased lipase, anemia, increased creatinine, increased ALT, increased AST, hyponatremia, increased amylase, and lymphopenia.

Tables 21 and 22 summarize adverse reactions and laboratory abnormalities, respectively, that occurred in >15% of Opdivo and ipilimumab-treated patients in CHECKMATE-214.

Table 21: Adverse Reactions in >15% of Patients Receiving Opdivo and Ipilimumab - CHECKMATE-214
Toxicity was graded per NCI CTCAE v4.
a Includes asthenia.
b Includes peripheral edema, peripheral swelling.
c Includes dermatitis described as acneiform, bullous, and exfoliative, drug eruption, rash described as exfoliative, erythematous, follicular, generalized, macular, maculopapular, papular, pruritic, and pustular, fixed-drug eruption.
d Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain.

Adverse Reaction

Opdivo and Ipilimumab
(n=547)

Sunitinib
(n=535)

Grades 1-4 (%)

Grades 3-4 (%)

Grades 1-4 (%)

Grades 3-4 (%)

Adverse Reaction

99

65

99

76

General

Fatiguea

58

8

69

13

Pyrexia

25

0.7

17

0.6

Edemab

16

0.5

17

0.6

Skin and Subcutaneous Tissue

Rashc

39

3.7

25

1.1

Pruritus/generalized pruritus

33

0.5

11

0

Gastrointestinal

Diarrhea

38

4.6

58

6

Nausea

30

2.0

43

1.5

Vomiting

20

0.9

28

2.1

Abdominal pain

19

1.6

24

1.9

Constipation

17

0.4

18

0

Musculoskeletal and Connective Tissue

Musculoskeletal paind

37

4.0

40

2.6

Arthralgia

23

1.3

16

0

Respiratory, Thoracic and Mediastinal

Cough/productive cough

28

0.2

25

0.4

Dyspnea/exertional dyspnea

20

2.4

21

2.1

Metabolism and Nutrition

Decreased appetite

21

1.8

29

0.9

Nervous System

Headache

19

0.9

23

0.9

Endocrine

Hypothyroidism

18

0.4

27

0.2

Table 22: Laboratory Values Worsening from Baselinea Occurring in >15% of Patients on Opdivo and Ipilimumab - CHECKMATE-214
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Opdivo and ipilimumab group (range: 490 to 538 patients) and sunitinib group (range: 485 to 523 patients).

Laboratory Abnormality

Opdivo and Ipilimumab

Sunitinib

Grades 1-4 (%)

Grades 3-4 (%)

Grades 1-4 (%)

Grades 3-4 (%)

Chemistry

Increased lipase

48

20

51

20

Increased creatinine

42

2.1

46

1.7

Increased ALT

41

7

44

2.7

Increased AST

40

4.8

60

2.1

Increased amylase

39

12

33

7

Hyponatremia

39

10

36

7

Increased alkaline phosphatase

29

2.0

32

1.0

Hyperkalemia

29

2.4

28

2.9

Hypocalcemia

21

0.4

35

0.6

Hypomagnesemia

16

0.4

26

1.6

Hematology

Anemia

43

3.0

64

9

Lymphopenia

36

5

63

14

In addition, among patients with TSH ≤ULN at baseline, a lower proportion of patients experienced a treatment-emergent elevation of TSH >ULN in the Opdivo and ipilimumab group compared to the sunitinib group (31% and 61%, respectively).

CHECKMATE-9ER

The safety of Opdivo with cabozantinib was evaluated in CHECKMATE-9ER, a randomized, open-label study in patients with previously untreated advanced RCC. Patients received Opdivo 240 mg over 30 minutes every 2 weeks with cabozantinib 40 mg orally once daily (n=320) or sunitinib 50 mg daily, administered orally for 4 weeks on treatment followed by 2 weeks off (n=320) [see Clinical Studies (14.5)]. Cabozantinib could be interrupted or reduced to 20 mg daily or 20 mg every other day. The median duration of treatment was 14 months (range: 0.2 to 27 months) in Opdivo and cabozantinib-treated patients. In this trial, 82% of patients in the Opdivo and cabozantinib arm were exposed to treatment for >6 months and 60% of patients were exposed to treatment for >1 year.

Serious adverse reactions occurred in 48% of patients receiving Opdivo and cabozantinib. The most frequent (≥2%) serious adverse reactions were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Fatal intestinal perforations occurred in 3 (0.9%) patients.

Adverse reactions leading to discontinuation of either Opdivo or cabozantinib occurred in 20% of patients: 7% Opdivo only, 8% cabozantinib only, and 6% both drugs due to same adverse reaction at the same time. Adverse reaction leading to dose interruption or reduction of either Opdivo or cabozantinib occurred in 83% of patients: 3% Opdivo only, 46% cabozantinib only, and 21% both drugs due to same adverse reaction at the same time, and 6% both drugs sequentially.

The most common adverse reactions reported in ≥20% of patients treated with Opdivo and cabozantinib were diarrhea, fatigue, hepatotoxicity, palmar-plantar erythrodysaesthesia syndrome, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.

Tables 23 and 24 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9ER.

Table 23: Adverse Reactions in >15% of Patients Receiving Opdivo and Cabozantinib - CHECKMATE-9ER
Toxicity was graded per NCI CTCAE v4.
a Includes abdominal discomfort, abdominal pain lower, abdominal pain upper.
b Includes gastroesophageal reflux disease.
c Includes asthenia.
d Includes hepatotoxicity, ALT increased, AST increased, blood alkaline phosphatase increased, gamma-glutamyl transferase increased, autoimmune hepatitis, blood bilirubin increased, drug induced liver injury, hepatic enzyme increased, hepatitis, hyperbilirubinemia, liver function test increased, liver function test abnormal, transaminases increased, hepatic failure.
e Includes mucosal inflammation, aphthous ulcer, mouth ulceration.
f Includes dermatitis, dermatitis acneiform, dermatitis bullous, exfoliative rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic.
g Includes blood pressure increased, blood pressure systolic increased.
h Includes primary hypothyroidism.
i Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain.
j Includes productive cough.
k Includes nasopharyngitis, pharyngitis, rhinitis.

Adverse Reaction

Opdivo and Cabozantinib
(n=320)

Sunitinib
(n=320)

Grades 1-4 (%)

Grades 3-4 (%)

Grades 1-4 (%)

Grades 3-4 (%)

Gastrointestinal

Diarrhea

64

7

47

4.4

Nausea

27

0.6

31

0.3

Abdominal paina

22

1.9

15

0.3

Vomiting

17

1.9

21

0.3

Dyspepsiab

15

0

22

0.3

General

Fatiguec

51

8

50

8

Hepatobiliary

Hepatotoxicityd

44

11

26

5

Skin and Subcutaneous Tissue

Palmar-plantar erythrodysaesthesia syndrome

40

8

41

8

Stomatitise

37

3.4

46

4.4

Rashf

36

3.1

14

0

Pruritus

19

0.3

4.4

0

Vascular

Hypertensiong

36

13

39

14

Endocrine

Hypothyroidismh

34

0.3

30

0.3

Musculoskeletal and Connective Tissue

Musculoskeletal paini

33

3.8

29

3.1

Arthralgia

18

0.3

9

0.3

Metabolism and Nutrition

Decreased appetite

28

1.9

20

1.3

Nervous System

Dysgeusia

24

0

22

0

Headache

16

0

12

0.6

Respiratory, Thoracic and Mediastinal

Coughj

20

0.3

17

0

Dysphonia

17

0.3

3.4

0

Infections and Infestations

Upper respiratory tract infectionk

20

0.3

8

0.3

Table 24: Laboratory Values Worsening from Baselinea Occurring in >20% of Patients on Opdivo and Cabozantinib - CHECKMATE-9ER
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Opdivo and cabozantinib group (range: 170 to 317 patients) and sunitinib group (range: 173 to 311 patients).

Laboratory Abnormality

Opdivo and Cabozantinib

Sunitinib

Grades 1-4 (%)

Grades 3-4 (%)

Grades 1-4 (%)

Grades 3-4 (%)

Chemistry

Increased ALT

79

9.8

39

3.5

Increased AST

77

7.9

57

2.6

Hypophosphatemia

69

28

48

10

Hypocalcemia

54

1.9

24

0.6

Hypomagnesemia

47

1.3

25

0.3

Hyperglycemia

44

3.5

44

1.7

Hyponatremia

43

11

36

12

Increased lipase

41

14

38

13

Increased amylase

41

10

28

6

Increased alkaline phosphatase

41

2.8

37

1.6

Increased creatinine

39

1.3

42

0.6

Hyperkalemia

35

4.7

27

1

Hypoglycemia

26

0.8

14

0.4

Hematology

Lymphopenia

42

6.6

45

10

Thrombocytopenia

41

0.3

70

9.7

Anemia

37

2.5

61

4.8

Leukopenia

37

0.3

66

5.1

Neutropenia

35

3.2

67

12

Previously Treated Renal Cell Carcinoma

CHECKMATE-025

The safety of Opdivo was evaluated in CHECKMATE-025, a randomized open-label trial in 803 patients with advanced RCC who had experienced disease progression during or after at least one anti-angiogenic treatment regimen received Opdivo 3 mg/kg over 60 minutes by intravenous infusion every 2 weeks (n=406) or everolimus 10 mg daily (n=397) [see Clinical Studies (14.5)]. The median duration of treatment was 5.5 months (range: 1 day to 29.6+ months) in Opdivo-treated patients and 3.7 months (range: 6 days to 25.7+ months) in everolimus-treated patients.

Rate of death on treatment or within 30 days of the last dose was 4.7% on the Opdivo arm. Serious adverse reactions occurred in 47% of patients receiving Opdivo. Study therapy was discontinued for adverse reactions in 16% of Opdivo patients. Forty-four percent (44%) of patients receiving Opdivo had a dose interruption for an adverse reaction.

The most frequent serious adverse reactions in at least 2% of patients were: acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. The most common adverse reactions (≥20%) were fatigue, cough, nausea, rash, dyspnea, diarrhea, constipation, decreased appetite, back pain, and arthralgia. The most common laboratory abnormalities which have worsened compared to baseline in ≥30% of patients include increased creatinine, lymphopenia, anemia, increased AST, increased alkaline phosphatase, hyponatremia, increased triglycerides, and hyperkalemia. In addition, among patients with TSH < ULN at baseline, a greater proportion of patients experienced a treatment-emergent elevation of TSH >ULN in the Opdivo group compared to the everolimus group (26% and 14%, respectively).

Tables 25 and 26 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-025.

Table 25: Adverse Reactions in >15% of Patients Receiving Opdivo - CHECKMATE-025
Toxicity was graded per NCI CTCAE v4.
a Includes asthenia, decreased activity, fatigue, and malaise.
b Includes nasopharyngitis, pharyngitis, rhinitis, and viral upper respiratory infection (URI).
c Includes colitis, enterocolitis, and gastroenteritis.
d Includes dermatitis, acneiform dermatitis, erythematous rash, generalized rash, macular rash, maculopapular rash, papular rash, pruritic rash, erythema multiforme, and erythema.

Adverse Reaction

Opdivo
(n=406)

Everolimus
(n=397)

Grades 1-4 (%)

Grades 3-4 (%)

Grades 1-4 (%)

Grades 3-4 (%)

Adverse Reaction

98

56

96

62

General

Fatiguea

56

6

57

7

Pyrexia

17

0.7

20

0.8

Respiratory, Thoracic and Mediastinal

Cough/productive cough

34

0

38

0.5

Dyspnea/exertional dyspnea

27

3.0

31

2.0

Upper respiratory infectionb

18

0

11

0

Gastrointestinal

Nausea

28

0.5

29

1

Diarrheac

25

2.2

32

1.8

Constipation

23

0.5

18

0.5

Vomiting

16

0.5

16

0.5

Skin and Subcutaneous Tissue

Rashd

28

1.5

36

1.0

Pruritus/generalized pruritus

19

0

14

0

Metabolism and Nutrition

Decreased appetite

23

1.2

30

1.5

Musculoskeletal and Connective Tissue

Arthralgia

20

1.0

14

0.5

Back pain

21

3.4

16

2.8

Other clinically important adverse reactions in CHECKMATE-025 were:

General Disorders and Administration Site Conditions: peripheral edema/edema

Gastrointestinal Disorders: abdominal pain/discomfort

Musculoskeletal and Connective Tissue Disorders: extremity pain, musculoskeletal pain

Nervous System Disorders: headache/migraine, peripheral neuropathy

Investigations: weight decreased

Skin Disorders: palmar-plantar erythrodysesthesia

Table 26: Laboratory Values Worsening from Baselinea Occurring in >15% of Patients on Opdivo - CHECKMATE-025
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Opdivo group (range: 259 to 401 patients) and everolimus group (range: 257 to 376 patients).

Laboratory Abnormality

Opdivo

Everolimus

Grades 1-4 (%)

Grades 3-4 (%)

Grades 1-4 (%)

Grades 3-4 (%)

Hematology

Lymphopenia

42

6

53

11

Anemia

39

8

69

16

Chemistry

Increased creatinine

42

2.0

45

1.6

Increased AST

33

2.8

39

1.6

Increased alkaline phosphatase

32

2.3

32

0.8

Hyponatremia

32

7

26

6

Hyperkalemia

30

4.0

20

2.1

Hypocalcemia

23

0.9

26

1.3

Increased ALT

22

3.2

31

0.8

Hypercalcemia

19

3.2

6

0.3

Lipids

Increased triglycerides

32

1.5

67

11

Increased cholesterol

21

0.3

55

1.4

Classical Hodgkin Lymphoma

The safety of Opdivo was evaluated in 266 adult patients with cHL (243 patients in the CHECKMATE-205 and 23 patients in the CHECKMATE-039 trials) [see Clinical Studies (14.6)]. Patients received Opdivo 3 mg/kg as an intravenous infusion over 60 minutes every 2 weeks until disease progression, maximal clinical benefit, or unacceptable toxicity.

The median age was 34 years (range: 18 to 72), 98% of patients had received autologous HSCT, none had received allogeneic HSCT, and 74% had received brentuximab vedotin. The median number of prior systemic regimens was 4 (range: 2 to 15). Patients received a median of 23 doses (cycles) of Opdivo (range: 1 to 48), with a median duration of therapy of 11 months (range: 0 to 23 months).

Eleven patients died from causes other than disease progression: 3 from adverse reactions within 30 days of the last nivolumab dose, 2 from infection 8 to 9 months after completing nivolumab, and 6 from complications of allogeneic HSCT. Serious adverse reactions occurred in 26% of patients. Dose delay for an adverse reaction occurred in 34% of patients. Opdivo was discontinued due to adverse reactions in 7% of patients.

The most frequent serious adverse reactions reported in ≥1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. The most common adverse reactions (≥20%) among all patients were upper respiratory tract infection, fatigue, cough, diarrhea, pyrexia, musculoskeletal pain, rash, nausea, and pruritus.

Tables 27 and 28 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-205 and CHECKMATE-039.

Table 27: Adverse Reactions Occurring in ≥10% of Patients - CHECKMATE-205 and CHECKMATE-039
Toxicity was graded per NCI CTCAE v4.
a Includes events occurring up to 30 days after last nivolumab dose, regardless of causality. After an immune-mediated adverse reaction, reactions following nivolumab rechallenge were included if they occurred up to 30 days after completing the initial nivolumab course.
b Includes nasopharyngitis, pharyngitis, rhinitis, and sinusitis.
c Includes pneumonia bacterial, pneumonia mycoplasmal, pneumocystis jirovecii pneumonia.
d Includes asthenia.
e Includes colitis.
f Includes abdominal discomfort and upper abdominal pain.
g Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, and pain in extremity.
h Includes dermatitis, dermatitis acneiform, dermatitis exfoliative, and rash described as macular, papular, maculopapular, pruritic, exfoliative, or acneiform.
i Includes hyperesthesia, hypoesthesia, paresthesia, dysesthesia, peripheral motor neuropathy, peripheral sensory neuropathy, and polyneuropathy. These numbers are specific to treatment-emergent events.

Adverse Reactiona

Opdivo (n=266)

All Grades (%)

Grades 3-4 (%)

Infections

Upper respiratory tract infectionb

44

0.8

Pneumonia/bronchopneumoniac

13

3.8

Nasal congestion

11

0

General

Fatigued

39

1.9

Pyrexia

29

<1

Respiratory, Thoracic and Mediastinal

Cough/productive cough

36

0

Dyspnea/exertional dyspnea

15

1.5

Gastrointestinal

Diarrheae

33

1.5

Nausea

20

0

Vomiting

19

<1

Abdominal painf

16

<1

Constipation

14

0.4

Musculoskeletal and Connective Tissue

Musculoskeletal paing

26

1.1

Arthralgia

16

<1

Skin and Subcutaneous Tissue

Rashh

24

1.5

Pruritus

20

0

Nervous System

Headache

17

<1

Neuropathy peripherali

12

<1

Injury, Poisoning and Procedural Complications

Infusion-related reaction

14

<1

Endocrine

Hypothyroidism/thyroiditis

12

0

Additional information regarding clinically important adverse reactions:

Immune-mediated pneumonitis: In CHECKMATE-205 and CHECKMATE-039, pneumonitis, including interstitial lung disease, occurred in 6.0% (16/266) of patients receiving Opdivo. Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients receiving Opdivo (one Grade 3 and 12 Grade 2). The median time to onset was 4.5 months (range: 5 days to 12 months). All 13 patients received systemic corticosteroids, with resolution in 12. Four patients permanently discontinued Opdivo due to pneumonitis. Eight patients continued Opdivo (three after dose delay), of whom two had recurrence of pneumonitis.

Peripheral neuropathy: Treatment-emergent peripheral neuropathy was reported in 12% (31/266) of all patients receiving Opdivo. Twenty-eight patients (11%) had new-onset peripheral neuropathy and 3 patients had worsening of neuropathy from baseline. The median time to onset was 50 (range: 1 to 309) days.

Complications of allogeneic HSCT after Opdivo: Of 17 patients with cHL from the CHECKMATE-205 and CHECKMATE-039 trials who underwent allogeneic HSCT after treatment with Opdivo, 6 patients (35%) died from transplant-related complications. Five deaths occurred in the setting of severe (Grade 3 to 4) or refractory GVHD. Hyperacute GVHD occurred in 2 patients (12%) and Grade 3 or higher GVHD was reported in 5 patients (29%). Hepatic VOD occurred in 1 patient, who received reduced-intensity conditioned allogeneic HSCT and died of GVHD and multi-organ failure.

Table 28 summarizes laboratory abnormalities in patients with cHL. The most common (≥20%) treatment-emergent laboratory abnormalities included cytopenias, liver function abnormalities, and increased lipase. Other common findings (≥10%) included increased creatinine, electrolyte abnormalities, and increased amylase.

Table 28: Laboratory Abnormalities Worsening from Baselinea Occurring in ≥10% of Patients - CHECKMATE-205 and CHECKMATE-039
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement: range: 203 to 266 patients.
b Includes events occurring up to 30 days after last nivolumab dose. After an immune-mediated adverse reaction, reactions following nivolumab rechallenge were included if they occurred within 30 days of completing the initial nivolumab course.
c In addition, in the safety population, fasting hyperglycemia (all grade 1-2) was reported in 27 of 69 (39%) evaluable patients and fasting hypoglycemia (all grade 1-2) in 11 of 69 (16%).

Laboratory Abnormality

Opdivoa
(n=266)

All Grades (%)b

Grades 3-4 (%)b

Hematology

Leukopenia

38

4.5

Neutropenia

37

5

Thrombocytopenia

37

3.0

Lymphopenia

32

11

Anemia

26

2.6

Chemistryc

Increased AST

33

2.6

Increased ALT

31

3.4

Increased lipase

22

9

Increased alkaline phosphatase

20

1.5

Hyponatremia

20

1.1

Hypokalemia

16

1.9

Increased creatinine

16

<1

Hypocalcemia

15

<1

Hyperkalemia

15

1.5

Hypomagnesemia

14

<1

Increased amylase

13

1.5

Increased bilirubin

11

1.5

Squamous Cell Carcinoma of the Head and Neck

The safety of Opdivo was evaluated in CHECKMATE-141, a randomized, active-controlled, open-label, multicenter trial in patients with recurrent or metastatic SCCHN with progression during or within 6 months of receiving prior platinum-based therapy [see Clinical Studies (14.7)]. The trial excluded patients with active autoimmune disease, medical conditions requiring systemic immunosuppression, or recurrent or metastatic carcinoma of the nasopharynx, squamous cell carcinoma of unknown primary histology, salivary gland or non-squamous histologies (e.g., mucosal melanoma). Patients received Opdivo 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=236) or investigator’s choice of either cetuximab (400 mg/m2 initial dose intravenously followed by 250 mg/m2 weekly), or methotrexate (40 to 60 mg/m2 intravenously weekly), or docetaxel (30 to 40 mg/m2 intravenously weekly). The median duration of exposure to nivolumab was 1.9 months (range: 1 day to 16.1+ months) in Opdivo-treated patients. In this trial, 18% of patients received Opdivo for >6 months and 2.5% of patients received Opdivo for >1 year.

The median age of all randomized patients was 60 years (range: 28 to 83); 28% of patients in the Opdivo group were ≥65 years of age and 37% in the comparator group were ≥65 years of age, 83% were male and 83% were White, 12% were Asian, and 4% were Black. Baseline ECOG performance status was 0 (20%) or 1 (78%), 45% of patients received only one prior line of systemic therapy, the remaining 55% of patients had two or more prior lines of therapy, and 90% had prior radiation therapy.

