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Opdivo

Generic Name: nivolumab
Dosage Form: injection

Indications and Usage for Opdivo

Unresectable or Metastatic Melanoma

Opdivo® as a single agent is indicated for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma [see Clinical Studies (14.1)].
Opdivo as a single agent is indicated for the treatment of patients with BRAF V600 mutation-positive unresectable or metastatic melanoma [see Clinical Studies (14.1)].
 
This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
Opdivo, in combination with ipilimumab, is indicated for the treatment of patients with unresectable or metastatic melanoma [see Clinical Studies (14.1)].
 
This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Metastatic Non-Small Cell Lung Cancer

Opdivo is indicated for the treatment of patients with metastatic non-small cell lung cancer (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 [see Clinical Studies (14.2)].

Renal Cell Carcinoma

Opdivo is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy [see Clinical Studies (14.3)].

Classical Hodgkin Lymphoma

Opdivo is indicated for the treatment of patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post-transplantation brentuximab vedotin [see Clinical Studies (14.4)]. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials [see Clinical Studies (14.4)].

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 [see Clinical Studies (14.5)].

Opdivo Dosage and Administration

Recommended Dosage for Melanoma

The recommended dose of Opdivo as a single agent is 240 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.

The recommended dose of Opdivo is 1 mg/kg administered as an intravenous infusion over 60 minutes, followed by ipilimumab on the same day, every 3 weeks for 4 doses [see Clinical Studies (14.1)]. The recommended subsequent dose of Opdivo, as a single agent, is 240 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. Review the Full Prescribing Information for ipilimumab prior to initiation.

Recommended Dosage for NSCLC

The recommended dose of Opdivo is 240 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.

Recommended Dosage for RCC

The recommended dose of Opdivo is 240 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.

Recommended Dosage for cHL

The recommended dose of Opdivo is 3 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.

Recommended Dosage for SCCHN

The recommended dose of Opdivo is 3 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.

Dose Modifications

Recommendations for Opdivo modifications are provided in Table 1. When Opdivo is administered in combination with ipilimumab, if Opdivo is withheld, ipilimumab should also be withheld.

There are no recommended dose modifications for hypothyroidism or hyperthyroidism.

Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions. Discontinue Opdivo in patients with severe or life-threatening infusion reactions.

Table 1:     Recommended Dose Modifications for Opdivo

Adverse Reaction

Severity*

Dose Modification

Colitis

Grade 2 diarrhea or colitis

Withhold dosea

Grade 3 diarrhea or colitis

Withhold dosea when administered as a single agent

 

Permanently discontinue when administered with ipilimumab

   

Grade 4 diarrhea or colitis

Permanently discontinue

 

Pneumonitis

Grade 2 pneumonitis

Withhold dosea

Grade 3 or 4 pneumonitis

Permanently discontinue

 

Hepatitis

Aspartate aminotransferase (AST)/or alanine aminotransferase (ALT) more than 3 and up to 5 times the upper limit of normal or total bilirubin more than 1.5 and up to 3 times the upper limit of normal

Withhold dosea

AST or ALT more than 5 times the upper limit of normal or total bilirubin more than 3 times the upper limit of normal

Permanently discontinue

 

Hypophysitis

Grade 2 or 3 hypophysitis

Withhold dosea

Grade 4 hypophysitis

Permanently discontinue

 

Adrenal Insufficiency

Grade 2 adrenal insufficiency

Withhold dosea

Grade 3 or 4 adrenal insufficiency

Permanently discontinue

 

Type 1 Diabetes Mellitus

Grade 3 hyperglycemia

Withhold dosea

Grade 4 hyperglycemia

Permanently discontinue

 

Nephritis and Renal Dysfunction

Serum creatinine more than 1.5 and up to 6 times the upper limit of normal

Withhold dosea

Serum creatinine more than 6 times the upper limit of normal

Permanently discontinue

 

Skin

Grade 3 rash or suspected Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN)

Withhold dosea

Grade 4 rash or confirmed SJS or TEN

Permanently discontinue

 

Encephalitis

New-onset moderate or severe neurologic signs or symptoms

Withhold dosea

Immune-mediated encephalitis

Permanently discontinue

 

Other

Other Grade 3 adverse reaction

     First occurrence

Withhold dosea

 

     Recurrence of same Grade 3 adverse reactions

Permanently discontinue

 

Life-threatening or Grade 4 adverse reaction

Permanently discontinue

 

Requirement for 10 mg per day or greater prednisone or equivalent for more than 12 weeks

Permanently discontinue

 

Persistent Grade 2 or 3 adverse reactions lasting 12 weeks or longer

Permanently discontinue

 

*Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events. Version 4.0 (NCI CTCAE v4).
a  Resume treatment when adverse reaction returns to Grade 0 or 1.

Preparation and Administration

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

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.
Mix diluted solution by gentle inversion. Do not shake.
Discard partially used vials or empty vials of Opdivo.
Storage of Infusion

The product does not contain a preservative.

After preparation, store the Opdivo infusion either:

at room temperature for no more than 4 hours from the time of preparation. This includes room temperature storage of the infusion in the IV container and time for administration of the infusion or
under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of infusion preparation.

Do not freeze.

Administration

Administer the infusion over 60 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).

Do not coadminister other drugs through the same intravenous line.

Flush the intravenous line at end of infusion.

When administered in combination with ipilimumab, infuse Opdivo first followed by ipilimumab on the same day. Use separate infusion bags and filters for each infusion.

Dosage Forms and Strengths

Injection: 40 mg/4 mL (10 mg/mL) and 100 mg/10 mL (10 mg/mL) solution in a single-dose vial.

Contraindications

None.

Warnings and Precautions

Immune-Mediated Pneumonitis

Opdivo can cause immune-mediated pneumonitis, defined as requiring use of corticosteroids and no clear alternate etiology. Fatal cases have been reported.

Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for moderate (Grade 2) or more severe (Grade 3-4) pneumonitis, followed by corticosteroid taper. Permanently discontinue Opdivo for severe (Grade 3) or life-threatening (Grade 4) pneumonitis and withhold Opdivo until resolution for moderate (Grade 2) pneumonitis [see Dosage and Administration (2.6)].

Opdivo as a Single Agent

In patients receiving Opdivo as a single agent, immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients. The median time to onset of immune‑mediated pneumonitis was 3.5 months (range: 1 day to 22.3 months). Immune-mediated pneumonitis led to permanent discontinuation of Opdivo in 1.1%, and withholding of Opdivo in 1.3% of patients. Approximately 89% of patients with pneumonitis received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 26 days (range: 1 day to 6 months). Complete resolution of symptoms following corticosteroid taper occurred in 67% of patients. Approximately 8% of patients had recurrence of pneumonitis after re-initiation of Opdivo.

Opdivo with Ipilimumab

In patients receiving Opdivo with ipilimumab, immune-mediated pneumonitis occurred in 6% (25/407) of patients. The median time to onset of immune-mediated pneumonitis was 1.6 months (range: 24 days to 10.1 months). Immune-mediated pneumonitis led to permanent discontinuation or withholding of Opdivo with ipilimumab in 2.2% and 3.7% of patients, respectively. Approximately 84% of patients with pneumonitis received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 30 days (range: 5 days to 11.8 months). Complete resolution occurred in 68% of patients. Approximately 13% of patients had recurrence of pneumonitis after re-initiation of Opdivo with ipilimumab.

Immune-Mediated Colitis

Opdivo can cause immune-mediated colitis, defined as requiring use of corticosteroids with no clear alternate etiology.

Monitor patients for signs and symptoms of colitis. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for severe (Grade 3) or life-threatening (Grade 4) colitis. Administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents followed by corticosteroid taper for moderate (Grade 2) colitis of more than 5 days duration; if worsening or no improvement occurs despite initiation of corticosteroids, increase dose to 1 to 2 mg/kg/day prednisone equivalents.

Withhold Opdivo for moderate or severe (Grade 2 or 3) colitis. Permanently discontinue Opdivo for life-threatening (Grade 4) or for recurrent colitis upon re-initiation of Opdivo [see Dosage and Administration (2.6)].

When administered in combination with ipilimumab, withhold Opdivo and ipilimumab for moderate colitis (Grade 2). Permanently discontinue Opdivo and ipilimumab for severe or life-threatening (Grade 3 or 4) colitis or for recurrent colitis [see Dosage and Administration (2.6)].

Opdivo as a Single Agent

In patients receiving Opdivo as a single agent, immune-mediated colitis occurred in 2.9% (58/1994) of patients; the median time to onset was 5.3 months (range: 2 days to 20.9 months). Immune-mediated colitis led to permanent discontinuation of Opdivo in 0.7% and withholding of Opdivo in 1% of patients. Approximately 91% of patients with colitis received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 23 days (range: 1 day to 9.3 months). Four patients required addition of infliximab to high-dose corticosteroids. Complete resolution occurred in 74% of patients. Approximately 16% of patients had recurrence of colitis after re-initiation of Opdivo.

Opdivo with Ipilimumab

In patients receiving Opdivo with ipilimumab, immune-mediated colitis occurred in 26% (107/407) of patients including three fatal cases. The median time to onset of immune-mediated colitis was 1.6 months (range: 3 days to 15.2 months). Immune-mediated colitis led to permanent discontinuation or withholding of Opdivo with ipilimumab in 16% and 7% of patients, respectively. Approximately 96% of patients with colitis received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 1.1 month (range: 1 day to 12 months). Approximately 23% of patients required addition of infliximab to high-dose corticosteroids. Complete resolution occurred in 75% of patients. Approximately 28% of patients had recurrence of colitis after re-initiation of Opdivo with ipilimumab.

Immune-Mediated Hepatitis

Opdivo can cause immune-mediated hepatitis, defined as requiring use of corticosteroids and no clear alternate etiology. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for severe (Grade 3) or life-threatening (Grade 4) transaminase elevations, with or without concomitant elevation in total bilirubin. Administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents for moderate (Grade 2) transaminase elevations. Withhold Opdivo for moderate (Grade 2) and permanently discontinue Opdivo for severe (Grade 3) or life‑threatening (Grade 4) immune‑mediated hepatitis [see Dosage and Administration (2.6)].

Opdivo as a Single Agent

In patients receiving Opdivo as a single agent, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients; the median time to onset was 3.3 months (range: 6 days to 9 months). Immune-mediated hepatitis led to permanent discontinuation of Opdivo in 0.7% and withholding of Opdivo in 1% of patients. All patients with hepatitis received high-dose corticosteroids (at least 40 mg prednisone equivalents) for a median duration of 23 days (range: 1 day to 2 months). Two patients required the addition of mycophenolic acid to high-dose corticosteroids. Complete resolution occurred in 74% of patients. Approximately 29% of patients had recurrence of hepatitis after re-initiation of Opdivo.

Opdivo with Ipilimumab

In patients receiving Opdivo with ipilimumab, immune-mediated hepatitis occurred in 13% (51/407) of patients; the median time to onset was 2.1 months (range: 15 days to 11 months). Immune-mediated hepatitis led to permanent discontinuation or withholding of Opdivo with ipilimumab in 6% and 5% of patients, respectively. Approximately 92% of patients with hepatitis received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 1.1 month (range: 1 day to 13.2 months). Complete resolution occurred in 75% of patients. Approximately 11% of patients had recurrence of hepatitis after re-initiation of Opdivo with ipilimumab.

Immune-Mediated Endocrinopathies

Hypophysitis

Opdivo can cause immune-mediated hypophysitis. Monitor patients for signs and symptoms of hypophysitis. Administer hormone replacement as clinically indicated and corticosteroids at a dose of 1 mg/kg/day prednisone equivalents followed by corticosteroid taper for moderate (Grade 2) or greater hypophysitis. Withhold Opdivo for moderate (Grade 2) or severe (Grade 3). Permanently discontinue Opdivo for life‑threatening (Grade 4) hypophysitis [see Dosage and Administration (2.6)].

In patients receiving Opdivo as a single agent, hypophysitis occurred in 0.6% (12/1994) of patients; the median time to onset was 4.9 months (range: 1.4 to 11 months). Hypophysitis led to permanent discontinuation of Opdivo in 0.1% and withholding of Opdivo in 0.2% of patients. Approximately 67% of patients with hypophysitis received hormone replacement therapy and 33% received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 14 days (range: 5 to 26 days).

In patients receiving Opdivo with ipilimumab, hypophysitis occurred in 9% (36/407) of patients; the median time to onset was 2.7 months (range: 27 days to 5.5 months). Hypophysitis led to permanent discontinuation or withholding of Opdivo with ipilimumab in 1.0% and 3.9% of patients, respectively. Approximately 75% of patients with hypophysitis received hormone replacement therapy and 56% received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 19 days (range: 1 day to 2.0 months).

Adrenal Insufficiency

Opdivo can cause immune-mediated adrenal insufficiency. Monitor patients for signs and symptoms of adrenal insufficiency. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by a corticosteroid taper for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency. Withhold Opdivo for moderate (Grade 2) and permanently discontinue Opdivo for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency [see Dosage and Administration (2.6)].

In patients receiving Opdivo as a single agent, adrenal insufficiency occurred in 1% (20/1994) of patients and the median time to onset was 4.3 months (range: 15 days to 21 months). Adrenal insufficiency led to permanent discontinuation of Opdivo in 0.1% and withholding of Opdivo in 0.5% of patients. Approximately 85% of patients with adrenal insufficiency received hormone replacement therapy and 25% received high‑dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 11 days (range: 1 day to 1 month).