Serious adverse reactions occurred in 49% of patients receiving Opdivo. Opdivo was discontinued in 14% of patients and was delayed in 24% of patients for an adverse reaction. Adverse reactions and laboratory abnormalities occurring in patients with SCCHN were generally similar to those occurring in patients with melanoma and NSCLC.

The most frequent serious adverse reactions reported in ≥2% of patients receiving Opdivo were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. The most common adverse reactions occurring in ≥10% of Opdivo-treated patients and at a higher incidence than investigator’s choice were cough and dyspnea. The most common laboratory abnormalities occurring in ≥10% of Opdivo-treated patients and at a higher incidence than investigator’s choice were increased alkaline phosphatase, increased amylase, hypercalcemia, hyperkalemia, and increased TSH.

Adjuvant Treatment of Urothelial Carcinoma

The safety of Opdivo was evaluated in CHECKMATE-274, a randomized, double-blind, multicenter trial of adjuvant Opdivo versus placebo in adult patients who had undergone radical resection of UC originating in the bladder or upper urinary tract (renal pelvis or ureter) and were at high risk of recurrence [see Clinical Studies (14.8)]. Patients received Opdivo 240 mg by intravenous infusion over 30 minutes every 2 weeks (n=351) or placebo (n=348) until recurrence or unacceptable toxicity for a maximum of 1 year. The median duration of Opdivo treatment was 8.8 months (range: 0 to 12.5).

Serious adverse reactions occurred in 30% of Opdivo patients. The most frequent serious adverse reaction reported in ≥2% of patients was urinary tract infection. Fatal adverse reactions occurred in 1% of patients; these included events of pneumonitis (0.6%). Opdivo was discontinued for adverse reactions in 18% of patients. Opdivo was delayed for adverse reaction in 33% of patients.

The most common adverse reactions (reported in ≥20% of patients) were rash, fatigue, diarrhea, pruritus, musculoskeletal pain, and urinary tract infection.

Tables 29 and 30 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-274.

Table 29: Adverse Reactions Occurring in ≥10% of Patients - CHECKMATE-274

Toxicity was graded per NCI CTCAE v4.
a Includes acne, blister, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis contact, eczema, eczema asteatotic, eczema nummular, erythema, erythema multiforme, lichen sclerosus, lichenoid keratosis, pemphigoid, photosensitivity reaction, pigmentation disorder, psoriasis, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rosacea, skin exfoliation, skin lesion, skin reaction, toxic skin eruption, and urticaria.
b Includes colitis, colitis microscopic, diarrhoea, duodenitis, enteritis, immune-mediated enterocolitis
c Includes abdominal pain, abdominal discomfort, abdominal tenderness, lower and upper abdominal pain.
d Includes musculoskeletal pain, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity and spinal pain.
e Includes cystitis, escherichia urinary tract infection, pyelonephritis, pyelonephritis acute, pyelonephritis chronic, urethritis, urinary tract infection, urinary tract infection bacterial, urinary tract infection staphylococcal, and urosepsis.
f Includes upper respiratory tract infection, nasopharyngitis, pharyngitis and rhinitis.
g Includes acute kidney injury, autoimmune nephritis, blood creatinine increased, glomerular filtration rate decreased, immune-mediated nephritis, nephritis, renal failure, and renal impairment.
h Includes cough, productive cough, and upper-airway cough syndrome.
i Includes dyspnea and exertional dyspnea.
j Includes dizziness, postural dizziness and vertigo.
k Includes aspartate aminotransferase increased, alanine aminotransferase increased, blood bilirubin increased, cholangitis, drug-induced liver injury, hepatic failure, hepatic function abnormal, hepatitis, hepatocellular injury, hyperbilirubinaemia, gamma-glutamyltransferase increased, liver injury, and transaminases increased.

Adverse Reaction

Opdivo

(n=351)

Placebo

(n=348)

All Grades (%)

Grades 3-4 (%)

All Grades (%)

Grades 3-4 (%)

Skin and Subcutaneous Tissue

Rasha

36

1.7

19

0.3

Pruritus

30

0

16

0

General

Fatigue/Asthenia

36

1.1

32

0.3

Pyrexia

10

0.3

10

0.3

Gastrointestinal

Diarrheab

30

2.8

27

1.7

Nausea

16

0.6

13

0

Abdominal painc

15

0.9

15

0.6

Constipation

13

0.3

15

0.3

Musculoskeletal and Connective Tissue

Musculoskeletal paind

28

0.6

24

0.9

Arthralgia

11

0.3

13

0

Infections

Urinary tract infectione

22

6

23

9

Upper respiratory tract infectionf

16

0.3

16

0.6

Endocrine

Hyperthyroidism

11

0

1.1

0

Hypothyroidism

11

0

2.3

0

Renal and Urinary Disorders

Renal dysfunctiong

17

1.7

16

0.9

Respiratory, Thoracic and Mediastinal

Coughh

14

0

11

0

Dyspneai

11

0.3

6

0.3

Metabolism and Nutrition

Decreased appetite

13

0.9

7

0.3

Nervous System Disorders

Dizzinessj

11

0.3

9

0

Hepatobiliary

Hepatitisk

11

4

8

0.6

Table 30: Laboratory Abnormalities Worsening from Baselinea Occurring in ≥10% of Patients - CHECKMATE-274

a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Opdivo group (range: 322 to 348 patients) and placebo group (range: 312 to 341 patients).

Laboratory Abnormality

Opdivo

(n=351)

Placebo

(n=348)

All Grades (%)

Grades 3-4 (%)

All Grades (%)

Grades 3-4 (%)

Chemistry

Increased creatinine

36

1.7

36

2.6

Increased amylase

34

8

23

3.2

Increased lipase

33

12

31

10

Hyperkalemia

32

5

30

6

Increased alkaline phosphatase

24

2.3

15

0.6

Increased AST

24

3.5

16

0.9

Increased ALT

23

2.9

15

0.6

Hyponatremia

22

4.1

17

1.8

Hypocalcemia

17

1.2

11

0.9

Hypomagnesemia

16

0

9

0

Hypercalcemia

12

0.3

8

0.3

Hematology

Lymphopenia

33

2.9

27

1.5

Anemia

30

1.4

28

0.9

Neutropenia

11

0.6

10

0.3

Advanced or Metastatic Urothelial Carcinoma

The safety of Opdivo was evaluated in CHECKMATE-275, a single arm trial in which 270 patients with locally advanced or metastatic urothelial carcinoma had disease progression during or following platinum-containing chemotherapy or had disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy [see Clinical Studies (14.8)]. Patients received Opdivo 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. The median duration of treatment was 3.3 months (range: 0 to 13.4+). Forty-six percent (46%) of patients had a dose interruption for an adverse reaction.

Fourteen patients (5.2%) died from causes other than disease progression. This includes 4 patients (1.5%) who died from pneumonitis or cardiovascular failure which was attributed to treatment with Opdivo. Serious adverse reactions occurred in 54% of patients. Opdivo was discontinued for adverse reactions in 17% of patients.

The most frequent serious adverse reactions reported in ≥2% of patients were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. The most common adverse reactions (reported in ≥20% of patients) were fatigue, musculoskeletal pain, nausea, and decreased appetite.

Tables 31 and 32 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-275.

Table 31: Adverse Reactions Occurring in ≥10% of Patients - CHECKMATE-275
Toxicity was graded per NCI CTCAE v4.
a Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity and spinal pain.
b Includes abdominal discomfort, lower and upper abdominal pain.
c Includes dermatitis, dermatitis acneiform, dermatitis bullous, and rash described as generalized, macular, maculopapular, or pruritic.
d Includes autoimmune thyroiditis, blood TSH decrease, blood TSH increase, hyperthyroidism, hypothyroidism, thyroiditis, thyroxine decreased, thyroxine free increased, thyroxine increased, tri-iodothyronine free increased, tri-iodothyronine increased.

Adverse Reaction

Opdivo
(n=270)

All Grades (%)

Grades 3-4 (%)

Adverse Reaction

99

51

General

Asthenia/fatigue/malaise

46

7

Pyrexia/tumor associated fever

17

0.4

Edema/peripheral edema/peripheral swelling

13

0.4

Musculoskeletal and Connective Tissue

Musculoskeletal paina

30

2.6

Arthralgia

10

0.7

Metabolism and Nutrition

Decreased appetite

22

2.2

Gastrointestinal

Nausea

22

0.7

Diarrhea

17

2.6

Constipation

16

0.4

Abdominal painb

13

1.5

Vomiting

12

1.9

Respiratory, Thoracic and Mediastinal

Cough/productive cough

18

0

Dyspnea/exertional dyspnea

14

3.3

Infections

Urinary tract infection/escherichia/fungal urinary tract infection

17

7

Skin and Subcutaneous Tissue

Rashc

16

1.5

Pruritus

12

0

Endocrine

Thyroid disordersd

15

0

Table 32: Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of Patients - CHECKMATE-275
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: range: 84 to 256 patients.

Laboratory Abnormality

Opdivoa

All Grades (%)

Grades 3-4 (%)

Chemistry

Hyperglycemia

42

2.4

Hyponatremia

41

11

Increased creatinine

39

2.0

Increased alkaline phosphatase

33

5.5

Hypocalcemia

26

0.8

Increased AST

24

3.5

Increased lipase

20

7

Hyperkalemia

19

1.2

Increased ALT

18

1.2

Increased amylase

18

4.4

Hypomagnesemia

16

0

Hematology

Lymphopenia

42

9

Anemia

40

7

Thrombocytopenia

15

2.4

Leukopenia

11

0

MSI-H or dMMR Metastatic Colorectal Cancer

The safety of Opdivo administered as a single agent or in combination with ipilimumab was evaluated in CHECKMATE-142, a multicenter, non-randomized, multiple parallel-cohort, open-label trial [see Clinical Studies (14.9)]. In CHECKMATE-142, 74 patients with mCRC received Opdivo 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks until disease progression or until intolerable toxicity and 119 patients with mCRC received Opdivo 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks for 4 doses, then Opdivo 3 mg/kg every 2 weeks until disease progression or until unacceptable toxicity.

In the Opdivo with ipilimumab cohort, serious adverse reactions occurred in 47% of patients. Treatment was discontinued in 13% of patients and delayed in 45% of patients for an adverse reaction. The most frequent serious adverse reactions reported in ≥2% of patients were colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration. The most common adverse reactions (reported in ≥20% of patients) were fatigue, diarrhea, pyrexia, musculoskeletal pain, abdominal pain, pruritus, nausea, rash, decreased appetite, and vomiting.

Tables 33 and 34 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-142. Based on the design of CHECKMATE-142, the data below cannot be used to identify statistically significant differences between the two cohorts summarized below for any adverse reaction.

Table 33: Adverse Reactions Occurring in ≥10% of Patients - CHECKMATE-142
Toxicity was graded per NCI CTCAE v4.
a Includes asthenia.
b Includes peripheral edema and peripheral swelling.
c Includes upper abdominal pain, lower abdominal pain, and abdominal discomfort.
d Includes back pain, pain in extremity, myalgia, neck pain, and bone pain.
e Includes dermatitis, dermatitis acneiform, and rash described as maculo-papular, erythematous, and generalized.
f Includes nasopharyngitis and rhinitis.

Adverse Reaction

Opdivo
(n=74)

Opdivo and Ipilimumab
(n=119)

All Grades (%)

Grades 3-4 (%)

All Grades (%)

Grades 3-4 (%)

General

Fatiguea

54

5

49

6

Pyrexia

24

0

36

0

Edemab

12

0

7

0

Gastrointestinal

Diarrhea

43

2.7

45

3.4

Abdominal painc

34

2.7

30

5

Nausea

34

1.4

26

0.8

Vomiting

28

4.1

20

1.7

Constipation

20

0

15

0

Musculoskeletal and Connective Tissue

Musculoskeletal paind

28

1.4

36

3.4

Arthralgia

19

0

14

0.8

Respiratory, Thoracic and Mediastinal

Cough

26

0

19

0.8

Dyspnea

8

1

13

1.7

Skin and Subcutaneous Tissue

Rashe

23

1.4

25

4.2

Pruritus

19

0

28

1.7

Dry Skin

7

0

11

0

Infections

Upper respiratory tract infectionf

20

0

9

0

Endocrine

Hyperglycemia

19

2.7

6

1

Hypothyroidism

5

0

14

0.8

Hyperthyroidism

4

0

12

0

Nervous System

Headache

16

0

17

1.7

Dizziness

14

0

11

0

Metabolism and Nutrition

Decreased appetite

14

1.4

20

1.7

Psychiatric

Insomnia

9

0

13

0.8

Investigations

Weight decreased

8

0

10

0

Clinically important adverse reactions reported in <10% of patients receiving Opdivo with ipilimumab were encephalitis (0.8%), necrotizing myositis (0.8%), and uveitis (0.8%).

Table 34: Laboratory Abnormalities Worsening from Baselinea Occurring in ≥10% of Patients - CHECKMATE-142
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available. Number of evaluable patients ranges from 62 to 71 for the Opdivo cohort and from 87 to 114 for the Opdivo and ipilimumab cohort.

Laboratory Abnormality

Opdivo
(n=74)

Opdivo and Ipilimumab
(n=119)

All Grades (%)

Grades 3-4 (%)

All Grades (%)

Grades 3-4 (%)

Hematology

Anemia

50

7

42

9

Lymphopenia

36

7

25

6

Neutropenia

20

4.3

18

0

Thrombocytopenia

16

1.4

26

0.9

Chemistry

Increased alkaline phosphatase

37

2.8

28

5

Increased lipase

33

19

39

12

Increased ALT

32

2.8

33

12

Increased AST

31

1.4

40

12

Hyponatremia

27

4.3

26

5

Hypocalcemia

19

0

16

0

Hypomagnesemia

17

0

18

0

Increased amylase

16

4.8

36

3.4

Increased bilirubin

14

4.2

21

5

Hypokalemia

14

0

15

1.8

Increased creatinine

12

0

25

3.6

Hyperkalemia

11

0

23

0.9

Hepatocellular Carcinoma

The safety of Opdivo 1 mg/kg in combination with ipilimumab 3 mg/kg was evaluated in a subgroup comprising 49 patients with HCC and Child-Pugh Class A cirrhosis enrolled in Cohort 4 of CHECKMATE-040, a multicenter, multiple cohort, open-label trial [see Clinical Studies (14.10)] who progressed on or were intolerant to sorafenib. Opdivo and ipilimumab were administered every 3 weeks for 4 doses, followed by single-agent Opdivo 240 mg every 2 weeks until disease progression or unacceptable toxicity. During the Opdivo and ipilimumab combination period, 33 of 49 (67%) patients received all 4 planned doses of Opdivo and ipilimumab. During the entire treatment period, the median duration of exposure to Opdivo was 5.1 months (range: 0 to 35+ months) and to ipilimumab was 2.1 months (range: 0 to 4.5 months). Forty-seven percent of patients were exposed to treatment for >6 months, and 35% of patients were exposed to treatment for >1 year. Serious adverse reactions occurred in 59% of patients. Treatment was discontinued in 29% of patients and delayed in 65% of patients for an adverse reaction.

The most frequent serious adverse reactions (reported in ≥4% of patients) were pyrexia, diarrhea, anemia, increased AST, adrenal insufficiency, ascites, esophageal varices hemorrhage, hyponatremia, increased blood bilirubin, and pneumonitis.

Tables 35 and 36 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-040.

Table 35: Adverse Reactions Occurring in ≥10% of Patients Receiving Opdivo in Combination with Ipilimumab in Cohort 4 of CHECKMATE-040

Adverse Reaction

Opdivo and Ipilimumab

(n=49)

All Grades (%)

Grades 3-4 (%)

Skin and Subcutaneous Tissue

Rash

53

8

Pruritus

53

4

Musculoskeletal and Connective Tissue

Musculoskeletal pain

41

2

Arthralgia

10

0

Gastrointestinal

Diarrhea

39

4

Abdominal pain

22

6

Nausea

20

0

Ascites

14

6

Constipation

14

0

Dry mouth

12

0

Dyspepsia

12

2

Vomiting

12

2

Stomatitis

10

0

Respiratory, Thoracic and Mediastinal

Cough

37

0

Dyspnea

14

0

Pneumonitis

10

2

Metabolism and Nutrition

Decreased appetite

35

2

General

Fatigue

27

2

Pyrexia

27

0

Malaise

18

2

Edema

16

2

Influenza-like illness

14

0

Chills

10

0

Nervous System

Headache

22

0

Dizziness

20

0

Endocrine

Hypothyroidism

20

0

Adrenal insufficiency

18

4

Investigations

Weight decreased

20

0

Psychiatric

Insomnia

18

0

Blood and Lymphatic System

Anemia

10

4

Infections

Influenza

10

2

Vascular

Hypotension

10

0

Clinically important adverse reactions reported in <10% of patients who received Opdivo with ipilimumab were hyperglycemia (8%), colitis (4%), and increased blood creatine phosphokinase (2%).

Table 36: Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of Patients Receiving Opdivo in Combination with Ipilimumab in Cohort 4 of CHECKMATE-040

Laboratory Abnormality

Opdivo and Ipilimumab

(n=47)

All Grades (%)

Grades 3-4 (%)

Hematology

Lymphopenia

53

13

Anemia

43

4.3

Neutropenia

43

9

Leukopenia

40

2.1

Thrombocytopenia

34

4.3

Chemistry

Increased AST

66

40

Increased ALT

66

21

Increased bilirubin

55

11

Increased lipase

51

26

Hyponatremia

49

32

Hypocalcemia

47

0

Increased alkaline phosphatase

40

4.3

Increased amylase

38

15

Hypokalemia

26

2.1

Hyperkalemia

23

4.3

Increased creatinine

21

0

Hypomagnesemia

11

0

In patients who received Opdivo with ipilimumab, virologic breakthrough occurred in 4 of 28 (14%) patients and 2 of 4 (50%) patients with active HBV or HCV at baseline, respectively. HBV virologic breakthrough was defined as at least a 1 log increase in HBV DNA for those patients with detectable HBV DNA at baseline. HCV virologic breakthrough was defined as a 1 log increase in HCV RNA from baseline.

Esophageal Cancer

Adjuvant Treatment of Resected Esophageal or Gastroesophageal Junction Cancer

The safety of Opdivo was evaluated in CHECKMATE-577, a randomized, placebo-controlled, double-blinded, multicenter trial in 792 treated patients with completely resected (negative margins) esophageal or gastroesophageal junction cancer who had residual pathologic disease following chemoradiotherapy (CRT) [see Clinical Studies (14.11)]. The trial excluded patients who did not receive concurrent CRT prior to surgery, had stage IV resectable disease, autoimmune disease, or any condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone or equivalent) or other immunosuppressive medications. Patients received either Opdivo 240 mg or placebo by intravenous infusion over 30 minutes every 2 weeks for 16 weeks followed by 480 mg or placebo by intravenous infusion over 30 minutes every 4 weeks beginning at week 17. Patients were treated until disease recurrence, unacceptable toxicity, or for up to 1 year total duration. The median duration of exposure was 10.1 months (range: <0.1 to 14 months) in Opdivo-treated patients and 9 months (range: <0.1 to 15 months) in placebo-treated patients. Among patients who received Opdivo, 61% were exposed for >6 months and 54% were exposed for >9 months.

Serious adverse reactions occurred in 33% of patients receiving Opdivo. A serious adverse reaction reported in ≥2% of patients who received Opdivo was pneumonitis. A fatal adverse reaction of myocardial infarction occurred in one patient who received Opdivo.

Opdivo was discontinued in 12% of patients and was delayed in 28% of patients for an adverse reaction.

Tables 37 and 38 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-577.

Table 37: Adverse Reactions Occurring in ≥10% of Patients Receiving Opdivo - CHECKMATE-577

a Includes upper abdominal pain, lower abdominal pain, and abdominal discomfort.
b Includes gastroesophageal reflux.
c Includes asthenia.
d Includes productive cough.
e Includes dyspnea exertional.
f Includes rash pustular, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, exfoliative rash, rash erythematous, rash macular, rash maculo-papular, rash popular, rash pruritic.
g Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, myalgia intercostal, neck pain, pain in extremity, spinal pain.

Adverse Reaction

Opdivo

(n=532)

Placebo

(n=260)

All Grades (%)

Grades 3-4 (%)

All Grades (%)

Grades 3-4 (%)

Adverse Reaction

96

34

93

32

Gastrointestinal

Diarrhea

29

0.9

29

0.8

Nausea

23

0.8

21

0

Abdominal Paina

17

0.8

20

1.5

Vomiting

15

0.6

16

1.2

Dysphagia

13

0.8

17

3.5

Dyspepsiab

12

0.2

16

0.4

Constipation

11

0

12

0

General

Fatiguec

34

1.3

29

1.5

Respiratory, Thoracic and Mediastinal

Coughd

20

0.2

21

0.4

Dyspneae

12

0.8

12

0.4

Skin and Subcutaneous Tissue

Rashf

21

0.9

10

0.4

Pruritus

13

0.4

6

0

Investigations

Weight decreased

13

0.4

9

0

Musculoskeletal and Connective Tissue

Musculoskeletal paing

21

0.6

20

0.8

Arthralgia

10

0.2

8

0

Metabolism and Nutrition

Decreased appetite

15

0.9

10

0.8

Endocrine

Hypothyroidism

11

0

1.5

0

Table 38: Laboratory Abnormalities Worsening from Baselinea Occurring in ≥10% of Patients - CHECKMATE-577

a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Opdivo group (range: 163 to 526 patients) and Placebo group (range: 86 to 256 patients).
b Includes alanine aminotransferase increased, aspartate aminotransferase increased.