In patients receiving Opdivo with ipilimumab, adrenal insufficiency occurred in 5% (21/407) of patients and the median time to onset was 3.0 months (range: 21 days to 9.4 months). Adrenal insufficiency led to permanent discontinuation or withholding of Opdivo with ipilimumab in 0.5% and 1.7% of patients, respectively. Approximately 57% of patients with adrenal insufficiency received hormone replacement therapy and 33% received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 9 days (range: 1 day to 2.7 months).

Hypothyroidism and Hyperthyroidism

Opdivo can cause autoimmune thyroid disorders. Monitor thyroid function prior to and periodically during Opdivo treatment. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. There are no recommended dose adjustments of Opdivo for hypothyroidism or hyperthyroidism.

In patients receiving Opdivo as a single agent, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 9% (171/1994) of patients; the median time to onset was 2.9 months (range: 1 day to 16.6 months). Approximately 79% of patients with hypothyroidism received levothyroxine and 4% also required corticosteroids. Resolution occurred in 35% of patients.

Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving Opdivo as a single agent; the median time to onset was 1.5 months (range: 1 day to 14.2 months). Approximately 26% of patients with hyperthyroidism received methimazole, 9% received carbimazole, 4% received propylthiouracil, and 9% received corticosteroids. Resolution occurred in 76% of patients.

In patients receiving Opdivo with ipilimumab, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (89/407) of patients; the median time to onset was 2.1 months (range: 1 day to 10.1 months). Approximately 73% of patients with hypothyroidism or thyroiditis received levothyroxine. Resolution occurred in 45% of patients.

Hyperthyroidism occurred in 8% (34/407) of patients receiving Opdivo with ipilimumab: the median time to onset was 23 days (range: 3 days to 3.7 months). Approximately 29% of patients with hyperthyroidism received methimazole and 24% received carbimazole. Resolution occurred in 94% of patients.

Type 1 Diabetes Mellitus

Opdivo can cause Type 1 diabetes mellitus. Monitor for hyperglycemia. Withhold Opdivo in cases of severe (Grade 3) hyperglycemia until metabolic control is achieved. Permanently discontinue Opdivo for life‑threatening (Grade 4) hyperglycemia [see Dosage and Administration (2.6)].

In patients receiving Opdivo as a single agent, diabetes occurred in 0.9% (17/1994) of patients including two cases of diabetic ketoacidosis. The median time to onset was 4.4 months (range: 15 days to 22 months).

In patients receiving Opdivo with ipilimumab, diabetes occurred in 1.5% (6/407) of patients; the median time to onset was 2.5 months (range: 1.3 to 4.4 months). Opdivo with ipilimumab was withheld in a patient and permanently discontinued in a second patient who developed diabetes.

Immune-Mediated Nephritis and Renal Dysfunction

Opdivo can cause immune-mediated nephritis, defined as renal dysfunction or ≥Grade 2 increased creatinine, requirement for corticosteroids, and no clear alternate etiology. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for life-threatening (Grade 4) increased serum creatinine. Administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents for moderate (Grade 2) or severe (Grade 3) increased serum creatinine, if worsening or no improvement occurs, increase dose of corticosteroids to 1 to 2 mg/kg/day prednisone equivalents.

Withhold Opdivo for moderate (Grade 2) or severe (Grade 3) increased serum creatinine. Permanently discontinue Opdivo for life-threatening (Grade 4) increased serum creatinine [see Dosage and Administration (2.6) and Adverse Reactions (6.1)].

Opdivo as a Single Agent

In patients receiving Opdivo as a single agent, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients; the median time to onset was 4.6 months (range: 23 days to 12.3 months). Immune-mediated nephritis and renal dysfunction led to permanent discontinuation of Opdivo in 0.3% and withholding of Opdivo in 0.8% of patients. All patients received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 21 days (range: 1 day to 15.4 months). Complete resolution occurred in 48% of patients. No patients had recurrence of nephritis or renal dysfunction after re-initiation of Opdivo.

Opdivo with Ipilimumab

In patients receiving Opdivo with ipilimumab, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients; the median time to onset was 2.7 months (range: 9 days to 7.9 months). Immune‑mediated nephritis and renal dysfunction led to permanent discontinuation or withholding of Opdivo with ipilimumab in 0.7% and 0.5% of patients, respectively. Approximately 67% of patients received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 13.5 days (range: 1 day to 1.1 months). Complete resolution occurred in all patients. Two patients resumed Opdivo with ipilimumab without recurrence of nephritis or renal dysfunction.

Immune-Mediated Skin Adverse Reactions

Opdivo can cause immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with fatal outcome. For symptoms or signs of SJS or TEN, withhold Opdivo and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue Opdivo [see Dosage and Administration (2.6)].

For immune-mediated rash, administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by a corticosteroid taper for severe (Grade 3) or life‑threatening (Grade 4) rash. Withhold Opdivo for severe (Grade 3) rash and permanently discontinue Opdivo for life-threatening (Grade 4) rash.

Opdivo as a Single Agent

In patients receiving Opdivo as a single agent, immune-mediated rash occurred in 9% (171/1994) of patients; the median time to onset was 2.8 months (range: <1 day to 25.8 months). Immune-mediated rash led to permanent discontinuation of Opdivo in 0.3% and withholding of Opdivo in 0.8% of patients. Approximately 16% of patients with rash received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 12 days (range: 1 days to 8.9 months) and 85% received topical corticosteroids. Complete resolution occurred in 48% of patients. Recurrence of rash occurred in 1.4% of patients who resumed Opdivo after resolution of rash.

Opdivo with Ipilimumab

In patients receiving Opdivo with ipilimumab, immune-mediated rash occurred in 22.6% (92/407) of patients; the median time to onset was 18 days (range: 1 day to 9.7 months). Immune-mediated rash led to permanent discontinuation or withholding of Opdivo with ipilimumab in 0.5% and 3.9% of patients, respectively. Approximately 17% of patients with rash received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 14 days (range: 2 days to 4.7 months). Complete resolution occurred in 47% of patients. Approximately 6% of patients who resumed Opdivo and ipilimumab after resolution had recurrence of rash.

Immune-Mediated Encephalitis

ODPIVO can cause immune-mediated encephalitis with no clear alternate etiology. Evaluation of patients with neurologic symptoms may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture.

Withhold Opdivo in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out infectious or other causes of moderate to severe neurologic deterioration. If other etiologies are ruled out, administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for patients with immune-mediated encephalitis, followed by corticosteroid taper. Permanently discontinue Opdivo for immune-mediated encephalitis [seeDosage and Administration (2.6)].

Opdivo as a Single Agent

In patients receiving Opdivo as a single agent, encephalitis occurred in 0.2% (3/1994). Fatal limbic encephalitis occurred in one patient after 7.2 months of exposure despite discontinuation of Opdivo and administration of corticosteroids. In the other two patients encephalitis occurred post-allogeneic HSCT [see Warnings and Precautions (5.10)].

Opdivo with Ipilimumab

Encephalitis occurred in one patient receiving Opdivo with ipilimumab (0.2%) after 1.7 months of exposure.

Other Immune-Mediated Adverse Reactions

Opdivo can cause other clinically significant immune-mediated adverse reactions. Immune-mediated adverse reactions may occur after discontinuation of Opdivo therapy. For any suspected immune-mediated adverse reactions, exclude other causes. Based on the severity of the adverse reaction, permanently discontinue or withhold Opdivo, administer high-dose corticosteroids, and if appropriate, initiate hormone-replacement therapy. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider restarting Opdivo after completion of corticosteroid taper based on the severity of the event [see Dosage and Administration (2.6)].

Across clinical trials of Opdivo administered as a single agent or in combination with ipilimumab, the following clinically significant immune-mediated adverse reactions occurred in less than 1.0% of patients receiving Opdivo: uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain‑Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), myositis, myocarditis, rhabdomyolysis, motor dysfunction, vasculitis, and myasthenic syndrome.

Infusion Reactions

Opdivo can cause severe infusion reactions, which have been reported in less than 1.0% of patients in clinical trials. Discontinue Opdivo in patients with severe or life-threatening infusion reactions. Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions [see Dosage and Administration (2.6)].

Opdivo as a Single Agent

In patients receiving Opdivo as a single agent, infusion-related reactions occurred in 6.4% (127/1994) of patients.

Opdivo with Ipilimumab

In patients receiving Opdivo with ipilimumab, infusion-related reactions occurred in 2.5% (10/407) of patients.

Complications of Allogeneic HSCT after Opdivo

Complications, including fatal events, occurred in patients who received allogeneic HSCT after Opdivo. Outcomes were evaluated in 17 patients from Trials 8 and 9 who underwent allogeneic HSCT after discontinuing Opdivo (15 with reduced-intensity conditioning, two with myeloablative conditioning). The median age at HSCT was 33 (range: 18 to 56), and a median of 9 doses of Opdivo had been administered (range: 4 to 16). Six of 17 patients (35%) died from complications of allogeneic HSCT after Opdivo. Five deaths occurred in the setting of severe or refractory GVHD. Grade 3 or higher acute GVHD was reported in 5/17 patients (29%). Hyperacute GVHD, defined as GVHD occurring within 14 days after stem cell infusion, was reported in 2 patients (20%). A steroid-requiring febrile syndrome, without an identified infectious cause, was reported in six patients (35%) within the first 6 weeks post-transplantation, with five patients responding to steroids. Two cases of encephalitis were reported: one case of Grade 3 lymphocytic encephalitis without an identified infectious cause, which occurred and resolved on steroids, and one case of Grade 3 suspected viral encephalitis which was resolved with antiviral treatment. Hepatic veno-occlusive disease (VOD) occurred in one patient, who received reduced-intensity conditioned allogeneic HSCT and died of GVHD and multi-organ failure.

Other cases of hepatic VOD after reduced-intensity conditioned allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor blocking antibody before transplantation. Cases of fatal hyperacute GVHD have also been reported.

These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT.

Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, severe (Grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune-mediated adverse reactions, and intervene promptly.

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 an Opdivo-containing regimen and for at least 5 months after the last dose of Opdivo [see Use in Specific Populations (8.1, 8.3)].

Adverse Reactions

The following adverse reactions are discussed in greater detail in other sections of the labeling.

Immune-Mediated Pneumonitis [see Warnings and Precautions (5.1)]
Immune-Mediated Colitis [see Warnings and Precautions (5.2)]
Immune-Mediated Hepatitis [see Warnings and Precautions (5.3)]
Immune-Mediated Endocrinopathies [see Warnings and Precautions (5.4)]
Immune-Mediated Nephritis and Renal Dysfunction [see Warnings and Precautions (5.5)]
Immune-Mediated Skin Adverse Reactions [see Warnings and Precautions (5.6)]
Immune-Mediated Encephalitis [see Warnings and Precautions (5.7)]
Other Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.8)]
Infusion Reactions [see Warnings and Precautions (5.9)]
Complications of Allogeneic HSCT after Opdivo [see Warnings and Precautions (5.10)]

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 the Warnings and Precautions section reflect exposure to Opdivo, as a single agent, for clinically significant adverse reactions in 1994 patients enrolled in Trials 1 through 8 or a single-arm trial in NSCLC (n=117) administering Opdivo as a single agent [see Warnings and Precautions (5.1, 5.8)]. In addition, clinically significant adverse reactions of Opdivo administered with ipilimumab were evaluated in 407 patients with melanoma enrolled in Trial 6 (n=313) or a Phase 2 randomized study (n=94), administering Opdivo with ipilimumab, supplemented by immune-mediated adverse reaction reports in ongoing clinical trials [see Warnings and Precautions (5.1, 5.8)].

The data described below reflect exposure to Opdivo as a single agent in Trials 1, 4, and 6, and to Opdivo with ipilimumab in Trial 6, which are randomized, active-controlled trials conducted in patients with unresectable or metastatic melanoma. Also described below are single-agent Opdivo data from Trials 2 and 3, which are randomized trials in patients with metastatic NSCLC, Trial 5, which is a randomized trial in patients with advanced RCC, Trials 7 and 8, which are open-label, multiple-cohort trials in patients with cHL, and Trial 9, a randomized trial in patients with recurrent or metastatic SCCHN.

Unresectable or Metastatic Melanoma

Previously Treated Metastatic Melanoma

The safety of Opdivo as a single agent was evaluated in Trial 1, a randomized, open-label trial in which 370 patients with unresectable or metastatic melanoma received Opdivo 3 mg/kg every 2 weeks (n=268) or investigator’s choice of chemotherapy (n=102), either dacarbazine 1000 mg/m2 every 3 weeks or the combination of carboplatin AUC 6 every 3 weeks plus paclitaxel 175 mg/m2 every 3 weeks [see Clinical Studies (14.1)]. 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 greater than 6 months and 3% of patients received Opdivo for greater than 1 year.

In Trial 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.

The trial 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 LDH at baseline (51% vs. 38%).

Opdivo was discontinued for adverse reactions in 9% of patients. Twenty-six percent of patients receiving Opdivo had a drug delay for an adverse reaction. Serious adverse reactions occurred in 41% of patients receiving Opdivo. 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 less than 5% of patients receiving Opdivo were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase.

Table 2 summarizes the adverse reactions that occurred in at least 10% of Opdivo-treated patients in Trial 1. The most common adverse reaction (reported in at least 20% of patients) was rash.