Laboratory Abnormality

Opdivo

(n=532)

Placebo

(n=260)

All Grades (%)

Grades 3-4 (%)

All Grades (%)

Grades 3-4 (%)

Chemistry

Increased AST

27

2.1

22

0.8

Increased alkaline phosphatase

25

0.8

18

0.8

Increased albumin

21

0.2

18

0

Increased ALT

20

1.9

16

1.2

Increased amylase

20

3.9

13

1.3

Hyponatremia

19

1.7

12

1.2

Hyperkalemia

17

0.8

15

1.6

Hypokalemia

12

1

11

1.2

Transaminases increasedb

11

1.5

6

1.2

Hematology

Lymphopenia

44

17

35

12

Anemia

27

0.8

21

0.4

Neutropenia

24

1.5

23

0.4

Esophageal Squamous Cell Carcinoma

The safety of Opdivo was evaluated in ATTRACTION-3, a randomized, active-controlled, open-label, multicenter trial in 209 patients with unresectable advanced, recurrent or metastatic ESCC refractory or intolerant to at least one fluoropyrimidine- and platinum-based chemotherapy [see Clinical Studies (14.11)]. The trial excluded patients who were refractory or intolerant to taxane therapy, had brain metastases that were symptomatic or required treatment, had autoimmune disease, used systemic corticosteroids or immunosuppressants, had apparent tumor invasion of organs adjacent to the esophageal tumor or had stents in the esophagus or respiratory tract. Patients received Opdivo 240 mg by intravenous infusion over 30 minutes every 2 weeks (n=209) or investigator’s choice: docetaxel 75 mg/m2 intravenously every 3 weeks (n=65) or paclitaxel 100 mg/m2 intravenously once a week for 6 weeks followed by 1 week off (n=143). Patients were treated until disease progression or unacceptable toxicity. The median duration of exposure was 2.6 months (range: 0 to 29.2 months) in Opdivo-treated patients and 2.6 months (range: 0 to 21.4 months) in docetaxel- or paclitaxel-treated patients. Among patients who received Opdivo, 26% were exposed for >6 months and 10% were exposed for >1 year.

Serious adverse reactions occurred in 38% of patients receiving Opdivo. Serious adverse reactions reported in ≥2% of patients who received Opdivo were pneumonia, esophageal fistula, interstitial lung disease and pyrexia. The following fatal adverse reactions occurred in patients who received Opdivo: interstitial lung disease or pneumonitis (1.4%), pneumonia (1.0%), septic shock (0.5%), esophageal fistula (0.5%), gastrointestinal hemorrhage (0.5%), pulmonary embolism (0.5%), and sudden death (0.5%).

Opdivo was discontinued in 13% of patients and was delayed in 27% of patients for an adverse reaction.

Tables 39 and 40 summarize the adverse reactions and laboratory abnormalities, respectively, in ATTRACTION-3.

Table 39: Adverse Reactions Occurring in ≥10% of Patients Receiving Opdivo - ATTRACTION-3
Toxicity was graded per NCI CTCAE v4.
a Includes urticaria, drug eruption, eczema, eczema asteatotic, eczema nummular, palmar-plantar erythrodysaesthesia syndrome, erythema, erythema multiforme, blister, skin exfoliation, Stevens-Johnson syndrome, dermatitis, dermatitis described as acneiform, bullous, or contact, and rash described as maculo-papular, generalized, or pustular.
b Includes hypophagia, and food aversion.
c Includes colitis.
d Includes spondylolisthesis, periarthritis, musculoskeletal chest pain, neck pain, arthralgia, back pain, myalgia, pain in extremity, arthritis, bone pain, and periarthritis calcarea.
e Includes influenza, influenza like illness, pharyngitis, nasopharyngitis, tracheitis, and bronchitis and upper respiratory infection with bronchitis.
f Includes pneumonia aspiration, pneumonia bacterial, and lung infection. Two patients (1.0%) died of pneumonia in the Opdivo treatment arm. Two patients (1.0%) died of pneumonia in the chemotherapy treatment arm; these deaths occurred with paclitaxel only.
g Includes productive cough.
h Includes tumor-associated fever.
i Includes asthenia.
j Includes hemoglobin decreased, and iron deficiency anemia.
k Includes blood thyroid stimulating hormone increased.

Adverse Reaction

Opdivo

(n=209)

Docetaxel or Paclitaxel

(n=208)

All Grades (%)

Grades 3-4 (%)

All Grades (%)

Grades 3-4 (%)

Skin and Subcutaneous Tissue

Rasha

22

1.9

28

1

Pruritus

12

0

7

0

Metabolism and Nutrition

Decreased appetiteb

21

1.9

35

5

Gastrointestinal

Diarrheac

18

1.9

17

1.4

Constipation

17

0

19

0

Nausea

11

0

20

0.5

Musculoskeletal and Connective Tissue

Musculoskeletal paind

17

0

26

1.4

Infections

Upper respiratory tract infectione

17

1.0

14

0

Pneumoniaf

13

5

19

9

Respiratory, Thoracic and Mediastinal

Coughg

16

0

14

0.5

General

Pyrexiah

16

0.5

19

0.5

Fatiguei

12

1.4

27

4.8

Blood and Lymphatic System

Anemiaj

13

8

30

13

Endocrine

Hypothyroidismk

11

0

1.4

0

Table 40: Laboratory Abnormalities Worsening from Baselinea Occurring in ≥10% of Patients - ATTRACTION-3
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Opdivo group (209 patients) and Docetaxel or Paclitaxel group (range: 207 to 208 patients).

Laboratory Abnormality

Opdivo

(n=209)

Docetaxel or Paclitaxel

(n=208)

All Grades (%)

Grades 3-4 (%)

All Grades (%)

Grades 3-4 (%)

Chemistry

Increased creatinine

78

0.5

68

0.5

Hyperglycemia

52

5

62

5

Hyponatremia

42

11

50

12

Increased AST

40

6

30

1.0

Increased alkaline phosphatase

33

4.8

24

1.0

Increased ALT

31

5

22

1.9

Hypercalcemia

22

6

14

2.9

Hyperkalemia

22

0.5

31

1.0

Hypoglycemia

14

1.4

14

0.5

Hypokalemia

11

2.9

13

3.4

Hematology

Lymphopenia

46

19

72

43

Anemia

42

9

71

17

Leukopenia

11

0.5

79

45

Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma

The safety of Opdivo in combination with chemotherapy was evaluated in CHECKMATE-649, a randomized, multicenter, open-label trial in patients with previously untreated advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma [see Clinical Studies (14.12)]. The trial excluded patients who were known human epidermal growth factor receptor 2 (HER2) positive, or had untreated CNS metastases. Patients were randomized to receive Opdivo in combination with chemotherapy or chemotherapy. Patients received one of the following treatments:

Opdivo 240 mg in combination with mFOLFOX6 (fluorouracil, leucovorin and oxaliplatin) every 2 weeks or mFOLFOX6 every 2 weeks.
Opdivo 360 mg in combination with CapeOX (capecitabine and oxaliplatin) every 3 weeks or CapeOX every 3 weeks.

Patients were treated with Opdivo in combination with chemotherapy or chemotherapy until disease progression, unacceptable toxicity, or up to 2 years. The median duration of exposure was 6.8 months (range: 0 to 33.5 months) in Opdivo and chemotherapy-treated patients. Among patients who received Opdivo and chemotherapy, 54% were exposed for >6 months and 28% were exposed for >1 year.

Fatal adverse reactions occurred in 16 (2.0%) patients who were treated with Opdivo in combination with chemotherapy; these included pneumonitis (4 patients), febrile neutropenia (2 patients), stroke (2 patients), gastrointestinal toxicity, intestinal mucositis, septic shock, pneumonia, infection, gastrointestinal bleeding, mesenteric vessel thrombosis, and disseminated intravascular coagulation. Serious adverse reactions occurred in 52% of patients treated with Opdivo in combination with chemotherapy. Opdivo and/or chemotherapy were discontinued in 44% of patients and at least one dose was withheld in 76% of patients due to an adverse reaction.

The most frequent serious adverse reactions reported in ≥2% of patients treated with Opdivo in combination with chemotherapy were vomiting (3.7%), pneumonia (3.6%), anemia (3.6%), pyrexia (2.8%), diarrhea (2.7%), febrile neutropenia (2.6%), and pneumonitis (2.4%). The most common adverse reactions reported in ≥20% of patients treated with Opdivo in combination with chemotherapy were peripheral neuropathy, nausea, fatigue, diarrhea, vomiting, decreased appetite, abdominal pain, constipation, and musculoskeletal pain.

Tables 41 and 42 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-649.

Table 41: Adverse Reactions in ≥10% of Patients Receiving Opdivo and Chemotherapy - CHECKMATE-649
Toxicity was graded per NCI CTCAE v4.
a Includes dysaesthesia, hypoaesthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, and peripheral sensory neuropathy.
b Includes abdominal discomfort, abdominal pain lower, and abdominal pain upper.
c Includes aphthous ulcer, mouth ulceration, and mucosal inflammation.
d Includes asthenia.
e Includes tumor associated fever.
f Includes swelling, generalized edema, edema peripheral, and peripheral swelling.
g Includes blood albumin decreased.
h Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, and spinal pain.
i Includes dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, drug eruption, exfoliative rash, nodular rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash vesicular.
j Includes productive cough.
k Includes nasopharyngitis, pharyngitis, and rhinitis.

Adverse Reaction

Opdivo and mFOLFOX6 or CapeOX

(n=782)

mFOLFOX6 or CapeOX
(n=767)

All Grades (%)

Grades 3-4 (%)

All Grades (%)

Grades 3-4 (%)

Adverse Reaction

99

69

98

59

Nervous System

Peripheral neuropathya

53

7

46

4.8

Headache

11

0.8

6

0.3

Gastrointestinal

Nausea

48

3.2

44

3.7

Diarrhea

39

5

34

3.7

Vomiting

31

4.2

29

4.2

Abdominal painb

27

2.8

24

2.6

Constipation

25

0.6

21

0.4

Stomatitisc

17

1.8

13

0.8

General

Fatigued

44

7

40

5

Pyrexiae

19

1.0

11

0.4

Edemaf

12

0.5

8

0.1

Metabolism and Nutrition

Decreased appetite

29

3.6

26

2.5

Hypoalbuminemiag

14

0.3

9

0.3

Investigations

Weight decreased

17

1.3

15

0.7

Increased lipase

14

7

8

3.7

Increased amylase

12

3.1

5

0.4

Musculoskeletal and Connective Tissue

Musculoskeletal painh

20

1.3

14

2.0

Skin and Subcutaneous Tissue

Rashi

18

1.7

4.4

0.1

Palmar-plantar erythrodysesthesia syndrome

13

1.5

12

0.8

Respiratory, Thoracic and Mediastinal

Coughj

13

0.1

9

0

Infections and Infestations

Upper respiratory tract infectionk

10

0.1

7

0.1

Table 42: Laboratory Values Worsening from Baselinea Occurring in ≥10% of Patients - CHECKMATE-649
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Opdivo and mFOLFOX6 or CapeOX group (407 to 767 patients) or mFOLFOX6 or CapeOX group (range: 405 to 735 patients).

Laboratory Abnormality

Opdivo and mFOLFOX6 or CapeOX
(n=782)

mFOLFOX6 or CapeOX
(n=767)

Grades 1-4 (%)

Grades 3-4 (%)

Grades 1-4 (%)

Grades 3-4 (%)

Hematology

Neutropenia

73

29

62

23

Leukopenia

69

12

59

9

Thrombocytopenia

68

7

63

4.4

Anemia

59

14

60

10

Lymphopenia

59

12

49

9

Chemistry

Increased AST

52

4.6

47

1.9

Hypocalcemia

42

1.6

37

1.0

Hyperglycemia

41

3.9

38

2.7

Increased ALT

37

3.4

30

1.9

Hyponatremia

34

6

24

5

Hypokalemia

27

7

24

4.8

Hyperbilirubinemia

24

2.8

21

2.0

Increased creatinine

15

1.0

9

0.5

Hyperkalemia

14

1.4

11

0.7

Hypoglycemia

12

0.7

9

0.2

Hypernatremia

11

0.5

7.1

0

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to Opdivo with the incidences of antibodies to other products may be misleading.

Of the 2085 patients who were treated with Opdivo as a single agent at dose of 3 mg/kg every 2 weeks and evaluable for the presence of anti-nivolumab antibodies, 11% tested positive for treatment-emergent anti-nivolumab antibodies by an electrochemiluminescent (ECL) assay and 0.7% had neutralizing antibodies against nivolumab. There was no evidence of altered pharmacokinetic profile or increased incidence of infusion-related reactions with anti-nivolumab antibody development.

Of the patients with melanoma, advanced renal cell carcinoma, metastatic colorectal cancer, metastatic or recurrent non-small cell lung cancer, and malignant pleural mesothelioma who were treated with Opdivo and ipilimumab and evaluable for the presence of anti-nivolumab antibodies, the incidence of anti-nivolumab antibodies was 26% (132/516) with Opdivo 3 mg/kg followed by ipilimumab 1 mg/kg every 3 weeks, 36.7% (180/491) and 25.7% (69/269) with Opdivo 3 mg/kg every 2 weeks and ipilimumab 1 mg every 6 weeks in non-small cell lung cancer and malignant pleural mesothelioma patients, respectively, and 38% (149/394) with Opdivo 1 mg/kg followed by ipilimumab 3 mg/kg every 3 weeks. The incidence of neutralizing antibodies against nivolumab was 0.8% (4/516) with Opdivo 3 mg/kg followed by ipilimumab 1 mg/kg every 3 weeks, 1.4% (7/491) and 0.7% (2/269) with Opdivo 3 mg/kg every 2 weeks and ipilimumab 1 mg every 6 weeks in non-small cell lung cancer and malignant pleural mesothelioma patients, respectively, and 4.6% (18/394) with Opdivo 1 mg/kg followed by ipilimumab 3 mg/kg every 3 weeks.

Of the patients with hepatocellular carcinoma who were treated with Opdivo and ipilimumab every 3 weeks for 4 doses followed by Opdivo every 2 weeks and were evaluable for the presence of anti-nivolumab antibodies, the incidence of anti-nivolumab antibodies was 45% (20/44) with Opdivo 3 mg/kg followed by ipilimumab 1 mg/kg and 56% (27/48) with Opdivo 1 mg/kg followed by ipilimumab 3 mg/kg; the corresponding incidence of neutralizing antibodies against nivolumab was 14% (6/44) and 23% (11/48), respectively.

Of the patients with NSCLC who were treated with Opdivo 360 mg every 3 weeks in combination with ipilimumab 1 mg/kg every 6 weeks and platinum-doublet chemotherapy, and were evaluable for the presence of anti-nivolumab antibodies, the incidence of anti-nivolumab antibodies was 34% (104/308); the incidence of neutralizing antibodies against nivolumab was 2.6% (8/308).

There was no evidence of increased incidence of infusion-related reactions with anti-nivolumab antibody development.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Opdivo. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Eye: Vogt-Koyanagi-Harada (VKH) syndrome

Complications of Opdivo Treatment After Allogeneic HSCT: Treatment refractory, severe acute and chronic GVHD

Blood and lymphatic system disorders: hemophagocytic lymphohistiocytosis (HLH) (including fatal cases), autoimmune hemolytic anemia (including fatal cases)

USE IN SPECIFIC POPULATIONS

Pregnancy

Risk Summary

Based on data from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], Opdivo can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death (see Data). Human IgG4 is known to cross the placental barrier and nivolumab is an immunoglobulin G4 (IgG4); therefore, nivolumab has the potential to be transmitted from the mother to the developing fetus. The effects of Opdivo are likely to be greater during the second and third trimesters of pregnancy. There are no available data on Opdivo use in pregnant women to evaluate a drug-associated risk. Advise pregnant women of the potential risk to a fetus.

The background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

Data

Animal Data

A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus and to increase fetal loss. The effects of nivolumab on prenatal and postnatal development were evaluated in monkeys that received nivolumab twice weekly from the onset of organogenesis through delivery, at exposure levels of between 9 and 42 times higher than those observed at the clinical dose of 3 mg/kg (based on AUC). Nivolumab administration resulted in a non–dose-related increase in spontaneous abortion and increased neonatal death. Based on its mechanism of action, fetal exposure to nivolumab may increase the risk of developing immune-mediated disorders or altering the normal immune response and immune-mediated disorders have been reported in PD-1 knockout mice. In surviving infants (18 of 32 compared to 11 of 16 vehicle-exposed infants) of cynomolgus monkeys treated with nivolumab, there were no apparent malformations and no effects on neurobehavioral, immunological, or clinical pathology parameters throughout the 6-month postnatal period.

Lactation

Risk Summary

There are no data on the presence of nivolumab in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment and for 5 months after the last dose of Opdivo.

Females and Males of Reproductive Potential

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating Opdivo [see Use in Specific Populations (8.1)].

Contraception

Opdivo can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with Opdivo and for at least 5 months following the last dose.

Pediatric Use

The safety and effectiveness of Opdivo as a single agent and in combination with ipilimumab have been established in pediatric patients age 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Use of Opdivo for this indication is supported by evidence from adequate and well-controlled studies of Opdivo in adults with MSI-H or dMMR mCRC with additional population pharmacokinetic data demonstrating that age and body weight had no clinically meaningful effect on the steady-state exposure of nivolumab, that drug exposure is generally similar between adults and pediatric patients age 12 years and older for monoclonal antibodies, and that the course of MSI-H or dMMR mCRC is sufficiently similar in adults and pediatric patients to allow extrapolation of data in adults to pediatric patients [see Dosage and Administration (2.2), Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.9)].

The safety and effectiveness of Opdivo have not been established (1) in pediatric patients <12 years old with MSI-H or dMMR mCRC or (2) in pediatric patients less than 18 years old for the other approved indications [see Indications and Usage (1)].

Geriatric Use

Of the 1359 patients randomized to single-agent Opdivo in CHECKMATE-017, CHECKMATE-057, CHECKMATE-066, CHECKMATE-025, and CHECKMATE-067, 39% were 65 years or older and 9% were 75 years or older. No overall differences in safety or effectiveness were reported between elderly patients and younger patients.

In CHECKMATE-275 (metastatic or advanced urothelial cancer), 55% of patients were 65 years or older and 14% were 75 years or older. No overall differences in safety or effectiveness were reported between elderly patients and younger patients.

In CHECKMATE-274 (adjuvant treatment of urothelial cancer), 56% of patients were 65 years or older and 19% were 75 years or older. No overall differences in safety or effectiveness were reported between elderly patients and younger patients.

In CHECKMATE-238 (adjuvant treatment of melanoma), 26% of patients were 65 years or older and 3% were 75 years or older. No overall differences in safety or effectiveness were reported between elderly patients and younger patients.

In ATTRACTION-3 (esophageal squamous cell carcinoma), 53% of patients were 65 years or older and 10% were 75 years or older. No overall differences in safety or effectiveness were reported between elderly patients and younger patients.

In CHECKMATE-577 (adjuvant treatment of esophageal or gastroesophageal junction cancer), 36% of patients were 65 years or older and 5% were 75 years or older. No overall differences in safety or effectiveness were reported between elderly patients (65 years or older) and younger patients.

CHECKMATE-037, CHECKMATE-205, CHECKMATE-039, CHECKMATE-141, and CHECKMATE-142 did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients.

Of the 314 patients randomized to Opdivo administered with ipilimumab in CHECKMATE-067, 41% were 65 years or older and 11% were 75 years or older. No overall differences in safety or effectiveness were reported between elderly patients and younger patients.

Of the 550 patients randomized to Opdivo 3 mg/kg administered with ipilimumab 1 mg/kg in CHECKMATE-214 (renal cell carcinoma), 38% were 65 years or older and 8% were 75 years or older. No overall difference in safety was reported between elderly patients and younger patients. In elderly patients with intermediate or poor risk, no overall difference in effectiveness was reported.

Of the 49 patients who received Opdivo 1 mg/kg in combination with ipilimumab 3 mg/kg in CHECKMATE-040 (hepatocellular carcinoma), 29% were between 65 years and 74 years of age and 8% were 75 years or older. Clinical studies of Opdivo in combination with ipilimumab did not include sufficient numbers of patients with hepatocellular carcinoma aged 65 and over to determine whether they respond differently from younger patients.

Of the 576 patients randomized to Opdivo 3 mg/kg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks in CHECKMATE-227 (NSCLC), 48% were 65 years or older and 10% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there was a higher discontinuation rate due to adverse reactions in patients aged 75 years or older (29%) relative to all patients who received Opdivo with ipilimumab (18%). Of the 396 patients in the primary efficacy population (PD-L1 ≥1%) randomized to Opdivo 3 mg/kg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks in CHECKMATE-227, the hazard ratio for overall survival was 0.70 (95% CI: 0.55, 0.89) in the 199 patients younger than 65 years compared to 0.91 (95% CI: 0.72, 1.15) in the 197 patients 65 years or older [see Clinical Studies (14.3)].

Of the 361 patients randomized to Opdivo 360 mg every 3 weeks in combination with ipilimumab 1 mg/kg every 6 weeks and platinum-doublet chemotherapy every 3 weeks (for 2 cycles) in CHECKMATE-9LA (NSCLC), 51% were 65 years or older and 10% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there was a higher discontinuation rate due to adverse reactions in patients aged 75 years or older (43%) relative to all patients who received Opdivo with ipilimumab and chemotherapy (24%). For patients aged 75 years or older who received chemotherapy only, the discontinuation rate due to adverse reactions was 16% relative to all patients who had a discontinuation rate of 13%. Based on an updated analysis for overall survival, of the 361 patients randomized to Opdivo in combination with ipilimumab and platinum-doublet chemotherapy in CHECKMATE-9LA, the hazard ratio for overall survival was 0.61 (95% CI: 0.47, 0.80) in the 176 patients younger than 65 years compared to 0.73 (95% CI: 0.56, 0.95) in the 185 patients 65 years or older.