Table 2:     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]) (Trial 1)
Adverse Reaction Opdivo
(n=268)
Chemotherapy
(n=102)
All Grades Grades 3-4 All Grades Grades 3-4
Percentage (%) of Patients
Toxicity was graded per NCI CTCAE v4.
a  Rash is a composite term which includes maculopapular rash, erythematous rash, pruritic rash, follicular rash, macular rash, papular rash, pustular rash, vesicular rash, and acneiform dermatitis.
b  Upper respiratory tract infection is a composite term which includes rhinitis, pharyngitis, and nasopharyngitis.

Skin and Subcutaneous Tissue Disorders

     Rasha

21

0.4

7

0

     Pruritus

19

0

3.9

0

Respiratory, Thoracic, and Mediastinal Disorders

     Cough

17

0

6

0

Infections

     Upper respiratory tract infectionb

11

0

2.0

0

General Disorders and Administration Site Conditions

     Peripheral edema

10

0

5

0

Other clinically important adverse reactions in less than 10% of patients treated with Opdivo in Trial 1 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 3:     Laboratory Abnormalities Worsening from Baseline 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]) (Trial 1)
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

Percentage of Patients with Worsening Laboratory Test from Baselinea

Opdivo

Chemotherapy

All Grades

Grades 3-4

All Grades

Grades 3-4

Increased AST

28

2.4

12

1.0

Increased alkaline phosphatase

22

2.4

13

1.1

Hyponatremia

25

5

18

1.1

Increased ALT

16

1.6

5

0

Hyperkalemia

15

2.0

6

0

Previously Untreated Metastatic Melanoma

Trial 4

The safety of Opdivo was also evaluated in Trial 4, a randomized, double-blind, active-controlled trial in which 411 previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma received Opdivo 3 mg/kg every 2 weeks (n=206) or dacarbazine 1000 mg/m2 every 3 weeks (n=205) [see Clinical Studies (14.1)]. 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 greater than 6 months and 12% of patients received Opdivo for greater than 1 year.

The trial excluded patients with autoimmune disease and patients requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications.

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%).

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. Serious adverse reactions occurred in 36% of patients receiving Opdivo. Grade 3 and 4 adverse reactions occurred in 41% of patients receiving Opdivo. The most frequent Grade 3 and 4 adverse reactions reported in at least 2% of patients receiving Opdivo were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%).

Table 4 summarizes selected adverse reactions that occurred in at least 10% of Opdivo-treated patients. The most common adverse reactions (reported in at least 20% of patients and at a higher incidence than in the dacarbazine arm) were fatigue, musculoskeletal pain, rash, and pruritus.

Table 4:     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]) (Trial 5)
Adverse Reaction Opdivo
(n=206)
Dacarbazine
(n=205)
All Grades Grades 3-4 All Grades Grades 3-4
Percentage (%) of Patients
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.

General Disorders and Administration Site Conditions

     Fatigue

49

1.9

39

3.4

     Edemaa

12

1.5

4.9

0

Musculoskeletal and Connective Tissue Disorders

     Musculoskeletal painb

32

2.9

25

2.4

Skin and Subcutaneous Tissue Disorders

     Rashc

28

1.5

12

0

     Pruritus

23

0.5

12

0

     Erythema

10

0

2.9

0

     Vitiligo

11

0

0.5

0

Infections

     Upper respiratory tract infectiond

17

0

6

0

Other clinically important adverse reactions in less than 10% of patients treated with Opdivo in Trial 5 were:

Nervous System Disorders: peripheral neuropathy

Table 5:     Laboratory Abnormalities Worsening from Baseline 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]) (Trial 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 group (range: 194 to 197 patients) and dacarbazine group (range: 186 to 193 patients).

Laboratory Abnormality

Percentage of Patients with Worsening Laboratory Test from Baselinea

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

Trial 6

The safety of Opdivo, administered with ipilimumab or as a single agent, was evaluated in Trial 6 [see Clinical Studies (14.1)], a randomized (1:1:1), a double-blind trial in which 937 patients with previously untreated, unresectable or metastatic melanoma received:

Opdivo 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks for 4 doses followed by Opdivo 3 mg/kg as a single agent every 2 weeks (Opdivo plus ipilimumab arm; n=313),
Opdivo 3 mg/kg every 2 weeks (Opdivo arm; n=313), or
Ipilimumab 3 mg/kg 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 18.8 months) for the Opdivo plus ipilimumab arm and 6.6 months (range: 1 day to 17.3 months) for the Opdivo arm. In the Opdivo plus ipilimumab arm, 39% were exposed to Opdivo for ≥6 months and 24% exposed for >1 year. In the Opdivo arm, 53% were exposed for ≥6 months and 32% for >1 year.

Trial 6 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.

The trial population characteristics were: 65% male, median age 61 years, 97% White, baseline ECOG performance status 0 (73%) or 1 (27%), 93% with 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.

In Trial 6, serious adverse reactions (73% and 37%), adverse reactions leading to permanent discontinuation (43% and 14%) or to dosing delays (55% and 28%), and Grade 3 or 4 adverse reactions (72% and 44%) all occurred more frequently in the Opdivo plus ipilimumab arm relative to the Opdivo arm.

The most frequent (≥10%) serious adverse reactions in the Opdivo plus ipilimumab arm and the Opdivo arm, respectively, were diarrhea (13% and 2.6%), colitis (10% and 1.6%), and pyrexia (10% and 0.6%). The most frequent adverse reactions leading to discontinuation of both drugs in the Opdivo plus ipilimumab arm and of Opdivo in the Opdivo arm, respectively, were diarrhea (8% and 1.9%), colitis (8% and 0.6%), increased ALT (4.8% and 1.3%), increased AST (4.5% and 0.6%), and pneumonitis (1.9% and 0.3%). The most common (≥20%) adverse reactions in the Opdivo plus ipilimumab arm were fatigue, rash, diarrhea, nausea, pyrexia, vomiting, and dyspnea. The most common (≥20%) adverse reactions in the Opdivo arm were fatigue, rash, diarrhea, and nausea. Table 6 summarizes the incidence of adverse reactions occurring in at least 10% of patients in either Opdivo-containing arm in Trial 6.

Table 6:     Adverse Reactions Occurring in ≥10% of Patients on the Opdivo plus 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]) (Trial 6)
Adverse Reaction Percentage (%) of Patients
Opdivo plus Ipilimumab
(n=313)
Opdivo
(n=313)
Ipilimumab
(n=311)
All
Grades
Grades
3-4
All
Grades
Grades
3-4
All
Grades
Grades
3-4
Toxicity was graded per NCI CTCAE v4.
a  Fatigue is a composite term which includes asthenia and fatigue.
b  Rash is a composite term which includes pustular rash, dermatitis, acneiform dermatitis, allergic dermatitis, atopic dermatitis, bullous dermatitis, exfoliative dermatitis, psoriasiform dermatitis, drug eruption, erythema, exfoliative rash, erythematous rash, generalized rash, macular rash, maculopapular rash, morbilliform rash, papular rash, papulosquamous rash, pruritic rash, and seborrheic dermatitis.

General Disorders and Administration Site Conditions

     Fatiguea

59

6

53

1.9

50

3.9

     Pyrexia

37

1.6

14

0

17

0.6

Skin and Subcutaneous Tissue Disorders

     Rashb

53

5

40

1.6

42

3.9

Gastrointestinal Disorders

     Diarrhea

52

11

31

3.8

46

8

     Nausea

40

3.5

28

0.6

29

1.9

     Vomiting

28

3.5

17

1.0

16

1.6

Respiratory, Thoracic and Mediastinal Disorders

     Dyspnea

20

2.2

12

1.3

13

0.6

Other clinically important adverse reactions in less than 10% of patients treated with either Opdivo with ipilimumab or single-agent Opdivo in Trial 6 were:

Gastrointestinal Disorders: stomatitis, intestinal perforation

Skin and Subcutaneous Tissue Disorders: vitiligo

Musculoskeletal and Connective Tissue Disorders: myopathy, Sjogren’s syndrome, spondyloarthropathy

Nervous System Disorders: neuritis, peroneal nerve palsy

Table 7:     Laboratory Abnormalities Worsening from Baseline 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]) (Trial 6)
Laboratory Abnormality Percentage (%) of Patientsa
Opdivo plus Ipilimumab Opdivo Ipilimumab
Any
Grade
Grade
3-4
Any
Grade
Grade
3-4
Any
Grade
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 plus ipilimumab (range: 241 to 297); Opdivo (range: 260 to 306); ipilimumab (range: 253 to 304).

Chemistry

     Increased ALT

53

15

23

3.0

28

2.7

     Increased AST

47

13

27

3.7

27

1.7

     Hyponatremia

42

9

20

3.3

25

7

     Increased lipase

41

20

29

9

23

7

     Increased alkaline phosphatase

40

6

24

2.0

22

2.0

     Hypocalcemia

29

1.1

13

0.7

21

0.7

     Increased amylase

25

9.1

15

1.9

14

1.6

     Increased creatinine

23

2.7

16

0.3

16

1.3

Hematology

     Anemia

50

2.7

39

2.6

40

6

     Lymphopenia

35

4.8

39

4.3

27

3.4

Metastatic Non-Small Cell Lung Cancer

The safety of Opdivo in metastatic NSCLC was evaluated in Trial 2, 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 Trial 3, 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 (14.2)]. Patients received 3 mg/kg of Opdivo administered intravenously over 60 minutes every 2 weeks or docetaxel administered intravenously at 75 mg/m2 every 3 weeks. The median duration of therapy in Opdivo-treated patients in Trial 2 was 3.3 months (range: 1 day to 21.7+ months) and in Trial 3 was 2.6 months (range: 0 to 24.0+ months). In Trial 2, Trial 2, 36% of patients received Opdivo for at least 6 months and 18% of patients received Opdivo for at least 1 year and in Trial 3, 30% of patients received Opdivo for greater than 6 months and 20% of patients received Opdivo for greater than 1 year.

Trial 2 and Trial 3 excluded patients with active autoimmune disease, medical conditions requiring systemic immunosuppression, or with symptomatic interstitial lung disease.

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%).

Opdivo was discontinued in 11% of patients, and was delayed in 28% of patients for an adverse reaction. Serious adverse reactions occurred in 46% of patients receiving Opdivo. The most frequent serious adverse reactions reported in at least 2% of patients receiving Opdivo were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Trial 3, 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.

Across both trials, the most common adverse reactions (reported in at least 20% of patients) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. Table 8 summarizes selected adverse reactions occurring more frequently in at least 10% of Opdivo-treated patients.

Table 8:     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]) (Trials 2 and 3)
Adverse Reaction Opdivo
(n=418)
Docetaxel
(n=397)
All Grades Grades 3-4 All Grades Grades 3-4
Percentage (%) of Patients
Toxicity was graded per NCI CTCAE v4.

Respiratory, Thoracic, and Mediastinal Disorders

     Cough

31

0.7

24

0

Metabolism and Nutrition Disorders

     Decreased appetite

28

1.4

23

1.5

Skin and Subcutaneous Tissue Disorders

     Pruritus

10

0.2

2.0

0

Other clinically important adverse reactions observed in patients treated with Opdivo and which occurred at a similar incidence in docetaxel-treated patients and not listed elsewhere in section 6 include: fatigue/asthenia (48% Grade 1-4, 5% Grade 3-4), musculoskeletal pain (33%), pleural effusion (4.5%), pulmonary embolism (3.3%).

Table 9:     Laboratory Abnormalities Worsening from Baseline 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]) (Trials 2 and 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 (range: 405 to 417 patients) and docetaxel group (range: 372 to 390 patients); TSH: Opdivo group n=314 and docetaxel group n=297.
b  Not graded per NCI CTCAE v4.

Laboratory Abnormality

Percentage of Patients with Worsening Laboratory Test from Baselinea

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

Renal Cell Carcinoma

The safety of Opdivo was evaluated in Trial 5, a randomized open-label trial in which 803 patients with advanced RCC who had experienced disease progression during or after at least one anti-angiogenic treatment regimens received Opdivo 3 mg/kg every 2 weeks (n=406) or everolimus 10 mg daily (n=397) [see Clinical Studies (14.3)]. 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.

Study therapy was discontinued for adverse reactions in 16% of Opdivo patients and 19% of everolimus patients. Forty-four percent (44%) of patients receiving Opdivo had a drug delay for an adverse reaction. Serious adverse reactions occurred in 47% of patients receiving Opdivo. The most frequent serious adverse reactions reported in at least 2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia.

Rate of death on treatment or within 30 days of the last dose of study drug was 4.7% on the Opdivo arm versus 8.6% on the everolimus arm.

The most common adverse reactions (reported in at least 20% of patients) were asthenic conditions, cough, nausea, rash, dyspnea, diarrhea, constipation, decreased appetite, back pain, and arthralgia. Table 10 summarizes adverse reactions that occurred in greater than 15% of Opdivo-treated patients.

Table 10:     Grade 1-4 Adverse Reactions in >15% of Patients Receiving Opdivo (Trial 5)
Toxicity was graded per NCI CTCAE v4.
a  Asthenic conditions covering PTs asthenia, decreased activity, fatigue, and malaise.
b  Includes nasopharyngitis, pharyngitis, rhinitis, and viral 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.