Of the 303 patients randomized to Opdivo 3 mg/kg every 2 weeks in combination with ipilimumab 1 mg/kg every 6 weeks in CHECKMATE-743 (malignant pleural mesothelioma), 77% were 65 years old or older and 26% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there were higher rates of serious adverse reactions and discontinuation due to adverse reactions in patients aged 75 years or older (68% and 35%, respectively) relative to all patients who received Opdivo with ipilimumab (54% and 28%, respectively). For patients aged 75 years or older who received chemotherapy, the rate of serious adverse reactions was 34% and the discontinuation rate due to adverse reactions was 26% relative to 28% and 19% respectively for all patients. The hazard ratio for overall survival was 0.76 (95% CI: 0.52, 1.11) in the 71 patients younger than 65 years compared to 0.74 (95% CI: 0.59, 0.93) in the 232 patients 65 years or older randomized to Opdivo in combination with ipilimumab.

Of the 320 patients who received Opdivo in combination with cabozantinib in CHECKMATE-9ER (renal cell carcinoma), 41% were 65 years or older and 9% were 75 years or older. No overall difference in safety was reported between elderly patients and younger patients.

Of the 1581 patients randomized to Opdivo 240 mg every 2 weeks or 360 mg every 3 weeks administered in combination with fluoropyrimidine- and platinum-containing chemotherapy in CHECKMATE-649 (GC, GEJC, or EAC), 39% were 65 years or older and 10% were 75 years or older. No overall difference in safety was reported between elderly patients and younger patients.

Opdivo Description

Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody. Nivolumab is an IgG4 kappa immunoglobulin that has a calculated molecular mass of 146 kDa. It is expressed in a recombinant Chinese Hamster Ovary (CHO) cell line.

Opdivo is a sterile, preservative-free, non-pyrogenic, clear to opalescent, colorless to pale-yellow liquid that may contain light (few) particles.

Opdivo (nivolumab) injection for intravenous use is supplied in single-dose vials. Each mL of Opdivo solution contains nivolumab 10 mg, mannitol (30 mg), pentetic acid (0.008 mg), polysorbate 80 (0.2 mg), sodium chloride (2.92 mg), sodium citrate dihydrate (5.88 mg), and Water for Injection, USP. May contain hydrochloric acid and/or sodium hydroxide to adjust pH to 6.

Opdivo - Clinical Pharmacology

Mechanism of Action

Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth.

Combined nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) mediated inhibition results in enhanced T-cell function that is greater than the effects of either antibody alone, and results in improved anti-tumor responses in metastatic melanoma and advanced RCC. In murine syngeneic tumor models, dual blockade of PD-1 and CTLA-4 resulted in increased anti-tumor activity.

Pharmacokinetics

Nivolumab pharmacokinetics (PK) was assessed using a population PK approach for both single-agent Opdivo and Opdivo with ipilimumab. The PK of nivolumab was studied in patients over a dose range of 0.1 mg/kg to 20 mg/kg administered as a single dose or as multiple doses of Opdivo as a 60-minute intravenous infusion every 2 or 3 weeks. The exposure to nivolumab increases dose proportionally over the dose range of 0.1 to 10 mg/kg administered every 2 weeks. The predicted exposure of nivolumab after a 30-minute infusion is comparable to that observed with a 60-minute infusion. Steady-state concentrations of nivolumab were reached by 12 weeks when administered at 3 mg/kg every 2 weeks, and systemic accumulation was 3.7-fold.

Distribution

The geometric mean volume of distribution at steady state (Vss) and coefficient of variation (CV%) is 6.8 L (27.3%).

Elimination

Nivolumab clearance (CL) decreases over time, with a mean maximal reduction from baseline values (CV%) of 24.5% (47.6%) resulting in a geometric mean steady-state clearance (CLss) (CV%) of 8.2 mL/h (53.9%) in patients with metastatic tumors; the decrease in CLss is not considered clinically relevant. Nivolumab clearance does not decrease over time in patients with completely resected melanoma, as the geometric mean population clearance is 24% lower in this patient population compared with patients with metastatic melanoma at steady state.

The geometric mean elimination half-life (t1/2) is 25 days (77.5%).

Specific Populations

The following factors had no clinically important effect on the clearance of nivolumab: age (29 to 87 years), weight (35 to 160 kg), sex, race, baseline LDH, PD-L1 expression, solid tumor type, tumor size, renal impairment (eGFR ≥ 15 mL/min/1.73 m2), and mild (total bilirubin [TB] less than or equal to the ULN and AST greater than ULN or TB greater than 1 to 1.5 times ULN and any AST) or moderate hepatic impairment (TB greater than 1.5 to 3 times ULN and any AST). Nivolumab has not been studied in patients with severe hepatic impairment (TB greater than 3 times ULN and any AST).

Drug Interaction Studies

When Opdivo 3 mg/kg every 3 weeks was administered in combination with ipilimumab 1 mg/kg every 3 weeks, the CL of nivolumab and ipilimumab were unchanged compared to nivolumab or ipilimumab administered alone.

When Opdivo 1 mg/kg every 3 weeks was administered in combination with ipilimumab 3 mg/kg every 3 weeks, the CL of nivolumab was increased by 29% compared to Opdivo administered alone and the CL of ipilimumab was unchanged compared to ipilimumab administered alone.

When Opdivo 3 mg/kg every 2 weeks was administered in combination with ipilimumab 1 mg/kg every 6 weeks, the CL of nivolumab was unchanged compared to Opdivo administered alone and the CL of ipilimumab was increased by 30% compared to ipilimumab administered alone.

When Opdivo 360 mg every 3 weeks was administered in combination with ipilimumab 1 mg/kg every 6 weeks and chemotherapy, the CL of nivolumab was unchanged compared to Opdivo administered alone and the CL of ipilimumab increased by 22% compared to ipilimumab administered alone.

When administered in combination, the CL of nivolumab increased by 20% in the presence of anti-nivolumab antibodies.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been performed to assess the potential of nivolumab for carcinogenicity or genotoxicity. Fertility studies have not been performed with nivolumab. In 1-month and 3-month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs; however, most animals in these studies were not sexually mature.

Animal Toxicology and/or Pharmacology

In animal models, inhibition of PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. M. tuberculosis–infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-1 knockout mice have also shown decreased survival following infection with lymphocytic choriomeningitis virus.

Clinical Studies

Unresectable or Metastatic Melanoma

Previously Treated Metastatic Melanoma

CHECKMATE-037 (NCT01721746) was a multicenter, open-label trial that randomized (2:1) patients with unresectable or metastatic melanoma to receive Opdivo 3 mg/kg intravenously every 2 weeks or investigator’s choice of chemotherapy, either single-agent dacarbazine 1000 mg/m2 every 3 weeks or the combination of carboplatin AUC 6 intravenously every 3 weeks and paclitaxel 175 mg/m2 intravenously every 3 weeks. Patients were required to have progression of disease on or following ipilimumab treatment and, if BRAF V600 mutation positive, a BRAF inhibitor. The trial excluded patients with autoimmune disease, medical conditions requiring systemic immunosuppression, ocular melanoma, active brain metastasis, or a history of Grade 4 ipilimumab-related adverse reactions (except for endocrinopathies) or Grade 3 ipilimumab-related adverse reactions that had not resolved or were inadequately controlled within 12 weeks of the initiating event. Tumor assessments were conducted 9 weeks after randomization then every 6 weeks for the first year, and every 12 weeks thereafter.

Efficacy was evaluated in a single-arm, non-comparative, planned interim analysis of the first 120 patients who received Opdivo in CHECKMATE-037 and in whom the minimum duration of follow-up was 6 months. The major efficacy outcome measures in this population were confirmed overall response rate (ORR) as measured by blinded independent central review using Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and duration of response.

Among the 120 patients treated with Opdivo, the median age was 58 years (range: 25 to 88), 65% of patients were male, 98% were White, and the ECOG performance score was 0 (58%) or 1 (42%). Disease characteristics were M1c disease (76%), BRAF V600 mutation positive (22%), elevated LDH (56%), history of brain metastases (18%), and two or more prior systemic therapies for metastatic disease (68%).

The ORR was 32% (95% confidence interval [CI]: 23, 41), consisting of 4 complete responses and 34 partial responses in Opdivo-treated patients. Of 38 patients with responses, 87% had ongoing responses with durations ranging from 2.6+ to 10+ months, which included 13 patients with ongoing responses of 6 months or longer.

There were responses in patients with and without BRAF V600 mutation-positive melanoma. A total of 405 patients were randomized and the median duration of OS was 15.7 months (95% CI: 12.9, 19.9) in Opdivo-treated patients compared to 14.4 months (95% CI: 11.7, 18.2) (HR 0.95; 95.54% CI: 0.73, 1.24) in patients assigned to investigator’s choice of treatment. Figure 1 summarizes the OS results.

Figure 1: Overall Survival - CHECKMATE-037*

* The primary OS analysis was not adjusted to account for subsequent therapies, with 54 (40.6%) patients in the chemotherapy arm subsequently receiving an anti-PD1 treatment. OS may be confounded by dropout, imbalance of subsequent therapies, and differences in baseline factors.

Previously Untreated Metastatic Melanoma

CHECKMATE-066

CHECKMATE-066 (NCT01721772) was a multicenter, double-blind, randomized (1:1) trial in 418 patients with BRAF V600 wild-type unresectable or metastatic melanoma. Patients were randomized to receive either Opdivo 3 mg/kg by intravenous infusion every 2 weeks or dacarbazine 1000 mg/m2 intravenously every 3 weeks until disease progression or unacceptable toxicity. Randomization was stratified by PD-L1 status (≥5% of tumor cell membrane staining by immunohistochemistry vs. <5% or indeterminate result) and M stage (M0/M1a/M1b versus M1c). Key eligibility criteria included histologically confirmed, unresectable or metastatic, cutaneous, mucosal, or acral melanoma; no prior therapy for metastatic disease; completion of prior adjuvant or neoadjuvant therapy at least 6 weeks prior to randomization; ECOG performance status 0 or 1; absence of autoimmune disease; and absence of active brain or leptomeningeal metastases. The trial excluded patients with ocular melanoma. Tumor assessments were conducted 9 weeks after randomization then every 6 weeks for the first year and then every 12 weeks thereafter. The major efficacy outcome measure was overall survival (OS). Additional outcome measures included investigator-assessed progression-free survival (PFS) and ORR per RECIST v1.1.

The trial population characteristics were: median age was 65 years (range: 18 to 87), 59% were male, and 99.5% were White. Disease characteristics were M1c stage disease (61%), cutaneous melanoma (74%), mucosal melanoma (11%), elevated LDH level (37%), PD-L1 ≥5% tumor cell membrane expression (35%), and history of brain metastasis (4%). More patients in the Opdivo arm had an ECOG performance status of 0 (71% vs. 58%).

CHECKMATE-066 demonstrated a statistically significant improvement in OS for the Opdivo arm compared with the dacarbazine arm in an interim analysis based on 47% of the total planned events for OS. At the time of analysis, 88% (63/72) of Opdivo-treated patients had ongoing responses, which included 43 patients with ongoing response of 6 months or longer. Efficacy results are shown in Table 43 and Figure 2.

Table 43: Efficacy Results - CHECKMATE-066
a Not Reached
b Based on a stratified proportional hazards model.
c Based on stratified log-rank test.
d p-value is compared with the allocated alpha of 0.0021 for this interim analysis.

Opdivo
(n=210)

Dacarbazine
(n=208)

Overall Survival

Deaths (%)

50 (24)

96 (46)

Median (months) (95% CI)

NRa

10.8 (9.3, 12.1)

Hazard ratio (95% CI)b

0.42 (0.30, 0.60)

p-valuec,d

<0.0001

Progression-free Survival

Disease progression or death (%)

108 (51)

163 (78)

Median (months) (95% CI)

5.1 (3.5, 10.8)

2.2 (2.1, 2.4)

Hazard ratio (95% CI)b

0.43 (0.34, 0.56)

p-valuec,d

<0.0001

Overall Response Rate

34%

9%

(95% CI)

(28, 41)

(5, 13)

Complete response rate

4%

1%

Partial response rate

30%

8%

Figure 2: Overall Survival - CHECKMATE-066

CHECKMATE-067

CHECKMATE-067 (NCT01844505) was a multicenter, randomized (1:1:1), double-blind trial in 945 patients with previously untreated, unresectable or metastatic melanoma to one of the following arms: Opdivo and ipilimumab, Opdivo, or ipilimumab. Patients were required to have completed adjuvant or neoadjuvant treatment at least 6 weeks prior to randomization and have no prior treatment with anti-CTLA-4 antibody and no evidence of active brain metastasis, ocular melanoma, autoimmune disease, or medical conditions requiring systemic immunosuppression.

Patients were randomized to receive:

Opdivo 1 mg/kg with ipilimumab 3 mg/kg intravenously every 3 weeks for 4 doses, followed by Opdivo as a single agent at a dose of 3 mg/kg by intravenous infusion every 2 weeks (Opdivo and ipilimumab arm),
Opdivo 3 mg/kg by intravenous infusion every 2 weeks (Opdivo arm), or
Ipilimumab 3 mg/kg intravenously every 3 weeks for 4 doses, followed by placebo every 2 weeks (ipilimumab arm).

Randomization was stratified by PD-L1 expression (≥5% vs. <5% tumor cell membrane expression) as determined by a clinical trial assay, BRAF V600 mutation status, and M stage per the AJCC staging system (M0, M1a, M1b vs. M1c). Tumor assessments were conducted 12 weeks after randomization then every 6 weeks for the first year, and every 12 weeks thereafter. The major efficacy outcome measures were investigator-assessed PFS per RECIST v1.1 and OS. Additional efficacy outcome measures were confirmed ORR and duration of response.

The trial population characteristics were: median age 61 years (range: 18 to 90); 65% male; 97% White; ECOG performance score 0 (73%) or 1 (27%). Disease characteristics were: AJCC Stage IV disease (93%); M1c disease (58%); elevated LDH (36%); history of brain metastases (4%); BRAF V600 mutation-positive melanoma (32%); PD-L1 ≥5% tumor cell membrane expression as determined by the clinical trials assay (46%); and prior adjuvant therapy (22%).

CHECKMATE-067 demonstrated statistically significant improvements in OS and PFS for patients randomized to either Opdivo-containing arm as compared with the ipilimumab arm. The trial was not designed to assess whether adding ipilimumab to Opdivo improves PFS or OS compared to Opdivo as a single agent. Efficacy results are shown in Table 44 and Figure 3.

Table 44: Efficacy Results - CHECKMATE-067
a OS results are based on final OS analysis with 28 months of minimum follow-up; PFS (co-primary endpoint) and ORR (secondary endpoint) results were based on primary analysis with 9 months of minimum follow-up.
b Based on a stratified proportional hazards model.
c Based on stratified log-rank test.
d If the maximum of the two OS p-values is less than 0.04 (a significance level assigned by the Hochberg procedure), then both p-values are considered significant.
e p-value is compared with .005 of the allocated alpha for final PFS treatment comparisons.
f Based on the stratified Cochran-Mantel-Haenszel test.
+ Censored observation

Opdivo and Ipilimumab
(n=314)

Opdivo
(n=316)

Ipilimumab
(n=315)

Overall Survivala

Deaths (%)

128 (41)

142 (45)

197 (63)

Hazard ratiob (vs. ipilimumab)
(95% CI)

0.55
(0.44, 0.69)

0.63
(0.50, 0.78)

p-valuec,d

<0.0001

<0.0001

Progression-free Survivala

Disease progression or death

151 (48%)

174 (55%)

234 (74%)

Median (months)
(95% CI)

11.5
(8.9, 16.7)

6.9
(4.3, 9.5)

2.9
(2.8, 3.4)

Hazard ratiob (vs. ipilimumab)
(95% CI)

0.42
(0.34, 0.51)

0.57
(0.47, 0.69)

p-valuec,e

<0.0001

<0.0001

Confirmed Overall Response Ratea

50%

40%

14%

(95% CI)

(44, 55)

(34, 46)

(10, 18)

p-valuef

<0.0001

<0.0001

Complete response

8.9%

8.5%

1.9%

Partial response

41%

31%

12%

Duration of Response

Proportion ≥6 months in duration

76%

74%

63%

Range (months)

1.2+ to 15.8+

1.3+ to 14.6+

1.0+ to 13.8+

Figure 3: Overall Survival - CHECKMATE-067

Based on a minimum follow-up of 48 months, the median OS was not reached (95% CI: 38.2, NR) in the Opdivo and ipilimumab arm. The median OS was 36.9 months (95% CI: 28.3, NR) in the Opdivo arm and 19.9 months (95% CI: 16.9, 24.6) in the ipilimumab arm.

Based on a minimum follow-up of 28 months, the median PFS was 11.7 months (95% CI: 8.9, 21.9) in the Opdivo and ipilimumab arm, 6.9 months (95% CI: 4.3, 9.5) in the Opdivo arm, and 2.9 months (95% CI: 2.8, 3.2) in the ipilimumab arm. Based on a minimum follow-up of 28 months, the proportion of responses lasting ≥ 24 months was 55% in the Opdivo and ipilimumab arm, 56% in the Opdivo arm, and 39% in the ipilimumab arm.

Adjuvant Treatment of Melanoma

CHECKMATE-238 (NCT02388906) was a randomized, double-blind trial in 906 patients with completely resected Stage IIIB/C or Stage IV melanoma. Patients were randomized (1:1) to receive Opdivo 3 mg/kg by intravenous infusion every 2 weeks or ipilimumab 10 mg/kg intravenously every 3 weeks for 4 doses then every 12 weeks beginning at Week 24 for up to 1 year. Enrollment required complete resection of melanoma with margins negative for disease within 12 weeks prior to randomization. The trial excluded patients with a history of ocular/uveal melanoma, autoimmune disease, and any condition requiring systemic treatment with either corticosteroids (≥10 mg daily prednisone or equivalent) or other immunosuppressive medications, as well as patients with prior therapy for melanoma except surgery, adjuvant radiotherapy after neurosurgical resection for lesions of the central nervous system, and prior adjuvant interferon completed ≥6 months prior to randomization. Randomization was stratified by PD-L1 status (positive [based on 5% level] vs. negative/indeterminate) and AJCC stage (Stage IIIB/C vs. Stage IV M1a-M1b vs. Stage IV M1c). The major efficacy outcome measure was recurrence-free survival (RFS) defined as the time between the date of randomization and the date of first recurrence (local, regional, or distant metastasis), new primary melanoma, or death, from any cause, whichever occurs first and as assessed by the investigator. Patients underwent imaging for tumor recurrence every 12 weeks for the first 2 years then every 6 months thereafter.

The trial population characteristics were: median age was 55 years (range: 18 to 86), 58% were male, 95% were White, and 90% had an ECOG performance status of 0. Disease characteristics were AJCC Stage IIIB (34%), Stage IIIC (47%), Stage IV (19%), M1a-b (14%), BRAF V600 mutation positive (42%), BRAF wild-type (45%), elevated LDH (8%), PD-L1 ≥5% tumor cell membrane expression determined by clinical trial assay (34%), macroscopic lymph nodes (48%), and tumor ulceration (32%).

CHECKMATE-238 demonstrated a statistically significant improvement in RFS for patients randomized to the Opdivo arm compared with the ipilimumab 10 mg/kg arm. Efficacy results are shown in Table 45 and Figure 4.

Table 45: Efficacy Results - CHECKMATE-238
Opdivo
N=453
Ipilimumab 10 mg/kg
N=453
Recurrence-free Survival
a Not reached.
b Based on a stratified proportional hazards model.
c Based on a stratified log-rank test.
d p-value is compared with 0.0244 of the allocated alpha for this analysis.
e At the time of the final OS analysis, fewer overall survival events were observed than originally anticipated (approximately 302).

Number of events, n (%)

154 (34%)

206 (45%)

Median (months)
(95% CI)

NRa

NRa
(16.56, NRa)

Hazard ratiob
(95% CI)
p-valuec,d

0.65
(0.53, 0.80)
p<0.0001

Overall Survival

Number of events, n (%)e

100 (22%)

111 (25%)

Median (months)
(95% CI)

NRa

NRa

Hazard ratiob
(95% CI)
p-value

0.87
(0.67, 1.14)
0.3148

Figure 4: Recurrence-free Survival - CHECKMATE-238

Metastatic Non-Small Cell Lung Cancer

First-line Treatment of Metastatic Non-Small Cell Lung Cancer (NSCLC) Expressing PD-L1 (≥1%): In Combination with Ipilimumab

CHECKMATE-227 (NCT02477826) was a randomized, open-label, multi-part trial in patients with metastatic or recurrent NSCLC. The study included patients (18 years of age or older) with histologically confirmed Stage IV or recurrent NSCLC (per the 7th International Association for the Study of Lung Cancer [ASLC] classification), ECOG performance status 0 or 1, and no prior anticancer therapy. Patients were enrolled regardless of their tumor PD-L1 status. Patients with known EGFR mutations or ALK translocations sensitive to available targeted inhibitor therapy, untreated brain metastases, carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the study. Patients with treated brain metastases were eligible if neurologically returned to baseline at least 2 weeks prior to enrolment, and either off corticosteroids, or on a stable or decreasing dose of <10 mg daily prednisone equivalents.