Opdivo

(n=406)

Everolimus

(n=397)

Percentage (%) of Patients

Grades 1-4

Grades 3-4

Grades 1-4

Grades 3-4

Adverse Reaction

98

56

96

62

General Disorders and Administration Site Conditions

     Asthenic conditionsa

56

6

57

7

     Pyrexia

17

0.7

20

0.8

Respiratory, Thoracic and Mediastinal Disorders

     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 Disorders

     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 Disorders

     Rashd

28

1.5

36

1.0

     Pruritus/generalized pruritus

19

0

14

0

Metabolism and Nutrition Disorders

     Decreased appetite

23

1.2

30

1.5

Musculoskeletal and Connective Tissue Disorders

     Arthralgia

20

1.0

14

0.5

     Back pain

21

3.4

16

2.8

Other clinically important adverse reactions in Trial 5 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

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, elevated triglycerides, and hyperkalemia. Table 11 summarizes the laboratory abnormalities that occurred in greater than 15% of Opdivo-treated patients.

Table 11:     Grade 1-4 Laboratory Values Worsening from Baseline Occurring in >15% of Patients on Opdivo (Trial 5)
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

Percentage of Patients with Worsening Laboratory Test from Baselinea

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

In addition, among patients with TSH less than ULN at baseline, a greater proportion of patients experienced a treatment-emergent elevation of TSH greater than ULN in the Opdivo group compared to the everolimus group (26% and 14%, respectively).

Classical Hodgkin Lymphoma

The safety of Opdivo 3 mg/kg every 2 weeks was evaluated in 263 adult patients with cHL (240 patients in Trial 7 and 23 patients in Trial 8). Treatment could continue 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: 1 to 15). Patients received a median of 10 doses (cycles) of Opdivo (range: 1 to 48), with a median duration of therapy of 4.8 months (range: 0.3 to 24 months).

Opdivo was discontinued due to adverse reactions in 4.2% of patients. Twenty-three percent (23%) of patients had a dose delay for an adverse reaction. Serious adverse reactions occurred in 21% of patients. The most frequent serious adverse reactions reported in at least 1% of patients were infusion-related reaction, pneumonia, pleural effusion, pyrexia, rash, and pneumonitis. Ten patients died from causes other than disease progression, including 6 who died from complications of allogeneic HSCT.

The most common adverse reactions (reported in at least 20%) among all patients (safety population), were fatigue, upper respiratory tract infection, pyrexia, diarrhea, and cough.

Among the subset of patients in the efficacy population, the most common adverse reactions also included rash, musculoskeletal pain, pruritus, nausea, arthralgia, and peripheral neuropathy. Serious adverse reactions occurred in 27% of these patients.

Table 12 summarizes both the adverse reactions that occurred in at least 10% of patients in the safety population (n=263) and the efficacy population (n=95). There is a greater incidence of adverse reactions in the subset of patients evaluated for efficacy; these patients received a median of 17 doses of Opdivo and a median of 5 prior systemic regimens [see Clinical Studies (14.4)].

Table 12:     Non-Hematologic Adverse Reactions Occurring in ≥10% of Patients with cHL (Trials 7 and 8)
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 asthenia.
c  Includes abdominal discomfort and upper abdominal pain.
d  Includes nasopharyngitis, pharyngitis, rhinitis, and sinusitis.
e  Includes pneumonia bacterial, pneumonia mycoplasmal, pneumocystis jirovecii pneumonia.
f  Includes dermatitis, dermatitis acneiform, dermatitis exfoliative, and rash described as macular, papular, maculopapular, pruritic, exfoliative, or acneiform.
g  Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, and pain in extremity.
h  Includes hyperesthesia, hypoesthesia, paresthesia, dysesthesia, peripheral motor neuropathy, peripheral sensory neuropathy, and polyneuropathy.

Opdivo cHL
Safety Population
(n=263)

Opdivo cHL
Efficacy Population
(n=95)

Percentage (%) of Patients

Adverse Reactiona

All Grades

Grades 3-4

All Grades

Grades 3-4

General Disorders and Administration Site Conditions

     Fatigueb

32

1.1

43

1.1

     Pyrexia

24

0.8

35

1.1

Gastrointestinal Disorders

     Diarrhea

23

0.8

30

1.1

     Nausea

17

0

23

0

     Vomiting

15

0.8

16

1.1

     Abdominal painc

11

0.8

13

2.1

     Constipation

9

0.4

14

0

Infections

     Upper respiratory tract infectiond

28

0.4

48

1.1

     Pneumonia/bronchopneumoniae

9

3.0

19

5.3

Respiratory, Thoracic and Mediastinal Disorders

     Cough/productive cough

22

0

35

0

     Dyspnea/exertional dyspnea

10

0.8

16

2.1

Skin and Subcutaneous Tissue Disorders

     Rashf

19

1.5

31

3.2

     Pruritus

17

0

25

0

Musculoskeletal and Connective Tissue Disorders

     Musculoskeletal paing

19

1.1

27

1.1

     Arthralgia

11

0

21

0

Endocrine Disorders

     Hypothyroidism/thyroiditis

12

0

17

0

     Hyperglycemia/Blood Glucose Increased

9

0.4

14

1.1

Nervous System Disorders

     Headache

12

0.4

12

1.1

     Neuropathy peripheralh

11

0.4

21

0

Injury, Poisoning and Procedural Complications

     Infusion-related reaction

12

0.4

18

0

Additional information regarding clinically important adverse reactions

Immune-mediated pneumonitis: In Trials 7 and 8, pneumonitis, including interstitial lung disease, occurred in 4.9% (13/263) of patients receiving Opdivo. Immune-mediated pneumonitis occurred in 3.4% (9/263) of patients receiving Opdivo (one Grade 3 and eight Grade 2). The median time to onset was 2.2 months (range: 1 day to 10.1 months). All nine patients received systemic corticosteroids, with resolution in seven. One patient permanently discontinued Opdivo due to Grade 2 pneumonitis. Dose delay occurred in three patients. Five patients resumed Opdivo, of whom none had recurrence of pneumonitis.

Peripheral neuropathy: In Trials 7 and 8, peripheral neuropathy was observed in 11% (30/263) of all patients receiving Opdivo. Twenty-two patients (8%) had new-onset peripheral neuropathy, and four patients had worsening from baseline. Four additional patients with peripheral neuropathy at baseline (three Grade 1 and one Grade 2) did not worsen. All events were Grade 1 or 2, except for 1 Grade 3 event (0.4%).

Complications of allogeneic HSCT after Opdivo: [see Warnings and Precautions (5.10)].

Table 13:     Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of Opdivo-Treated cHL Patients (Trials 7 and 8)
a  Number of evaluable patients for the safety population ranges from 226 to 253.
b  Number of evaluable patients for the efficacy population ranges from 80 to 85.
c  Includes events occurring up to 30 days after last nivolumab dose. After an immune-mediate adverse reaction, reactions following nivolumab rechallenge were included if they occurred within 30 days of completing the initial nivolumab course.