Primary efficacy results were based on Part 1a of the study, which was limited to patients with PD-L1 tumor expression ≥1%. Tumor specimens were evaluated prospectively using the PD-L1 IHC 28-8 pharmDx assay at a central laboratory. Randomization was stratified by tumor histology (non-squamous versus squamous). The evaluation of efficacy relied on the comparison between:

Opdivo 3 mg/kg administered intravenously over 30 minutes every 2 weeks in combination with ipilimumab 1 mg/kg administered intravenously over 30 minutes every 6 weeks; or
Platinum-doublet chemotherapy

Chemotherapy regimens consisted of pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) or pemetrexed (500 mg/m2) and carboplatin (AUC 5 or 6) for non-squamous NSCLC or gemcitabine (1000 or 1250 mg/m2) and cisplatin (75 mg/m2) or gemcitabine (1000 mg/m2) and carboplatin (AUC 5) (gemcitabine was administered on Days 1 and 8 of each cycle) for squamous NSCLC.

Study treatment continued until disease progression, unacceptable toxicity, or for up to 24 months. Treatment continued beyond disease progression if a patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Patients who discontinued combination therapy because of an adverse event attributed to ipilimumab were permitted to continue Opdivo as a single agent. Tumor assessments were performed every 6 weeks from the first dose of study treatment for the first 12 months, then every 12 weeks until disease progression or study treatment was discontinued. The primary efficacy outcome measure was OS. Additional efficacy outcome measures included PFS, ORR, and duration of response as assessed by BICR.

In Part 1a, a total of 793 patients were randomized to receive either Opdivo in combination with ipilimumab (n=396) or platinum-doublet chemotherapy (n=397). The median age was 64 years (range: 26 to 87) with 49% of patients ≥65 years and 10% of patients ≥75 years, 76% White, and 65% male. Baseline ECOG performance status was 0 (34%) or 1 (65%), 50% with PD-L1 ≥50%, 29% with squamous and 71% with non-squamous histology, 10% had brain metastases, and 85% were former/current smokers.

The study demonstrated a statistically significant improvement in OS for PD-L1 ≥1% patients randomized to the Opdivo and ipilimumab arm compared with the platinum-doublet chemotherapy arm. The OS results are presented in Table 46 and Figure 5.

Table 46: Efficacy Results (PD-L1 ≥1%) - CHECKMATE-227 Part 1a
a Kaplan-Meier estimate.
b Based on a stratified Cox proportional hazard model.

Opdivo and Ipilimumab
(n=396)

Platinum-Doublet Chemotherapy
(n=397)

Overall Survival

Events (%)

258 (65%)

298 (75%)

Median (months)a

(95% CI)

17.1

(15, 20.1)

14.9

(12.7, 16.7)

Hazard ratio (95% CI)b

0.79 (0.67, 0.94)

Stratified log-rank p-value

0.0066

Figure 5: Overall Survival (PD-L1 ≥1%) - CHECKMATE-227

BICR-assessed PFS showed a HR of 0.82 (95% CI: 0.69, 0.97), with a median PFS of 5.1 months (95% CI: 4.1, 6.3) in the Opdivo and ipilimumab arm and 5.6 months (95% CI: 4.6, 5.8) in the platinum-doublet chemotherapy arm. The BICR-assessed confirmed ORR was 36% (95% CI: 31, 41) in the Opdivo and ipilimumab arm and 30% (95% CI: 26, 35) in the platinum-doublet chemotherapy arm. Median duration of response observed in the Opdivo and ipilimumab arm was 23.2 months and 6.2 months in the platinum-doublet chemotherapy arm.

First-line Treatment of Metastatic or Recurrent NSCLC: In Combination with Ipilimumab and Platinum-Doublet Chemotherapy

CHECKMATE-9LA (NCT03215706) was a randomized, open-label trial in patients with metastatic or recurrent NSCLC. The trial included patients (18 years of age or older) with histologically confirmed Stage IV or recurrent NSCLC (per the 7th International Association for the Study of Lung Cancer classification [IASLC]), ECOG performance status 0 or 1, and no prior anticancer therapy (including EGFR and ALK inhibitors) for metastatic disease. Patients were enrolled regardless of their tumor PD-L1 status. Patients with known EGFR mutations or ALK translocations sensitive to available targeted inhibitor therapy, untreated brain metastases, carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the study. Patients with stable brain metastases were eligible for enrollment.

Patients were randomized 1:1 to receive either:

Opdivo 360 mg administered intravenously over 30 minutes every 3 weeks, ipilimumab 1 mg/kg administered intravenously over 30 minutes every 6 weeks, and platinum-doublet chemotherapy administered intravenously every 3 weeks for 2 cycles, or
platinum-doublet chemotherapy administered every 3 weeks for 4 cycles.

Platinum-doublet chemotherapy consisted of either carboplatin (AUC 5 or 6) and pemetrexed 500 mg/m2, or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 for non-squamous NSCLC; or carboplatin (AUC 6) and paclitaxel 200 mg/m2 for squamous NSCLC. Patients with non-squamous NSCLC in the control arm could receive optional pemetrexed maintenance therapy. Stratification factors for randomization were tumor PD-L1 expression level (≥1% versus <1% or non-quantifiable), histology (squamous versus non-squamous), and sex (male versus female). Study treatment continued until disease progression, unacceptable toxicity, or for up to 2 years. Treatment could continue beyond disease progression if a patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Patients who discontinued combination therapy because of an adverse reaction attributed to ipilimumab were permitted to continue Opdivo as a single agent as part of the study. Tumor assessments were performed every 6 weeks from the first dose of study treatment for the first 12 months, then every 12 weeks until disease progression or study treatment was discontinued. The primary efficacy outcome measure was OS. Additional efficacy outcome measures included PFS, ORR, and duration of response as assessed by BICR.

A total of 719 patients were randomized to receive either Opdivo in combination with ipilimumab and platinum-doublet chemotherapy (n=361) or platinum-doublet chemotherapy (n=358). The median age was 65 years (range: 26 to 86) with 51% of patients ≥65 years and 10% of patients ≥75 years. The majority of patients were White (89%) and male (70%). Baseline ECOG performance status was 0 (31%) or 1 (68%), 57% had tumors with PD-L1 expression ≥1% and 37% had tumors with PD-L1 expression that was <1%, 32% had tumors with squamous histology and 68% had tumors with non-squamous histology, 17% had CNS metastases, and 86% were former or current smokers.

The study demonstrated a statistically significant benefit in OS, PFS, and ORR. Efficacy results from the prespecified interim analysis when 351 events were observed (87% of the planned number of events for final analysis) are presented in Table 47.

Table 47: Efficacy Results - CHECKMATE-9LA
a Based on a stratified Cox proportional hazard model.
b p-value is compared with the allocated alpha of 0.033 for this interim analysis.
c p-value is compared with the allocated alpha of 0.0252 for this interim analysis.
d Kaplan-Meier estimate.
e Confidence interval based on the Clopper and Pearson Method.
f p-value is compared with the allocated alpha of 0.025 for this interim analysis.

Opdivo and Ipilimumab and Platinum-Doublet Chemotherapy
(n=361)

Platinum-Doublet Chemotherapy
(n=358)

Overall Survival

Events (%)

156 (43.2)

195 (54.5)

Median (months)

(95% CI)

14.1
(13.2, 16.2)

10.7
(9.5, 12.5)

Hazard ratio (96.71% CI)a

0.69 (0.55, 0.87)

Stratified log-rank p-valueb

0.0006

Progression-free Survival per BICR

Events (%)

232 (64.3)

249 (69.6)

Hazard ratio (97.48% CI)a

0.70 (0.57, 0.86)

Stratified log-rank p-valuec

0.0001

Median (months)d

(95% CI)

6.8
(5.6, 7.7)

5.0
(4.3, 5.6)

Overall Response Rate per BICR (%)

38

25

(95% CI)e

(33, 43)

(21, 30)

Stratified CMH test p-valuef

0.0003

Duration of Response per BICR

Median (months)

(95% CI)d

10.0
(8.2, 13.0)

5.1
(4.3, 7.0)

With an additional 4.6 months of follow-up, the hazard ratio for overall survival was 0.66 (95% CI: 0.55, 0.80) and median survival was 15.6 months (95% CI: 13.9, 20.0) and 10.9 months (95% CI: 9.5, 12.5) for patients receiving Opdivo and ipilimumab and platinum-doublet chemotherapy or platinum-doublet chemotherapy, respectively (Figure 6).

Figure 6: Overall Survival - CHECKMATE-9LA

Second-line Treatment of Metastatic Squamous NSCLC

CHECKMATE-017 (NCT01642004) was a randomized (1:1), open-label trial in 272 patients with metastatic squamous NSCLC who had experienced disease progression during or after one prior platinum doublet-based chemotherapy regimen. Patients received Opdivo 3 mg/kg by intravenous infusion every 2 weeks (n=135) or docetaxel 75 mg/m2 intravenously every 3 weeks (n=137). Randomization was stratified by prior paclitaxel vs. other prior treatment and region (US/Canada vs. Europe vs. Rest of World). This trial included patients regardless of their PD-L1 status. The trial excluded patients with autoimmune disease, medical conditions requiring systemic immunosuppression, symptomatic interstitial lung disease, or untreated brain metastasis. Patients with treated brain metastases were eligible if neurologically returned to baseline at least 2 weeks prior to enrollment, and either off corticosteroids, or on a stable or decreasing dose of <10 mg daily prednisone equivalents. The first tumor assessments were conducted 9 weeks after randomization and continued every 6 weeks thereafter. The major efficacy outcome measure was OS. Additional efficacy outcome measures were investigator-assessed ORR and PFS.

The trial population characteristics were: median age was 63 years (range: 39 to 85) with 44% ≥65 years of age and 11% ≥75 years of age. The majority of patients were White (93%) and male (76%); the majority of patients were enrolled in Europe (57%) with the remainder in US/Canada (32%) and the rest of the world (11%). Baseline ECOG performance status was 0 (24%) or 1 (76%) and 92% were former/current smokers. Baseline disease characteristics of the population as reported by investigators were Stage IIIb (19%), Stage IV (80%), and brain metastases (6%). All patients received prior therapy with a platinum-doublet regimen and 99% of patients had tumors of squamous-cell histology.

The trial demonstrated a statistically significant improvement in OS for patients randomized to Opdivo as compared with docetaxel at the prespecified interim analysis when 199 events were observed (86% of the planned number of events for final analysis). Efficacy results are shown in Table 48 and Figure 7.

Table 48: Efficacy Results - CHECKMATE-017
a Based on a stratified proportional hazards model.
b Based on stratified log-rank test.
c p-value is compared with .0315 of the allocated alpha for this interim analysis.
d Based on the stratified Cochran-Mantel-Haenszel test.
e Not Reached

Opdivo
(n=135)

Docetaxel
(n=137)

Overall Survival

Deaths (%)

86 (64%)

113 (82%)

Median (months)
(95% CI)

9.2
(7.3, 13.3)

6.0
(5.1, 7.3)

Hazard ratio (95% CI)a

0.59 (0.44, 0.79)

p-valueb,c

0.0002

Overall Response Rate

27 (20%)

12 (9%)

(95% CI)

(14, 28)

(5, 15)

p-valued

0.0083

Complete response

1 (0.7%)

0

Median duration of response (months)
(95% CI)

NRe
(9.8, NRe)

8.4
(3.6, 10.8)

Progression-free Survival

Disease progression or death (%)

105 (78%)

122 (89%)

Median (months)

3.5

2.8

Hazard ratio (95% CI)a

0.62 (0.47, 0.81)

p-valueb

0.0004

Figure 7: Overall Survival - CHECKMATE-017

Archival tumor specimens were retrospectively evaluated for PD-L1 expression. Across the trial population, 17% of 272 patients had non-quantifiable results. Among the 225 patients with quantifiable results, 47% had PD-L1 negative squamous NSCLC, defined as <1% of tumor cells expressing PD-L1 and 53% had PD-L1 positive squamous NSCLC defined as ≥1% of tumor cells expressing PD-L1. In pre-specified exploratory subgroup analyses, the hazard ratios for survival were 0.58 (95% CI: 0.37, 0.92) in the PD-L1 negative subgroup and 0.69 (95% CI: 0.45, 1.05) in the PD-L1 positive subgroup.

Second-line Treatment of Metastatic Non-Squamous NSCLC

CHECKMATE-057 (NCT01673867) was a randomized (1:1), open-label trial in 582 patients with metastatic non-squamous NSCLC who had experienced disease progression during or after one prior platinum doublet-based chemotherapy regimen. Appropriate prior targeted therapy in patients with known sensitizing EGFR mutation or ALK translocation was allowed. Patients received Opdivo 3 mg/kg by intravenous infusion every 2 weeks (n=292) or docetaxel 75 mg/m2 intravenously every 3 weeks (n=290). Randomization was stratified by prior maintenance therapy (yes vs. no) and number of prior therapies (1 vs. 2). The trial excluded patients with autoimmune disease, medical conditions requiring systemic immunosuppression, symptomatic interstitial lung disease, or untreated brain metastasis. Patients with treated brain metastases were eligible if neurologically stable. The first tumor assessments were conducted 9 weeks after randomization and continued every 6 weeks thereafter. The major efficacy outcome measure was OS. Additional efficacy outcome measures were investigator-assessed ORR and PFS. In addition, prespecified analyses were conducted in subgroups defined by PD-L1 expression.

The trial population characteristics: median age was 62 years (range: 21 to 85) with 42% of patients ≥65 years and 7% of patients ≥75 years. The majority of patients were White (92%) and male (55%); the majority of patients were enrolled in Europe (46%) followed by the US/Canada (37%) and the rest of the world (17%). Baseline ECOG performance status was 0 (31%) or 1 (69%), 79% were former/current smokers, 3.6% had NSCLC with ALK rearrangement, 14% had NSCLC with EGFR mutation, and 12% had previously treated brain metastases. Prior therapy included platinum-doublet regimen (100%) and 40% received maintenance therapy as part of the first-line regimen. Histologic subtypes included adenocarcinoma (93%), large cell (2.4%), and bronchoalveolar (0.9%).

CHECKMATE-057 demonstrated a statistically significant improvement in OS for patients randomized to Opdivo as compared with docetaxel at the prespecified interim analysis when 413 events were observed (93% of the planned number of events for final analysis). Efficacy results are shown in Table 49 and Figure 8.

Table 49: Efficacy Results - CHECKMATE-057
a Based on a stratified proportional hazards model.
b Based on stratified log-rank test.
c p-value is compared with .0408 of the allocated alpha for this interim analysis.
d Based on the stratified Cochran-Mantel-Haenszel test.
e Not Reached.

Opdivo
(n=292)

Docetaxel
(n=290)

Overall Survival

Deaths (%)

190 (65%)

223 (77%)

Median (months)
(95% CI)

12.2
(9.7, 15.0)

9.4
(8.0, 10.7)

Hazard ratio (95% CI)a

0.73 (0.60, 0.89)

p-valueb,c

0.0015

Overall Response Rate

56 (19%)

36 (12%)

(95% CI)

(15, 24)

(9, 17)

p-valued

0.02

Complete response

4 (1.4%)

1 (0.3%)

Median duration of response (months)
(95% CI)

17
(8.4, NRe)

6
(4.4, 7.0)

Progression-free Survival

Disease progression or death (%)

234 (80%)

245 (84%)

Median (months)

2.3

4.2

Hazard ratio (95% CI)a

0.92 (0.77, 1.11)

p-valueb

0.39

Figure 8: Overall Survival - CHECKMATE-057

Archival tumor specimens were evaluated for PD-L1 expression following completion of the trial. Across the trial population, 22% of 582 patients had non-quantifiable results. Of the remaining 455 patients, the proportion of patients in retrospectively determined subgroups based on PD-L1 testing using the PD-L1 IHC 28-8 pharmDx assay were: 46% PD-L1 negative, defined as <1% of tumor cells expressing PD-L1 and 54% had PD-L1 expression, defined as ≥1% of tumor cells expressing PD-L1. Among the 246 patients with tumors expressing PD-L1, 26% had ≥1% but <5% tumor cells with positive staining, 7% had ≥5% but <10% tumor cells with positive staining, and 67% had ≥10% tumor cells with positive staining. Figures 9 and 10 summarize the results of prespecified analyses of OS and PFS in subgroups determined by percentage of tumor cells expressing PD-L1.

Figure 9: Forest Plot: OS Based on PD-L1 Expression - CHECKMATE-057

Figure 10: Forest Plot: PFS Based on PD-L1 Expression - CHECKMATE-057

Malignant Pleural Mesothelioma

CHECKMATE-743 (NCT02899299) was a randomized, open-label trial in patients with unresectable malignant pleural mesothelioma. The trial included patients with histologically confirmed and previously untreated malignant pleural mesothelioma with no palliative radiotherapy within 14 days of initiation of therapy. Patients with interstitial lung disease, active autoimmune disease, medical conditions requiring systemic immunosuppression, or active brain metastasis were excluded from the trial.

Patients were randomized 1:1 to receive either:

Opdivo 3 mg/kg over 30 minutes by intravenous infusion every 2 weeks and ipilimumab 1 mg/kg over 30 minutes by intravenous infusion every 6 weeks for up to 2 years, or
cisplatin 75 mg/m2 and pemetrexed 500 mg/m2, or carboplatin 5 AUC and pemetrexed 500 mg/m2 administered every 3 weeks for 6 cycles.

Stratification factors for randomization were tumor histology (epithelioid vs. sarcomatoid or mixed histology subtypes) and sex (male vs. female). Study treatment continued for up to 2 years, or until disease progression or unacceptable toxicity. Patients who discontinued combination therapy because of an adverse reaction attributed to ipilimumab were permitted to continue Opdivo as a single agent. Treatment could continue beyond disease progression if a patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Tumor assessments were performed every 6 weeks from the first dose of study treatment for the first 12 months, then every 12 weeks until disease progression or study treatment was discontinued. The primary efficacy outcome measure was OS. Additional efficacy outcome measures included PFS, ORR, and duration of response as assessed by BICR utilizing modified RECIST criteria.

A total of 605 patients were randomized to receive either Opdivo in combination with ipilimumab (n=303) or chemotherapy (n=302). The median age was 69 years (range: 25 to 89), with 72% of patients ≥65 years and 26% ≥75 years; 85% were White, 11% were Asian, and 77% were male. Baseline ECOG performance status was 0 (40%) or 1 (60%), 35% had Stage III and 51% had Stage IV disease, 75% had epithelioid and 25% had non-epithelioid histology, 75% had tumors with PD-L1 expression ≥1%, and 22% had tumors with PD-L1 expression <1%.

The trial demonstrated a statistically significant improvement in OS for patients randomized to Opdivo in combination with ipilimumab compared to chemotherapy. Efficacy results from the prespecified interim analysis are presented in Table 50 and Figure 11.

Table 50: Efficacy Results - CHECKMATE-743
a At the time of the interim analysis, 419 deaths (89% of the deaths needed for the final analysis) had occurred.
b Kaplan-Meier estimate.
c Stratified Cox proportional hazard model.
d p-value is compared with the allocated alpha of 0.0345 for this interim analysis.
e Based on confirmed response by BICR.

Opdivo and Ipilimumab
(n=303)

Chemotherapy
(n=302)

Overall Survivala

Events (%)

200 (66)

219 (73)

Median (months)b

(95% CI)

18.1
(16.8, 21.5)

14.1
(12.5, 16.2)

Hazard ratio (95% CI)c

0.74 (0.61, 0.89)

Stratified log-rank p-valued

0.002

Progression-free Survival

Events (%)

218 (72)

209 (69)

Hazard ratio (95% CI)c

1.0 (0.82, 1.21)

Median (months)b

(95% CI)

6.8
(5.6, 7.4)

7.2
(6.9, 8.1)

Overall Response Ratee

40%

43%

(95% CI)

(34, 45)

(37, 49)

Duration of Response

Median (months)b
(95% CI)

11.0
(8.1, 16.5)

6.7
(5.3, 7.1)

Figure 11: Overall Survival - CHECKMATE-743

In a prespecified exploratory analysis based on histology, in the subgroup of patients with epithelioid histology, the hazard ratio (HR) for OS was 0.85 (95% CI: 0.68, 1.06), with median OS of 18.7 months in the Opdivo and ipilimumab arm and 16.2 months in the chemotherapy arm. In the subgroup of patients with non-epithelioid histology, the HR for OS was 0.46 (95% CI: 0.31, 0.70), with median OS of 16.9 months in the Opdivo and ipilimumab arm and 8.8 months in the chemotherapy arm.

Advanced Renal Cell Carcinoma

First-line Renal Cell Carcinoma

CHECKMATE-214

CHECKMATE-214 (NCT02231749) was a randomized (1:1), open-label trial in patients with previously untreated advanced RCC. Patients were included regardless of their PD-L1 status. CHECKMATE-214 excluded patients with any history of or concurrent brain metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression. Patients were stratified by International Metastatic RCC Database Consortium (IMDC) prognostic score and region.

Efficacy was evaluated in intermediate/poor risk patients with at least 1 or more of 6 prognostic risk factors as per the IMDC criteria (less than one year from time of initial renal cell carcinoma diagnosis to randomization, Karnofsky performance status <80%, hemoglobin less than the lower limit of normal, corrected calcium of >10 mg/dL, platelet count greater than the upper limit of normal, and absolute neutrophil count greater than the upper limit of normal).

Patients were randomized to Opdivo 3 mg/kg and ipilimumab 1 mg/kg intravenously every 3 weeks for 4 doses followed by Opdivo 3 mg/kg intravenously every two weeks (n=425), or sunitinib 50 mg orally daily for the first 4 weeks of a 6-week cycle (n=422). Treatment continued until disease progression or unacceptable toxicity.

The trial population characteristics were: median age was 61 years (range: 21 to 85) with 38% ≥65 years of age and 8% ≥75 years of age. The majority of patients were male (73%) and White (87%) and 26% and 74% of patients had a baseline KPS of 70% to 80% and 90% to 100%, respectively.

The major efficacy outcome measures were OS, PFS (independent radiographic review committee [IRRC]-assessed) and confirmed ORR (IRRC-assessed) in intermediate/poor risk patients. In this population, the trial demonstrated statistically significant improvement in OS and ORR for patients randomized to Opdivo and ipilimumab as compared with sunitinib (Table 51 and Figure 12). OS benefit was observed regardless of PD-L1 expression level. The trial did not demonstrate a statistically significant improvement in PFS. Efficacy results are shown in Table 51 and Figure 12.

Table 51: Efficacy Results - CHECKMATE-214
a Not Reached
b Based on a stratified proportional hazards model.
c Based on a stratified log-rank test.
d p-value is compared to alpha 0.002 in order to achieve statistical significance.
e Based on the stratified DerSimonian-Laird test.
f p-value is compared to alpha 0.001 in order to achieve statistical significance.
g Not Significant at alpha level of 0.009.

Intermediate/Poor-Risk

Opdivo and Ipilimumab
(n=425)

Sunitinib
(n=422)

Overall Survival

Deaths (%)

140 (32.9)

188 (44.5)

Median survival (months)

NRa

25.9

Hazard ratio (99.8% CI)b

0.63 (0.44, 0.89)

p-valuec,d

<0.0001

Confirmed Overall Response Rate (95% CI)

41.6% (36.9, 46.5)

26.5% (22.4, 31.0)

p-valuee,f

<0.0001

Complete response (CR)

40 (9.4)

5 (1.2)

Partial response (PR)

137 (32.2)

107 (25.4)

Median duration of response (months) (95% CI)

NRa (21.8, NRa)

18.2 (14.8, NRa)

Progression-free Survival

Disease progression or death (%)

228 (53.6)

228 (54.0)

Median (months)

11.6

8.4

Hazard ratio (99.1% CI)a

0.82 (0.64, 1.05)

p-valuec

NSg

Figure 12: Overall Survival (Intermediate/Poor Risk Population) - CHECKMATE-214

CHECKMATE-214 also randomized 249 favorable risk patients as per IMDC criteria to Opdivo and ipilimumab (n=125) or to sunitinib (n=124). These patients were not evaluated as part of the efficacy analysis population. OS in favorable risk patients receiving Opdivo and ipilimumab compared to sunitinib has a hazard ratio of 1.45 (95% CI: 0.75, 2.81). The efficacy of Opdivo and ipilimumab in previously untreated renal cell carcinoma with favorable-risk disease has not been established.

CHECKMATE-9ER

CHECKMATE-9ER (NCT03141177) was a randomized, open-label study of Opdivo combined with cabozantinib versus sunitinib in patients with previously untreated advanced RCC. CHECKMATE-9ER excluded patients with autoimmune disease or other medical conditions requiring systemic immunosuppression. Patients were stratified by IMDC prognostic score (favorable vs. intermediate vs. poor), PD-L1 tumor expression (≥1% vs. <1% or indeterminate), and region (US/Canada/Western Europe/Northern Europe vs. Rest of World).

Patients were randomized to Opdivo 240 mg intravenously every 2 weeks and cabozantinib 40 mg orally daily (n=323), or sunitinib 50 mg orally daily for the first 4 weeks of a 6-week cycle (4 weeks on treatment followed by 2 weeks off) (n=328). Treatment continued until disease progression per RECIST v1.1 or unacceptable toxicity. Treatment beyond RECIST-defined disease progression was permitted if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Tumor assessments were performed at baseline, after randomization at Week 12, then every 6 weeks until Week 60, and then every 12 weeks thereafter.

The trial population characteristics were: median age 61 years (range: 28 to 90) with 38% ≥65 years of age and 10% ≥75 years of age. The majority of patients were male (74%) and White (82%) and 23% and 77% of patients had a baseline KPS of 70% to 80% and 90% to 100%, respectively. Patient distribution by IMDC risk categories was 22% favorable, 58% intermediate, and 20% poor.

The major efficacy outcome measure was PFS (BICR assessed). Additional efficacy outcome measures were OS and ORR (BICR assessed). The trial demonstrated a statistically significant improvement in PFS, OS, and ORR for patients randomized to Opdivo and cabozantinib compared with sunitinib. Consistent results for PFS were observed across pre-specified subgroups of IMDC risk categories and PD-L1 tumor expression status. Efficacy results are shown in Table 52 and Figures 13 and 14.

Table 52: Efficacy Results - CHECKMATE-9ER
a Based on Kaplan-Meier estimates.
b Stratified Cox proportional hazards model.
c Based on stratified log-rank test
d 2-sided p-values from stratified log-rank test.
e Not Reached
f p-value is compared with the allocated alpha of 0.0111 for this interim analysis
g CI based on the Clopper-Pearson method.
h 2-sided p-value from Cochran-Mantel-Haenszel test.

Opdivo and Cabozantinib
(n=323)

Sunitinib
(n=328)

Progression-free Survival

Disease progression or death (%)

144 (45)

191 (58)

Median PFS (months)a (95% CI)

16.6 (12.5, 24.9)

8.3 (7.0, 9.7)

Hazard ratio (95% CI)b

0.51 (0.41, 0.64)

p-valuec,d

<0.0001

Overall Survival

Deaths (%)

67 (21)

99 (30)

Median OS (months)a (95% CI)

NRe

NR (22.6, NRe)

Hazard ratio (98.89% CI)b

0.60 (0.40, 0.89)

p-valuec,d,f

0.0010

Confirmed Objective Response Rate (95% CI)g

55.7% (50.1, 61.2)

27.1% (22.4, 32.3)

p-valueh

<0.0001

Complete Response

26 (8%)

15 (4.6%)

Partial Response

154 (48%)

74 (23%)

Median duration of response in months (95% CI)a

20.2 (17.3, NRe)

11.5 (8.3, 18.4)

Figure 13: Progression-free Survival - CHECKMATE-9ER

Figure 14: Overall Survival - CHECKMATE-9ER

Previously Treated Renal Cell Carcinoma

CHECKMATE-025

CHECKMATE-025 (NCT01668784) was a randomized (1:1), open-label trial in patients with advanced RCC who had experienced disease progression during or after one or two prior anti-angiogenic therapy regimens. Patients had to have a Karnofsky Performance Score (KPS) ≥70% and patients were included regardless of their PD-L1 status. The trial excluded patients with any history of or concurrent brain metastases, prior treatment with an mTOR inhibitor, active autoimmune disease, or medical conditions requiring systemic immunosuppression. Patients were stratified by region, Memorial Sloan Kettering Cancer Center (MSKCC) Risk Group and the number of prior anti-angiogenic therapies. Patients were randomized Opdivo 3 mg/kg by intravenous infusion every 2 weeks (n=410) or everolimus 10 mg orally daily (n=411). The first tumor assessments were conducted 8 weeks after randomization and continued every 8 weeks thereafter for the first year and then every 12 weeks until progression or treatment discontinuation, whichever occurred later. The major efficacy outcome measure was overall survival (OS).

The trial population characteristics were: median age was 62 years (range: 18 to 88) with 40% ≥65 years of age and 9% ≥75 years of age. The majority of patients were male (75%) and White (88%) and 34% and 66% of patients had a baseline KPS of 70% to 80% and 90% to 100%, respectively. The majority of patients (77%) were treated with one prior anti-angiogenic therapy. Patient distribution by MSKCC risk groups was 34% favorable, 47% intermediate, and 19% poor.

The trial demonstrated a statistically significant improvement in OS for patients randomized to Opdivo as compared with everolimus at the prespecified interim analysis when 398 events were observed (70% of the planned number of events for final analysis). OS benefit was observed regardless of PD-L1 expression level. Efficacy results are shown in Table 53 and Figure 15.

Table 53: Efficacy Results - CHECKMATE-025
Opdivo
(n=410)
Everolimus
(n=411)
a Not Reached
b Based on a stratified proportional hazards model.
c Based on a stratified log-rank test.
d p-value is compared with .0148 of the allocated alpha for this interim analysis.

Overall Survival

Deaths (%)

183 (45)

215 (52)

Median survival (months) (95% CI)

25.0 (21.7, NRa)

19.6 (17.6, 23.1)

Hazard ratio (95% CI)b

0.73 (0.60, 0.89)

p-valuec,d

0.0018

Confirmed Overall Response Rate (95% CI)

21.5% (17.6, 25.8)

3.9% (2.2, 6.2)

Median duration of response (months) (95% CI)

23.0 (12.0, NRa)

13.7 (8.3, 21.9)

Median time to onset of confirmed response (months) (min, max)

3.0 (1.4, 13.0)

3.7 (1.5, 11.2)

Figure 15: Overall Survival - CHECKMATE-025

Classical Hodgkin Lymphoma

Two studies evaluated the efficacy of Opdivo as a single agent in adult patients with cHL after failure of autologous HSCT.

CHECKMATE-205 (NCT02181738) was a single-arm, open-label, multicenter, multicohort trial in cHL. CHECKMATE-039 (NCT01592370) was an open-label, multicenter, dose escalation trial that included cHL. Both studies included patients regardless of their tumor PD-L1 status and excluded patients with ECOG performance status of 2 or greater, autoimmune disease, symptomatic interstitial lung disease, hepatic transaminases more than 3 times ULN, creatinine clearance <40 mL/min, prior allogeneic HSCT, or chest irradiation within 24 weeks. In addition, both studies required an adjusted diffusion capacity of the lungs for carbon monoxide (DLCO) of over 60% in patients with prior pulmonary toxicity.

Patients received Opdivo 3 mg/kg by intravenous infusion every 2 weeks until disease progression, maximal clinical benefit, or unacceptable toxicity. A cycle consisted of one dose. Dose reduction was not permitted.

Efficacy was evaluated by ORR as determined by an IRRC. Additional outcome measures included duration of response (DOR).

Efficacy was evaluated in 95 patients in CHECKMATE-205 and CHECKMATE-039 combined who had failure of autologous HSCT and post-transplantation brentuximab vedotin. The median age was 37 years (range: 18 to 72). The majority were male (64%) and White (87%). Patients had received a median of 5 prior systemic regimens (range: 2 to 15). They received a median of 27 doses of Opdivo (range: 3 to 48), with a median duration of therapy of 14 months (range: 1 to 23 months). Efficacy results are shown in Table 54.

Table 54: Efficacy in cHL after Autologous HSCT and Post-transplantation Brentuximab Vedotin
a Per 2007 revised International Working Group criteria.
b Kaplan-Meier estimate. Among responders, the median follow-up for DOR, measured from the date of first response, was 9.9 months.
c A + sign indicates a censored value.
d Not Reached

CHECKMATE-205 and CHECKMATE-039
(n=95)

Overall Response Rate, n (%)a

(95% CI)

63 (66%)

(56, 76)

Complete remission rate

(95% CI)

6 (6%)

(2, 13)

Partial remission rate

(95% CI)

57 (60%)

(49, 70)

Duration of Response (months)

Medianb

(95% CI)

Rangec

13.1

(9.5, NRd)

0+, 23.1+

Time to Response (months)

Median

Range

2.0

0.7, 11.1

Efficacy was also evaluated in 258 patients in CHECKMATE-205 and CHECKMATE-039 combined who had relapsed or progressive cHL after autologous HSCT. The analysis included the group described above. The median age was 34 years (range: 18 to 72). The majority were male (59%) and White (86%). Patients had a median of 4 prior systemic regimens (range: 2 to 15), with 85% having 3 or more prior systemic regimens and 76% having prior brentuximab vedotin. Of the 195 patients having prior brentuximab vedotin, 17% received it only before autologous HSCT, 78% received it only after HSCT, and 5% received it both before and after HSCT. Patients received a median of 21 doses of Opdivo (range: 1 to 48), with a median duration of therapy of 10 months (range: 0 to 23 months). Efficacy results are shown in Table 55.

Table 55: Efficacy in cHL after Autologous HSCT
a Kaplan-Meier estimate. Among responders, the median follow-up for DOR, measured from the date of first response, was 6.7 months.
b The estimated median duration of PR was 13.1 months (95% CI, 9.5, NE). The median duration of CR was not reached.
c Not Reached

CHECKMATE-205 and CHECKMATE-039
(n=258)

Overall Response Rate, n (%)

(95% CI)

179 (69%)

(63, 75)

Complete remission rate

(95% CI)

37 (14%)

(10, 19)

Partial remission rate

(95% CI)

142 (55%)

(49, 61)

Duration of Response (months)

Mediana,b

(95% CI)

Range

NRc

(12.0, NRc)

0+, 23.1+

Time to Response (months)

Median

Range

2.0

0.7, 11.1

Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck

CHECKMATE-141 (NCT02105636) was a randomized (2:1), active-controlled, open-label trial enrolling patients with metastatic or recurrent SCCHN who had experienced disease progression during or within 6 months of receiving platinum-based therapy administered in either the adjuvant, neo-adjuvant, primary (unresectable locally advanced) or metastatic setting. The trial excluded patients with autoimmune disease, medical conditions requiring immunosuppression, recurrent or metastatic carcinoma of the nasopharynx, squamous cell carcinoma of unknown primary histology, salivary gland or non-squamous histologies (e.g., mucosal melanoma), or untreated brain metastasis. Patients with treated brain metastases were eligible if neurologically stable. Patients were randomized to receive Opdivo 3 mg/kg by intravenous infusion every 2 weeks or investigator’s choice of cetuximab (400 mg/m2 initial dose intravenously followed by 250 mg/m2 weekly), or methotrexate (40 to 60 mg/m2 intravenously weekly), or docetaxel (30 to 40 mg/m2 intravenously weekly).

Randomization was stratified by prior cetuximab treatment (yes/no). The first tumor assessments were conducted 9 weeks after randomization and continued every 6 weeks thereafter. The major efficacy outcome measure was OS. Additional efficacy outcome measures were PFS and ORR.

A total of 361 patients were randomized; 240 patients to the Opdivo arm and 121 patients to the investigator’s choice arm (docetaxel: 45%; methotrexate: 43%; and cetuximab: 12%). The trial population characteristics were: median age was 60 years (range: 28 to 83) with 31% ≥65 years of age, 83% were White, 12% Asian, and 4% were Black, and 83% male. Baseline ECOG performance status was 0 (20%) or 1 (78%), 76% were former/current smokers, 90% had Stage IV disease, 45% of patients received only one prior line of systemic therapy, the remaining 55% received two or more prior lines of systemic therapy, and 25% had HPVp16-positive tumors, 24% had HPV p16-negative tumors, and 51% had unknown status.

The trial demonstrated a statistically significant improvement in OS for patients randomized to Opdivo as compared with investigator’s choice at a pre-specified interim analysis (78% of the planned number of events for final analysis). There were no statistically significant differences between the two arms for PFS (HR=0.89; 95% CI: 0.70, 1.13) or ORR (13.3% [95% CI: 9.3, 18.3] vs. 5.8% [95% CI: 2.4, 11.6] for nivolumab and investigator’s choice, respectively). Efficacy results are shown in Table 56 and Figure 16.

Table 56: Overall Survival - CHECKMATE-141
Opdivo
(n=240)
Cetuximab, Methotrexate or Docetaxel
(n=121)
a Based on stratified proportional hazards model.
b Based on stratified log-rank test.
c p-value is compared with 0.0227 of the allocated alpha for this interim analysis.

Overall Survival

Deaths (%)

133 (55%)

85 (70%)

Median (months)
(95% CI)

7.5
(5.5, 9.1)

5.1
(4.0, 6.0)

Hazard ratio (95% CI)a

0.70 (0.53, 0.92)

p-valueb,c

0.0101

Figure 16: Overall Survival - CHECKMATE-141

Archival tumor specimens were retrospectively evaluated for PD-L1 expression using the PD-L1 IHC 28-8 pharmDx assay. Across the trial population, 28% (101/361) of patients had non-quantifiable results. Among the 260 patients with quantifiable results, 43% (111/260) had PD-L1 negative SCCHN, defined as <1% of tumor cells expressing PD-L1, and 57% (149/260) had PD-L1 positive SCCHN, defined as ≥1% of tumor cells expressing PD-L1. In pre-specified exploratory subgroup analyses, the hazard ratio for survival was 0.89 (95% CI: 0.54, 1.45) with median survivals of 5.7 and 5.8 months for the nivolumab and chemotherapy arms, respectively, in the PD-L1 negative subgroup. The HR for survival was 0.55 (95% CI: 0.36, 0.83) with median survivals of 8.7 and 4.6 months for the nivolumab and chemotherapy arms, respectively, in the PD-L1 positive SCCHN subgroup.

Urothelial Carcinoma

Adjuvant Treatment of Urothelial Carcinoma (UC) at High Risk of Recurrence

CHECKMATE-274 (NCT02632409) was a randomized, double-blind, placebo-controlled study of adjuvant Opdivo in patients who were within 120 days of radical resection (R0) of UC of the bladder or upper urinary tract (renal pelvis or ureter) at high risk of recurrence. High risk of recurrence was defined as either 1) ypT2-ypT4a or ypN+ for patients who received neoadjuvant cisplatin or 2) pT3-pT4a or pN+ for patients who did not receive neoadjuvant cisplatin and who also either were ineligible for or refused adjuvant cisplatin. Patients were randomized 1:1 to receive Opdivo 240 mg or placebo by intravenous infusion every 2 weeks until recurrence or until unacceptable toxicity for a maximum treatment duration of 1 year. Patients were stratified by pathologic nodal status (N+ vs. N0/x with <10 nodes removed vs. N0 with ≥10 nodes removed), tumor cells expressing PD-L1 (≥1% vs. <1%/indeterminate as determined by the central lab using the PD-L1 IHC 28-8 pharmDx assay), and use of neoadjuvant cisplatin (yes vs. no).

The trial population characteristics were: median age of 67 years (range: 30 to 92); 76% male; 76% White, 22% Asian, 0.7% Black, and 0.1% American Indian or Alaska Native. Of the 335 (47%) of patients with node-positive UC, 44 (6%) had non–muscle-invasive (<pT2) primary tumors. ECOG performance status was 0 (63%), 1 (35%), or 2 (2%). Prior neoadjuvant cisplatin had been given to 43% of patients; of the 57% who did not receive prior neoadjuvant cisplatin, reasons listed were ineligibility (22%), patient preference (33%), and other/not reported (2%). Tumor PD-L1 expression was ≥1% in 40% of patients, and 21% of patients had upper tract UC.

The major efficacy outcome measures were investigator-assessed DFS in all randomized patients and in patients with tumors expressing PD-L1 ≥1%. DFS was defined as time to first recurrence (local urothelial tract, local non-urothelial tract, or distant metastasis), or death. Additional efficacy outcome measures included OS.

At the pre-specified interim analysis, CHECKMATE-274 demonstrated a statistically significant improvement in DFS for patients randomized to Opdivo vs. placebo in the all randomized patient population, as well as in the subpopulation of patients with PD-L1 ≥1%, as shown in Table 57 and Figure 17.

In exploratory subgroup analyses in patients with upper tract UC (n=149), no improvement in DFS was observed in the nivolumab arm compared to the placebo arm. The unstratified DFS hazard ratio estimate was 1.15 (95% CI: 0.74, 1.80).

In an exploratory subgroup analysis in patients with PD-L1 expression of <1% (n=414), the unstratified DFS hazard ratio estimate was 0.83 (95% CI: 0.64, 1.08).

OS data is immature with 33% of deaths in the overall randomized population. In the UTUC subpopulation, 37 deaths occurred (20 in the nivolumab arm, 17 in the placebo arm).

Table 57: Efficacy Results - CHECKMATE-274
N.R. Not reached, N.E. Not estimable
a Includes disease at baseline events (protocol deviations): n=1 in Opdivo arm and n=3 in placebo arm.
b Based on Kaplan-Meier estimates.
c Stratified Cox proportional hazard model. Hazard ratio is Opdivo over placebo.
d Log-rank test stratified by prior neoadjuvant cisplatin, pathological nodal status, PD-L1 status (≥1% vs <1%/indeterminate). Boundary for statistical significance in all randomized patients: p-value <0.01784.
e Log-rank test stratified by prior neoadjuvant cisplatin, pathological nodal status. Boundary for statistical significance in all randomized patients with PD-L1 ≥1%: p-value <0.01282.

All Randomized

PD-L1 ≥1%

Opdivo

(n=353)

Placebo

(n=356)

Opdivo

(n=140)

Placebo

(n=142)

Disease-free Survival

Eventsa, n (%)

Local recurrence

Distant recurrence

Death

170 (48)

47 (13)

108 (31)

14 (4)

204 (57)

64 (18)

127 (36)

10 (3)

55 (39)

10 (7)

40 (29)

5 (4)

81 (57)

24 (17)

52 (37)

5 (4)

Median DFS (months)b

(95% CI)

20.8

(16.5, 27.6)

10.8

(8.3, 13.9)

N.R.

(21.2, N.E.)

8.4

(5.6, 21.2)

Hazard ratioc

(95% CI)

0.70

(0.57, 0.86)

0.55

(0.39, 0.77)

p-value

0.0008d

0.0005e

Figure 17: Disease-free Survival in All Randomized Patients - CHECKMATE-274

Advanced or Metastatic Urothelial Carcinoma

CHECKMATE-275 (NCT02387996) was a single-arm trial in 270 patients with locally advanced or metastatic urothelial carcinoma who had disease progression during or following platinum-containing chemotherapy or who had disease progression within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen. Patients were excluded for active brain or leptomeningeal metastases, active autoimmune disease, medical conditions requiring systemic immunosuppression, and ECOG performance status >1. Patients received Opdivo 3 mg/kg by intravenous infusion every 2 weeks until unacceptable toxicity or either radiographic or clinical progression. Tumor response assessments were conducted every 8 weeks for the first 48 weeks and every 12 weeks thereafter. Major efficacy outcome measures included confirmed ORR as assessed by IRRC using RECIST v1.1 and DOR.

The median age was 66 years (range: 38 to 90), 78% were male, 86% were White. Twenty-seven percent had non-bladder urothelial carcinoma and 84% had visceral metastases. Thirty-four percent of patients had disease progression following prior platinum-containing neoadjuvant or adjuvant therapy. Twenty-nine percent of patients had received ≥2 prior systemic regimens in the metastatic setting. Thirty-six percent of patients received prior cisplatin only, 23% received prior carboplatin only, and 7% were treated with both cisplatin and carboplatin in the metastatic setting. Forty-six percent of patients had an ECOG performance status of 1. Eighteen percent of patients had a hemoglobin <10 g/dL, and twenty-eight percent of patients had liver metastases at baseline. Patients were included regardless of their PD-L1 status.

Tumor specimens were evaluated prospectively using the PD-L1 IHC 28-8 pharmDx assay at a central laboratory and the results were used to define subgroups for pre-specified analyses. Of the 270 patients, 46% were defined as having PD-L1 expression of ≥1% (defined as ≥1% of tumor cells expressing PD-L1). The remaining 54% of patients were classified as having PD-L1 expression of <1% (defined as <1% of tumor cells expressing PD-L1). Confirmed ORR in all patients and the two PD-L1 subgroups are shown in Table 58. Median time to response was 1.9 months (range: 1.6-7.2). In 77 patients who received prior systemic therapy only in the neoadjuvant or adjuvant setting, the ORR was 23.4% (95% CI: 14.5%, 34.4%).

Table 58: Efficacy Results - CHECKMATE-275

All Patients

N=270

PD-L1 <1%

N=146

PD-L1 ≥1%

N=124

Confirmed Overall Response Rate, n (%)

(95% CI)

53 (19.6%)

(15.1, 24.9)

22 (15.1%)

(9.7, 21.9)

31 (25.0%)

(17.7, 33.6)

Complete response rate

7 (2.6%)

1 (0.7%)

6 (4.8%)

Partial response rate

46 (17.0%)

21 (14.4%)

25 (20.2%)

Median Duration of Responsea (months) (range)

10.3 (1.9+, 12.0+)

7.6 (3.7, 12.0+)

NRb (1.9+, 12.0+)

a Estimated from the Kaplan-Meier Curve
b Not Reached

Microsatellite Instability-High or Mismatch Repair Deficient Metastatic Colorectal Cancer

CHECKMATE-142 (NCT02060188) was a multicenter, non-randomized, multiple parallel-cohort, open-label trial conducted in patients with locally determined dMMR or MSI-H metastatic CRC (mCRC) who had disease progression during or after prior treatment with fluoropyrimidine- , oxaliplatin- , or irinotecan-based chemotherapy. Key eligibility criteria were at least one prior line of treatment for metastatic disease, ECOG performance status 0 or 1, and absence of the following: active brain metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression.

Patients enrolled in the single agent Opdivo MSI-H mCRC cohort received Opdivo 3 mg/kg by intravenous infusion (IV) every 2 weeks. Patients enrolled in the Opdivo and ipilimumab MSI-H mCRC cohort received Opdivo 3 mg/kg and ipilimumab 1 mg/kg intravenously every 3 weeks for 4 doses, followed by Opdivo as a single agent at a dose of 3 mg/kg as intravenous infusion every 2 weeks. Treatment in both cohorts continued until unacceptable toxicity or radiographic progression.

Tumor assessments were conducted every 6 weeks for the first 24 weeks and every 12 weeks thereafter. Efficacy outcome measures included ORR and DOR as assessed by BICR using RECIST v1.1.

A total of 74 patients were enrolled in the single-agent MSI-H mCRC Opdivo cohort. The median age was 53 years (range: 26 to 79) with 23% ≥65 years of age and 5% ≥75 years of age, 59% were male and 88% were White. Baseline ECOG performance status was 0 (43%), 1 (55%), or 3 (1.4%) and 36% were reported to have Lynch Syndrome. Across the 74 patients, 72% received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan; 7%, 30%, 28%, 19%, and 16% received 0, 1, 2, 3, or ≥4 prior lines of therapy for metastatic disease, respectively, and 42% of patients had received an anti-EGFR antibody.

A total of 119 patients were enrolled in the Opdivo and ipilimumab MSI-H mCRC cohort. The median age was 58 years (range: 21 to 88), with 32% ≥65 years of age and 9% ≥75 years of age; 59% were male and 92% were White. Baseline ECOG performance status was 0 (45%) and 1 (55%), and 29% were reported to have Lynch Syndrome. Across the 119 patients, 69% had received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan; 10%, 40%, 24%, and 15% received 1, 2, 3, or ≥4 prior lines of therapy for metastatic disease, respectively, and 29% had received an anti-EGFR antibody.

Efficacy results for each of these single-arm cohorts are shown in Table 59.

Table 59: Efficacy Results - CHECKMATE-142
a Minimum follow-up 33.7 months for all patients treated with Opdivo (n=74).
b Minimum follow-up 27.5 months for all patients treated with Opdivo and ipilimumab (n=119).
c Estimated using the Clopper-Pearson method.

Opdivoa
MSI-H/dMMR Cohort

Opdivo and Ipilimumabb
MSI-H/dMMR Cohort

All Patients
(n=74)

Prior Treatment
(Fluoropyrimidine, Oxaliplatin, and Irinotecan)
(n=53)

All Patients
(n=119)

Prior Treatment
(Fluoropyrimidine, Oxaliplatin, and Irinotecan)
(n=82)

Overall Response Rate per BICR; n (%)

28 (38%)

17 (32%)

71 (60%)

46 (56%)

(95% CI)c

(27, 50)

(20, 46)

(50, 69)

(45, 67)

Complete Response (%)

8 (11%)

5 (9%)

17 (14%)

11 (13%)

Partial Response (%)

20 (27%)

12 (23%)

54 (45%)

35 (43%)

Duration of Response

Proportion of responders with ≥6 months response duration

86%

94%

89%

87%

Proportion of responders with ≥12 months response duration

82%

88%

77%

74%

Hepatocellular Carcinoma

CHECKMATE-040 (NCT01658878) was a multicenter, multiple cohort, open-label trial that evaluated the efficacy of Opdivo as a single agent and in combination with ipilimumab in patients with hepatocellular carcinoma (HCC) who progressed on or were intolerant to sorafenib. Additional eligibility criteria included histologic confirmation of HCC and Child-Pugh Class A cirrhosis. The trial excluded patients with active autoimmune disease, brain metastasis, a history of hepatic encephalopathy, clinically significant ascites, infection with HIV, or active co-infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) or HBV and hepatitis D virus (HDV); however, patients with only active HBV or HCV were eligible.

Tumor assessments were conducted every 6 weeks for 48 weeks and then every 12 weeks thereafter. The major efficacy outcome measure was confirmed overall response rate as assessed by BICR using RECIST v1.1 and modified RECIST (mRECIST) for HCC. Duration of response was also assessed.

The efficacy of Opdivo in combination with ipilimumab was evaluated in 49 patients (Cohort 4) who received Opdivo 1 mg/kg and ipilimumab 3 mg/kg administered every 3 weeks for 4 doses, followed by single-agent Opdivo at 240 mg every 2 weeks until disease progression or unacceptable toxicity. The median age was 60 years (range: 18 to 80), 88% were male, 74% were Asian, and 25% were White. Baseline ECOG performance status was 0 (61%) or 1 (39%). Fifty-seven (57%) percent of patients had active HBV infection, 8% had active HCV infection, and 35% had no evidence of active HBV or HCV. The etiology for HCC was alcoholic liver disease in 16% and non-alcoholic fatty liver disease in 6% of patients. Child-Pugh class and score was A5 for 82% and A6 for 18%; 80% of patients had extrahepatic spread; 35% had vascular invasion; and 51% had AFP levels ≥400 µg/L. Prior cancer treatment history included surgery (74%), radiotherapy (29%), or local treatment (59%). All patients had received prior sorafenib, of whom 10% were unable to tolerate sorafenib; 29% of patients had received 2 or more prior systemic therapies.

Efficacy results are shown in Table 60. The results for Opdivo in combination with ipilimumab in Cohort 4 are based on a minimum follow-up of 28 months.

Table 60: Efficacy Results - Cohort 4 of CHECKMATE-040
a Confirmed by BICR.
b Confidence interval is based on the Clopper and Pearson method.

Opdivo and Ipilimumab
(Cohort 4)
(n=49)

Overall Response Rate per BICR,a n (%), RECIST v1.1

16 (33%)

(95% CI)b

(20, 48)

Complete response

4 (8%)

Partial response

12 (24%)

Duration of Response per BICR,a RECIST v1.1

n=16

Range (months)

4.6, 30.5+

Percent with duration ≥6 months

88%

Percent with duration ≥12 months

56%

Percent with duration ≥24 months

31%

Overall Response Rate per BICR,a n (%), mRECIST

17 (35%)

(95% CI)b

(22, 50)

Complete response

6 (12%)

Partial response

11 (22%)

Esophageal Cancer

Adjuvant Treatment of Resected Esophageal or Gastroesophageal Junction Cancer

CHECKMATE-577 (NCT02743494) was a randomized, multicenter, double-blind trial in 794 patients with completely resected (negative margins) esophageal or gastroesophageal junction cancer who had residual pathologic disease following concurrent chemoradiotherapy (CRT). Patients were randomized (2:1) to receive either Opdivo 240 mg or placebo by intravenous infusion over 30 minutes every 2 weeks for 16 weeks followed by 480 mg or placebo by intravenous infusion over 30 minutes every 4 weeks beginning at week 17. Treatment was until disease recurrence, unacceptable toxicity, or for up to 1 year in total duration. Enrollment required complete resection within 4 to 16 weeks prior to randomization. The trial excluded patients who did not receive CRT prior to surgery, had stage IV resectable disease, autoimmune disease, or any condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone or equivalent) or other immunosuppressive medications. Randomization was stratified by tumor PD-L1 status (≥1% vs. <1% or indeterminate or non-evaluable), pathologic lymph node status (positive ≥ypN1 vs. negative ypN0), and histology (squamous vs. adenocarcinoma). The major efficacy outcome measure was disease-free survival (DFS) defined as the time between the date of randomization and the date of first recurrence (local, regional, or distant from the primary resected site) or death, from any cause, whichever occurred first as assessed by the investigator prior to subsequent anti-cancer therapy. Patients on treatment underwent imaging for tumor recurrence every 12 weeks for 2 years, and a minimum of one scan every 6 to 12 months for years 3 to 5.

The trial population characteristics were: median age 62 years (range: 26 to 86), 36% were ≥65 years of age, 85% were male, 15% were Asian, 82% were White, and 1.1% were Black. Disease characteristics were AJCC Stage II (35%) or Stage III (65%) at initial diagnosis carcinoma, EC (60%) or GEJC (40%) at initial diagnosis, with pathologic positive lymph node status (58%) at study entry and histological confirmation of predominant adenocarcinoma (71%) or squamous cell carcinoma (29%). The baseline Tumor PD-L1 status ≥1% was positive for 16% of patients and negative for 72% of patients. Baseline ECOG performance status was 0 (58%) or 1 (42%).

CHECKMATE-577 demonstrated a statistically significant improvement in DFS for patients randomized to the Opdivo arm as compared with the placebo arm. DFS benefit was observed regardless of tumor PD-L1 expression and histology.

Efficacy results are shown in Table 61 and Figure 18.

Table 61: Efficacy Results - CHECKMATE-577
a Based on a stratified proportional hazards model.
b Based on a stratified log-rank test.

Opdivo
(n=532)

Placebo
(n=262)

Disease-free Survival

Number of events, n (%)

241 (45%)

155 (59%)

Median (months)
(95% CI)

22.4

(16.6, 34.0)

11.0

(8.3, 14.3)

Hazard ratioa (95% CI)

0.69 (0.56, 0.85)

p-valueb

0.0003

Figure 18: Disease-free Survival - CHECKMATE-577

Esophageal Squamous Cell Cancer

ATTRACTION-3 (NCT02569242) was a multicenter, randomized (1:1), active-controlled, open-label trial in patients with unresectable advanced, recurrent, or metastatic ESCC, who were refractory or intolerant to at least one fluoropyrimidine- and platinum-based regimen. The trial enrolled patients regardless of PD-L1 status, but tumor specimens were evaluated prospectively using the PD-L1 IHC 28-8 pharmDx assay at a central laboratory. The trial excluded patients who were refractory or intolerant to taxane therapy, had brain metastases that were symptomatic or required treatment, had autoimmune disease, used systemic corticosteroids or immunosuppressants, or had apparent tumor invasion of organs adjacent to the esophageal tumor or had stents in the esophagus or respiratory tract. Patients were randomized to receive Opdivo 240 mg by intravenous infusion over 30 minutes every 2 weeks or investigator’s choice of taxane chemotherapy consisting of docetaxel (75 mg/m2 intravenously every 3 weeks) or paclitaxel (100 mg/m2 intravenously once a week for 6 weeks followed by 1 week off).

Randomization was stratified by region (Japan vs. Rest of World), number of organs with metastases (≤1 vs. ≥2), and PD-L1 status (≥1% vs. <1% or indeterminate). Patients were treated until disease progression, assessed by the investigator per RECIST v1.1, or unacceptable toxicity. The tumor assessments were conducted every 6 weeks for 1 year, and every 12 weeks thereafter. The major efficacy outcome measure was OS. Additional efficacy outcome measures were ORR and PFS as assessed by the investigator using RECIST v1.1 and DOR.

A total of 419 patients were randomized; 210 to the Opdivo arm and 209 to the investigator’s choice arm (docetaxel: 31%, paclitaxel: 69%). The trial population characteristics were: median age 65 years (range: 33 to 87), 53% were ≥65 years of age, 87% were male, 96% were Asian and 4% were White. Sixty-seven percent of patients had received one prior systemic therapy regimen and 26% had received two prior systemic therapy regimens prior to enrolling in ATTRACTION-3. Baseline ECOG performance status was 0 (50%) or 1 (50%).

ATTRACTION-3 demonstrated a statistically significant improvement in OS for patients randomized to Opdivo as compared with investigator’s choice of taxane chemotherapy. OS benefit was observed regardless of PD-L1 expression level. The minimum follow-up was 17.6 months. Efficacy results are shown in Table 62 and Figure 19.

Table 62: Efficacy Results - ATTRACTION-3
a Based on ITT analysis
b Based on a stratified proportional hazards model.
c Based on a stratified log-rank test.
d Based on Response Evaluable Set (RES) analysis, n=171 in Opdivo group and n=158 in investigator’s choice group.
e Based on stratified Cochran-Mantel-Haenszel test; p-value not significant.
f PFS not tested due to pre-specified hierarchical testing strategy.

Opdivo
(n=210)

Docetaxel or Paclitaxel
(n=209)

Overall Survivala

Deaths (%)

160 (76%)

173 (83%)

Median (months)

(95% CI)

10.9

(9.2, 13.3)

8.4

(7.2, 9.9)

Hazard ratio (95% CI)b

0.77 (0.62, 0.96)

p-valuec

0.0189

Overall Response Rated

33 (19.3)

34 (21.5)

(95% CI)

(13.7, 26.0)

(15.4, 28.8)

Complete response (%)

1 (0.6)

2 (1.3)

Partial response (%)

32 (18.7)

32 (20.3)

Median duration of response (months)

(95% CI)

6.9

(5.4, 11.1)

3.9

(2.8, 4.2)

p-valuee

0.6323

Progression-free Survivala, f

Disease progression or death (%)

187 (89)

176 (84)

Median (months)

(95% CI)

1.7

(1.5, 2.7)

3.4

(3.0, 4.2)

Hazard ratio (95% CI)b

1.1 (0.9, 1.3)

Figure 19: Overall Survival - ATTRACTION-3

Of the 419 patients, 48% had PD-L1 positive ESCC, defined as ≥1% of tumor cells expressing PD-L1. The remaining 52% had PD-L1 negative ESCC defined as <1% of tumor cells expressing PD-L1.

In a pre-specified exploratory analysis by PD-L1 status, the hazard ratio (HR) for OS was 0.69 (95% CI: 0.51, 0.94) with median survivals of 10.9 and 8.1 months for the Opdivo and investigator’s choice arms, respectively, in the PD-L1 positive subgroup. In the PD-L1 negative subgroup, the HR for OS was 0.84 (95% CI: 0.62, 1.14) with median survivals of 10.9 and 9.3 months for the Opdivo and investigator’s choice arms, respectively.

Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma

CHECKMATE-649 (NCT02872116) was a randomized, multicenter, open-label trial in patients (n=1581) with previously untreated advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma. The trial enrolled patients regardless of PD-L1 status, and tumor specimens were evaluated prospectively using the PD-L1 IHC 28-8 pharmDx assay at a central laboratory. The trial excluded patients who were known human epidermal growth factor receptor 2 (HER2) positive, or had untreated CNS metastases. Patients were randomized to receive Opdivo in combination with chemotherapy (n=789) or chemotherapy (n=792). Patients received one of the following treatments:

Opdivo 240 mg in combination with mFOLFOX6 (fluorouracil, leucovorin and oxaliplatin) every 2 weeks or mFOLFOX6 every 2 weeks.
Opdivo 360 mg in combination with CapeOX (capecitabine and oxaliplatin) every 3 weeks or CapeOX every 3 weeks.

Patients were treated until disease progression, unacceptable toxicity, or up to 2 years. In patients who received Opdivo in combination with chemotherapy and in whom chemotherapy was discontinued, Opdivo monotherapy was allowed to be given at 240 mg every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks up to 2 years after treatment initiation.

Randomization was stratified by tumor cell PD-L1 status (≥1% vs. <1% or indeterminate), region (Asia vs. US vs. Rest of World), ECOG performance status (0 vs. 1), and chemotherapy regimen (mFOLFOX6 vs. CapeOX). The major efficacy outcome measures, assessed in patients with PD-L1 CPS ≥5, were PFS assessed by BICR and OS. Additional efficacy outcome measures included OS and PFS in patients with PD-L1 CPS ≥1 and in all randomized patients, and ORR and DOR as assessed by BICR in patients with PD-L1 CPS ≥1 and ≥5, and in all randomized patients. Tumor assessments were conducted per RECIST v1.1 every 6 weeks up to and including week 48, then every 12 weeks thereafter.

The trial population characteristics were: median age 61 years (range: 18 to 90), 39% were ≥65 years of age, 70% were male, 24% were Asian, and 69% were White, and 1% were Black. Baseline ECOG performance status was 0 (42%) or 1 (58%). Seventy percent of patients had adenocarcinoma tumors in the stomach, 16% in the gastroesophageal junction, and 13% in the esophagus.

CHECKMATE-649 demonstrated a statistically significant improvement in OS and PFS for patients with PD-L1 CPS ≥5. Statistically significant improvement in OS was also demonstrated for all randomized patients. The minimum follow-up was 12.1 months. Efficacy results are shown in Table 63 and Figures 20, 21, and 22.

Table 63: Efficacy Results - CHECKMATE-649
a Based on stratified Cox proportional hazard model.
b Based on stratified log-rank test.
c Assessed by BICR.
d Based on confirmed response.
e Not evaluated for statistical significance.

Opdivo and mFOLFOX6
or CapeOX
(n=789)

mFOLFOX6
or CapeOX
(n=792)

Opdivo and mFOLFOX6
or CapeOX
(n=641)

mFOLFOX6
or CapeOX
(n=655)

Opdivo and mFOLFOX6
or CapeOX
(n=473)

mFOLFOX6
or CapeOX
(n=482)

All Patients

PD-L1 CPS ≥1

PD-L1 CPS ≥5

Overall Survival

Deaths (%)

544 (69)

591 (75)

434 (68)

492 (75)

309 (65)

362 (75)

Median (months)

(95% CI)

13.8

(12.6, 14.6)

11.6

(10.9, 12.5)

14.0

(12.6, 15.0)

11.3

(10.6, 12.3)

14.4

(13.1, 16.2)

11.1

(10.0, 12.1)

Hazard ratio

(95% CI)a

0.80 (0.71, 0.90)

0.77 (0.68, 0.88)

0.71 (0.61, 0.83)

p-valueb

0.0002

<0.0001

<0.0001

Progression-free Survivalc

Disease progression or death (%)

559 (70.8)

557 (70.3)

454 (70.8)

472 (72.1)

328 (69.3)

350 (72.6)

Median (months)

(95% CI)

7.7

(7.1, 8.5)

6.9

(6.6, 7.1)

7.5

(7.0, 8.4)

6.9

(6.1, 7.0)

7.7

(7.0, 9.2)

6.0

(5.6, 6.9)

Hazard ratio

(95% CI)a

0.77 (0.68, 0.87)

0.74 (0.65, 0.85)

0.68 (0.58, 0.79)

p-valueb

-e

-e

<0.0001

Overall Response Rate, n (%)c,d

370 (47)

293 (37)

314 (49)

249 (38)

237 (50)

184 (38)

(95% CI)

(43, 50)

(34, 40)

(45, 53)

(34, 42)

(46, 55)

(34, 43)

Complete response (%)

78 (10)

52 (7)

65 (10)

42 (6)

55 (12)

34 (7)

Partial response (%)

292 (37)

241 (30)

249 (39)

207 (32)

182 (38)

150 (31)

Duration of Response (months)c,d

Median

(95% CI)

Range

8.5

(7.2, 9.9)

1.0+, 29.6+

6.9

(5.8, 7.2)

1.2+, 30.8+

8.5

(7.7, 10.3)

1.1+, 29.6+

6.9

(5.8, 7.6)

1.2+, 30.8+

9.5

(8.1, 11.9)

1.1+, 29.6+

6.9

(5.6, 7.9)

1.2+, 30.8+

In an exploratory analysis in patients with PD-L1 CPS<1 (n=265), the median OS was 13.1 months (95% CI: 9.8, 16.7) for the Opdivo and chemotherapy arm and 12.5 months (95% CI: 10.1, 13.8) for the chemotherapy arm, with a stratified HR of 0.85 (95% CI: 0.63, 1.15).

In an exploratory analysis in patients with PD-L1 CPS<5 (n=606), the median OS was 12.4 months (95% CI: 10.6, 14.3) for the Opdivo and chemotherapy arm and 12.3 months (95% CI: 11.0, 13.2) for the chemotherapy arm, with a stratified HR of 0.94 (95% CI: 0.78, 1.14).

Figure 20: Overall Survival (All Patients) - CHECKMATE-649

Figure 21: Overall Survival (PD-L1 CPS ≥1) - CHECKMATE-649

Figure 22: Overall Survival (PD-L1 CPS ≥5) - CHECKMATE-649

How Supplied/Storage and Handling

Opdivo® (nivolumab) Injection is available as follows:

Carton Contents NDC

40 mg/4 mL single-dose vial

0003-3772-11

100 mg/10 mL single-dose vial

0003-3774-12

120 mg/12 mL single-dose vial

0003-3756-14

240 mg/24 mL single-dose vial

0003-3734-13

Store under refrigeration at 2°C to 8°C (36°F to 46°F). Protect from light by storing in the original package until time of use. Do not freeze or shake.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Immune-Mediated Adverse Reactions

Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and withholding or discontinuation of Opdivo, including:

Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath [see Warnings and Precautions (5.1)].
Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain [see Warnings and Precautions (5.1)].
Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding [see Warnings and Precautions (5.1)].
Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypophysitis, adrenal insufficiency, hypothyroidism, hyperthyroidism, and diabetes mellitus [see Warnings and Precautions (5.1)].
Nephritis and Renal Dysfunction: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis including decreased urine output, blood in urine, swelling in ankles, loss of appetite, and any other symptoms of renal dysfunction [see Warnings and Precautions (5.1)].
Skin Adverse Reactions: Advise patients to contact their healthcare provider immediately for rash [see Warnings and Precautions (5.1)].

Infusion-Related Reactions

Advise patients of the potential risk of infusion-related reactions [see Warnings and Precautions (5.2)].

Complications of Allogeneic HSCT

Advise patients of potential risk of post-transplant complications [see Warnings and Precautions (5.3)].

Embryo-Fetal Toxicity

Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)].
Advise females of reproductive potential to use effective contraception during treatment with Opdivo and for at least 5 months following the last dose [see Use in Specific Populations (8.3)].

Lactation

Advise women not to breastfeed during treatment with Opdivo and for 5 months after the last dose [see Use in Specific Populations (8.2)].

Manufactured by:
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
U.S. License No. 1713

MEDICATION GUIDE

Opdivo® (op-DEE-voh)
(nivolumab)
Injection

Read this Medication Guide before you start receiving Opdivo and before each infusion. There may be new information. If your healthcare provider prescribes Opdivo in combination with ipilimumab (YERVOY®), also read the Medication Guide that comes with ipilimumab. If your healthcare provider prescribes Opdivo in combination with cabozantinib, also read the Patient Information that comes with cabozantinib. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What is the most important information I should know about Opdivo?

Opdivo is a medicine that may treat certain cancers by working with your immune system. Opdivo can cause your immune system to attack normal organs and tissues in any area of your body and can affect the way they work. These problems can sometimes become severe or can lead to death. These problems may happen anytime during treatment or even after your treatment has ended. You may have more than one of these problems at the same time. Some of these problems may happen more often when Opdivo is used in combination with another therapy.

Call or see your healthcare provider right away if you develop any new or worse signs or symptoms, including:

Lung problems.

new or worsening cough
shortness of breath
chest pain

Intestinal problems.

diarrhea (loose stools) or more frequent bowel movements than usual
stools that are black, tarry, sticky, or have blood or mucus
severe stomach-area (abdominal) pain or tenderness

Liver problems.

yellowing of your skin or the whites of your eyes
severe nausea or vomiting
pain on the right side of your stomach area (abdomen)
dark urine (tea colored)
bleeding or bruising more easily than normal

Hormone gland problems.

headaches that will not go away or unusual headaches
eye sensitivity to light
eye problems
rapid heart beat
increased sweating
extreme tiredness
weight gain or weight loss
feeling more hungry or thirsty than usual
urinating more often than usual
hair loss
feeling cold
constipation
your voice gets deeper
dizziness or fainting
changes in mood or behavior, such as decreased sex drive, irritability, or forgetfulness

Kidney problems.

decrease in your amount of urine
blood in your urine
swelling of your ankles
loss of appetite

Skin problems.

rash
itching
skin blistering or peeling
painful sore or ulcers in mouth or nose, throat, or genital area

Problems can also happen in other organs and tissues. These are not all of the signs and symptoms of immune system problems that can happen with Opdivo. Call or see your healthcare provider right away for any new or worsening signs or symptoms, which may include:

Chest pain, irregular heartbeat, shortness of breath or swelling of ankles
Confusion, sleepiness, memory problems, changes in mood or behavior, stiff neck, balance problems, tingling or numbness of the arms or legs
Double vision, blurry vision, sensitivity to light, eye pain, changes in eye sight
Persistent or severe muscle pain or weakness, muscle cramps
Low red blood cells, bruising

Getting medical treatment right away may help keep these problems from becoming more serious.

Your healthcare provider will check you for these problems during treatment with Opdivo. Your healthcare provider may treat you with corticosteroid or hormone replacement medicines. Your healthcare provider may also need to delay or completely stop treatment with Opdivo, if you have severe side effects.

What is Opdivo?

Opdivo is a prescription medicine used to treat:

people with a type of skin cancer called melanoma:
o
Opdivo may be used alone or in combination with ipilimumab to treat melanoma that has spread or cannot be removed by surgery (advanced melanoma), or
o
Opdivo may be used alone to help prevent melanoma from coming back after it and lymph nodes that contain cancer have been removed by surgery.
people with a type of advanced stage lung cancer called non-small cell lung cancer (NSCLC).
o
Opdivo may be used in combination with ipilimumab as your first treatment for NSCLC:
when your lung cancer has spread to other parts of your body (metastatic), and
your tumors are positive for PD-L1, but do not have an abnormal EGFR or ALK gene.
o
Opdivo may be used in combination with ipilimumab and 2 cycles of chemotherapy that contains platinum and another chemotherapy medicine, as the first treatment of your NSCLC when your lung cancer:
has spread or grown, or comes back, and
your tumor does not have an abnormal EGFR or ALK gene.
o
Opdivo may be used when your lung cancer:
has spread or grown, and
you have tried chemotherapy that contains platinum, and it did not work or is no longer working.
If your tumor has an abnormal EGFR or ALK gene, you should have also tried an FDA-approved therapy for tumors with these abnormal genes, and it did not work or is no longer working.
adults with a type of cancer that affects the lining of the lungs and chest wall called malignant pleural mesothelioma.
o
Opdivo may be used in combination with ipilimumab as your first treatment for malignant pleural mesothelioma that cannot be removed by surgery.
people with kidney cancer (renal cell carcinoma).
o
Opdivo may be used in combination with ipilimumab in certain people when their cancer has spread (advanced RCC), and you have not already had treatment for your advanced RCC.
o
Opdivo may be used in combination with cabozantinib when your cancer has spread (advanced RCC), and you have not already had treatment for your advanced RCC.
o
Opdivo may be used alone when your cancer has spread or grown after treatment with other cancer medicines.
adults with a type of blood cancer called classical Hodgkin lymphoma.
o
Opdivo may be used if:
your cancer has come back or spread after a type of stem cell transplant that uses your own stem cells (autologous), and
you used the medicine brentuximab vedotin before or after your stem cell transplant, or
you received at least 3 kinds of treatment including a stem cell transplant that uses your own stem cells (autologous).
people with head and neck cancer (squamous cell carcinoma).
o
Opdivo may be used when your head and neck cancer:
has come back or spread, and
you have tried chemotherapy that contains platinum and it did not work or is no longer working.
people with cancer of the lining of the urinary tract (urothelial carcinoma).
o
Opdivo may be used to help prevent cancer of the urinary tract from coming back after it was removed by surgery.
o
Opdivo may be used when your urinary tract cancer has spread or grown (locally advanced or metastatic), and:
you have tried chemotherapy that contains platinum, and it did not work or is no longer working, or
your cancer worsened within 12 months of treatment with chemotherapy that contains platinum, either before or after surgery to remove your cancer.
adults and children 12 years of age and older, with a type of colon or rectal cancer (colorectal cancer).
o
Opdivo may be used alone or in combination with ipilimumab when your colon or rectal cancer:
has spread to other parts of the body (metastatic),
is microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), and
you have tried treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, and it did not work or is no longer working.
people with liver cancer (hepatocellular carcinoma).
o
Opdivo may be used in combination with ipilimumab if you have previously received treatment with sorafenib.
people with cancer of the tube that connects your throat to your stomach (esophageal cancer).
o
Opdivo may be used to help prevent your esophageal or gastroesophageal junction cancer from coming back when:
your esophageal or gastroesophageal junction cancer has been treated with chemoradiation followed by surgery to completely remove the cancer, but
some cancer cells were still present in the removed tumor or lymph nodes.
o
Opdivo may be used when your esophageal cancer:
is a type called squamous cell carcinoma, and
cannot be removed with surgery, and
has come back or spread to other parts of the body after you have received chemotherapy that contains fluoropyrimidine and platinum.
people with cancer of the stomach (gastric cancer), cancer where the esophagus joins the stomach (gastroesophageal junction cancer), and in people with esophageal adenocarcinoma.
o
Opdivo may be used in combination with chemotherapy that contains fluoropyrimidine and platinum when your gastric, gastroesophageal junction, or esophageal cancer:
cannot be removed with surgery, or
has spread to other parts of the body.

It is not known if Opdivo is safe and effective when used:

in children younger than 12 years of age with MSI-H or dMMR metastatic colorectal cancer, or
in children younger than 18 years of age for the treatment of any other cancers.

Before receiving Opdivo, tell your healthcare provider about all of your medical conditions, including if you:

have immune system problems such as Crohn’s disease, ulcerative colitis, or lupus
have received an organ transplant
have received or plan to receive a stem cell transplant that uses donor stem cells (allogeneic)
have received radiation treatment to your chest area in the past and have received other medicines that are like Opdivo
have a condition that affects your nervous system, such as myasthenia gravis or Guillain-Barré syndrome
are pregnant or plan to become pregnant. Opdivo can harm your unborn baby.
Females who are able to become pregnant:
o
Your healthcare provider should do a pregnancy test before you start receiving Opdivo.
o
You should use an effective method of birth control during and for at least 5 months after the last dose of Opdivo. Talk to your healthcare provider about birth control methods that you can use during this time.
o
Tell your healthcare provider right away if you become pregnant during treatment with Opdivo.
are breastfeeding or plan to breastfeed. It is not known if Opdivo passes into your breast milk. Do not breastfeed during treatment with Opdivo.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

How will I receive Opdivo?

Your healthcare provider will give you Opdivo into your vein through an intravenous (IV) line over 30 minutes.
When Opdivo is used alone, it is usually given every 2 weeks or 4 weeks depending on the dose you are receiving.
When Opdivo is used in combination with ipilimumab (except for treating NSCLC), Opdivo is usually given every 3 weeks, for a total of 4 doses. Ipilimumab will be given on the same day. After that, Opdivo will be given alone every 2 weeks or 4 weeks depending on the dose you are receiving.
For NSCLC that has spread to other parts of your body, when Opdivo is used in combination with ipilimumab, Opdivo is given either every 2 weeks or every 3 weeks, and ipilimumab is given every 6 weeks for up to 2 years. Your healthcare provider will determine if you will also need to receive chemotherapy every 3 weeks for 2 cycles.
For malignant pleural mesothelioma, Opdivo is given every 3 weeks and ipilimumab is given every 6 weeks for up to 2 years.
For RCC, when used in combination with cabozantinib, Opdivo is usually given every 2 weeks or 4 weeks depending on the dose you are receiving. Cabozantinib is given once daily by mouth.
For gastric cancer, gastroesophageal junction cancer and esophageal adenocarcinoma, when used in combination with fluoropyrimidine and platinum-containing chemotherapy, Opdivo is given every 2 weeks or 3 weeks depending on the dose you are receiving. Chemotherapy will be given on the same day.
Your healthcare provider will decide how many treatments you need.
Your healthcare provider will do blood tests to check you for side effects.
If you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment.

What are the possible side effects of Opdivo?

Opdivo can cause serious side effects, including:

See “What is the most important information I should know about Opdivo?”
Severe infusion reactions. Tell your healthcare provider or nurse right away if you get these symptoms during an infusion of Opdivo:
o
chills or shaking
o
itching or rash
o
flushing
o
shortness of breath or wheezing
o
dizziness
o
feel like passing out
o
fever
o
back or neck pain
Complications of stem cell transplant that uses donor stem cells (allogeneic). These complications can be severe and can lead to death. These complications may happen if you underwent transplantation either before or after being treated with Opdivo. Your healthcare provider will monitor you for signs of complications if you have an allogeneic stem cell transplant.

The most common side effects of Opdivo when used alone include:

feeling tired
rash
pain in muscles, bones, and joints
itchy skin
diarrhea
nausea
weakness
cough
vomiting
shortness of breath
constipation
decreased appetite
back pain
upper respiratory tract infection
fever
headache
stomach-area (abdominal) pain
urinary tract infection

The most common side effects of Opdivo when used in combination with ipilimumab include:

feeling tired
diarrhea
rash
itching
nausea
pain in muscles, bones, and joints
fever
cough
decreased appetite
vomiting
stomach-area (abdominal) pain
shortness of breath
upper respiratory tract infection
headache
low thyroid hormone levels (hypothyroidism)
decreased weight
dizziness

The most common side effects of Opdivo when used in combination with ipilimumab and chemotherapy include:

feeling tired
pain in muscles, bones, and joints
nausea
diarrhea
rash
decreased appetite
constipation
itching

The most common side effects of Opdivo when used in combination with cabozantinib include:

diarrhea
feeling tired or weak
liver problems. See “What is the most important information I should know about Opdivo?”
rash, redness, pain, swelling or blisters on the palms of your hands or soles of your feet
mouth sores
rash
high blood pressure
low thyroid hormone levels
pain in muscles, bones, and joints
decreased appetite
nausea
change in the sense of taste
stomach-area (abdominal) pain
cough
upper respiratory tract infection

The most common side effects of Opdivo when used in combination with fluoropyrimidine and platinum-containing chemotherapy include:

numbness, pain, tingling, or burning in your hands or feet
nausea
feeling tired
diarrhea
vomiting
decreased appetite
stomach-area (abdominal) pain
constipation
pain in muscles, bones, and joints

These are not all the possible side effects of Opdivo.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of Opdivo.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about Opdivo that is written for health professionals.

What are the ingredients in Opdivo?

Active ingredient: nivolumab

Inactive ingredients: mannitol, pentetic acid, polysorbate 80, sodium chloride, sodium citrate dihydrate, and Water for Injection. May contain hydrochloric acid and/or sodium hydroxide.

Manufactured by: Bristol-Myers Squibb Company, Princeton, NJ 08543 USA U.S. License No. 1713

Opdivo® and YERVOY® are trademarks of Bristol-Myers Squibb Company. Other brands listed are the trademarks of their respective owners.

For more information, call 1-855-673-4861 or go to www.Opdivo.com.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Revised: August 2021

Opdivo 40 mg/4 mL Representative Packaging

See How Supplied section for a complete list of available packages of Opdivo.

NDC 0003-3772-11
Rx only

Opdivo®
(nivolumab)
injection

40 mg/4 mL
(10 mg/mL)

For intravenous Infusion Only
Single-dose vial; Discard unused portion.
Please provide enclosed Medication Guide to the patient.

Bristol Myers Squibb

Opdivo 100 mg/10 mL Representative Packaging

NDC 0003-3774-12
Rx only

Opdivo®
(nivolumab)
injection

100 mg/10 mL
(10 mg/mL)

For Intravenous Infusion Only
Single-dose vial; Discard unused portion.
Please provide enclosed Medication Guide to the patient.

Bristol Myers Squibb

Opdivo 120 mg/12 mL Representative Packaging

NDC 0003-3756-14
Rx only

Opdivo®
(nivolumab)
injection

120 mg/12 mL
(10 mg/mL)

For Intravenous Infusion Only
Single-dose vial; Discard unused portion.
Please provide enclosed Medication Guide to the patient.

Bristol Myers Squibb

Opdivo 240 mg/24 mL Representative Packaging

NDC 0003-3734-13
Rx only

Opdivo®
(nivolumab)
injection

240 mg/24 mL
(10 mg/mL)

For Intravenous Infusion Only
Single-dose vial; Discard unused portion.
Please provide enclosed Medication Guide to the patient.

Bristol Myers Squibb

Opdivo
nivolumab injection
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0003-3772
Route of Administration INTRAVENOUS DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
NIVOLUMAB (NIVOLUMAB) NIVOLUMAB 10 mg in 1 mL
Inactive Ingredients
Ingredient Name Strength
MANNITOL 30 mg in 1 mL
PENTETIC ACID 0.008 mg in 1 mL
POLYSORBATE 80 0.2 mg in 1 mL
SODIUM CHLORIDE 2.92 mg in 1 mL
TRISODIUM CITRATE DIHYDRATE 5.88 mg in 1 mL
WATER
HYDROCHLORIC ACID
SODIUM HYDROXIDE
Packaging
# Item Code Package Description
1 NDC:0003-3772-11 1 VIAL, SINGLE-DOSE in 1 CARTON
1 4 mL in 1 VIAL, SINGLE-DOSE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
BLA BLA125554 12/22/2014
Opdivo
nivolumab injection
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0003-3774
Route of Administration INTRAVENOUS DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
NIVOLUMAB (NIVOLUMAB) NIVOLUMAB 10 mg in 1 mL
Inactive Ingredients
Ingredient Name Strength
MANNITOL 30 mg in 1 mL
PENTETIC ACID 0.008 mg in 1 mL
POLYSORBATE 80 0.2 mg in 1 mL
SODIUM CHLORIDE 2.92 mg in 1 mL
TRISODIUM CITRATE DIHYDRATE 5.88 mg in 1 mL
WATER
HYDROCHLORIC ACID
SODIUM HYDROXIDE
Packaging
# Item Code Package Description
1 NDC:0003-3774-12 1 VIAL, SINGLE-DOSE in 1 CARTON
1 10 mL in 1 VIAL, SINGLE-DOSE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
BLA BLA125554 12/22/2014
Opdivo
nivolumab injection
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0003-3734
Route of Administration INTRAVENOUS DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
NIVOLUMAB (NIVOLUMAB) NIVOLUMAB 10 mg in 1 mL
Inactive Ingredients
Ingredient Name Strength
MANNITOL 30 mg in 1 mL
PENTETIC ACID 0.008 mg in 1 mL
POLYSORBATE 80 0.2 mg in 1 mL
SODIUM CHLORIDE 2.92 mg in 1 mL
TRISODIUM CITRATE DIHYDRATE 5.88 mg in 1 mL
WATER
HYDROCHLORIC ACID
SODIUM HYDROXIDE
Packaging
# Item Code Package Description
1 NDC:0003-3734-13 1 VIAL, SINGLE-DOSE in 1 CARTON
1 24 mL in 1 VIAL, SINGLE-DOSE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
BLA BLA125554 12/08/2017
Opdivo
nivolumab injection
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0003-3756
Route of Administration INTRAVENOUS DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
NIVOLUMAB (NIVOLUMAB) NIVOLUMAB 10 mg in 1 mL
Inactive Ingredients
Ingredient Name Strength
MANNITOL 30 mg in 1 mL
PENTETIC ACID 0.008 mg in 1 mL
POLYSORBATE 80 0.2 mg in 1 mL
SODIUM CHLORIDE 2.92 mg in 1 mL
TRISODIUM CITRATE DIHYDRATE 5.88 mg in 1 mL
WATER
HYDROCHLORIC ACID
SODIUM HYDROXIDE
Packaging
# Item Code Package Description
1 NDC:0003-3756-14 1 VIAL, SINGLE-DOSE in 1 CARTON
1 12 mL in 1 VIAL, SINGLE-DOSE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
BLA BLA125554 08/30/2021
Labeler - E.R. Squibb & Sons, L.L.C. (011550092)
E.R. Squibb & Sons, L.L.C.

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