Opdivo cHL
Safety Populationa

Opdivo cHL
Efficacy Populationb

Laboratory Abnormality

Percentage (%) of Patientsc

All Grades

Grades 3-4

All Grades

Grades 3-4

Hematology

     Neutropenia

29

3.6

37

6

     Thrombocytopenia

28

2.4

33

3.2

     Lymphopenia

24

8

32

7

     Anemia

22

2.8

27

2.1

Chemistry

     Increased ALT

24

2.0

25

2.1

     Increased AST

23

2.4

32

3.2

     Increased alkaline phosphatase

17

1.6

21

2.1

     Increased lipase

16

6.5

28

12

     Hyponatremia

14

0.8

15

1.1

     Hypokalemia

11

1.6

14

3.2

     Hypocalcemia

11

0.4

14

1.1

     Hypomagnesemia

10

0.4

15

1.3

     Increased creatinine

10

0

15

0

     Increased bilirubin

9

0.8

10

0

Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck

The safety of Opdivo was evaluated in Trial 9, 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 (14.5)]. Patients received 3 mg/kg of Opdivo (n=236) administered intravenously (IV) over 60 minutes every 2 weeks or investigator’s choice of either:

cetuximab (n=13), 400 mg/m2 loading dose IV followed by 250 mg/m2 weekly
or methotrexate (n=46) 40 to 60 mg/m2 IV weekly, or
docetaxel (n=52) 30 to 40 mg/m2 IV 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 greater than 6 months and 2.5% of patients received Opdivo for greater than 1 year.

Trial 9 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).

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.

Opdivo was discontinued in 14% of patients and was delayed in 24% of patients for an adverse reaction. Serious adverse reactions occurred in 49% of patients receiving Opdivo. The most frequent serious adverse reactions reported in at least 2% of patients receiving Opdivo were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. Adverse reactions and laboratory abnormalities occurring in patients with SCCHN were generally similar to those occurring in patients with melanoma and NSCLC. 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.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity.

Of 1586 patients who were treated with Opdivo as a single agent 3 mg/kg every 2 weeks and evaluable for the presence of anti-nivolumab antibodies, 157 patients (9.9%) tested positive for treatment-emergent anti-nivolumab antibodies by an electrochemiluminescent (ECL) assay and nine patients (0.6%) had neutralizing antibodies against nivolumab. There was no evidence of altered pharmacokinetic profile or increased incidence of infusion reactions with anti-nivolumab antibody development.

Of 394 patients who were treated with Opdivo with ipilimumab and evaluable for the presence of anti-nivolumab antibodies, 149 patients (37.8%) tested positive for treatment-emergent anti-nivolumab antibodies by an ECL assay and 18 patients (4.6%) had neutralizing antibodies against nivolumab. Of the 391 patients evaluable for the presence of anti-ipilimumab antibodies, 33 patients (8.4%) tested positive for treatment-emergent anti-ipilimumab antibodies by an ECL assay and one patient (0.3%) had neutralizing antibodies against ipilimumab. There was no evidence of increased incidence of infusion reactions with anti-nivolumab antibody development.

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.

Drug Interactions

No formal pharmacokinetic drug-drug interaction studies have been conducted with Opdivo.

USE IN SPECIFIC POPULATIONS

Pregnancy

Risk Summary

Based on its mechanism of action and data from animal studies, Opdivo can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. 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 human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown; however, 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 of nivolumab (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

It is not known whether Opdivo is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Opdivo, advise women to discontinue breastfeeding during treatment with Opdivo.

Females and Males of Reproductive Potential

Contraception

Based on its mechanism of action, 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 of Opdivo.

Pediatric Use

The safety and effectiveness of Opdivo have not been established in pediatric patients.

Geriatric Use

Of the 1359 patients randomized to single-agent Opdivo in Trials 2 through 6, 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.

Trials 1, 7, 8, and 9 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 Trial 6, 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.

Renal Impairment

Based on a population pharmacokinetic analysis, no dose adjustment is recommended in patients with renal impairment [see Clinical Pharmacology (12.3)].

Hepatic Impairment

Based on a population pharmacokinetic analysis, no dose adjustment is recommended for patients with mild hepatic impairment. Opdivo has not been studied in patients with moderate or severe hepatic impairment [see Clinical Pharmacology (12.3)].

Overdosage

There is no information on overdosage with Opdivo.

Opdivo Description

Nivolumab is a human monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Nivolumab is an IgG4 kappa immunoglobulin that has a calculated molecular mass of 146 kDa.

Opdivo is a sterile, preservative-free, non-pyrogenic, clear to opalescent, colorless to pale-yellow liquid that may contain light (few) particles. Opdivo injection for intravenous infusion 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. In murine syngeneic tumor models, dual blockade of PD-1 and CTLA-4 resulted in increased anti-tumor activity.

Pharmacodynamics

Based on dose/exposure efficacy and safety relationships, there are no clinically significant differences in safety and efficacy between a nivolumab dose of 240 mg or 3mg/kg every 2 weeks in patients with melanoma, NSCLC, and RCC.

Pharmacokinetics

Nivolumab pharmacokinetics (PK) was assessed using a population PK approach for both single-agent Opdivo and Opdivo with ipilimumab.

Opdivo as a single agent: The PK of single-agent nivolumab was studied in patients over a dose range of 0.1 to 20 mg/kg administered as a single dose or as multiple doses of Opdivo every 2 or 3 weeks. Nivolumab clearance decreases over time, with a mean maximal reduction (% coefficient of variation [CV%]) from baseline values of approximately 24.5% (47.6%) resulting in a geometric mean steady state clearance (CLss) (CV%) of 8.2 mL/h (53.9%), the decrease in CLss is not considered clinically relevant. The geometric mean volume of distribution at steady state (Vss) (CV%) is 6.8 L (27.3%), and geometric mean elimination half-life (t1/2) is 25 days (77.5%). Steady-state concentrations of nivolumab were reached by approximately 12 weeks when administered at 3 mg/kg every 2 weeks, and systemic accumulation was approximately 3.7-fold. The exposure to nivolumab increased dose proportionally over the dose range of 0.1 to 10 mg/kg administered every 2 weeks.

Opdivo with ipilimumab: The geometric mean (CV%) CL, Vss, and terminal half-life of nivolumab were 10.0 mL/h (50.3%), 7.92 L (30.1%), and 24.8 days (94.3%), respectively. When administered in combination, the CL of nivolumab was increased by 24%, whereas there was no effect on the clearance of ipilimumab.

When administered in combination, the clearance of nivolumab increased by 42% in the presence of anti-nivolumab antibodies. There was no effect of anti-ipilimumab antibodies on the clearance of ipilimumab.

Specific Populations: The population PK analysis suggested that the following factors had no clinically important effect on the clearance of nivolumab: age (29 to 87 years), weight (35 to 160 kg), gender, race, baseline LDH, PD-L1 expression, solid tumor type, tumor size, renal impairment, and mild hepatic impairment.

Renal Impairment: The effect of renal impairment on the clearance of nivolumab was evaluated by a population PK analysis in patients with mild (eGFR 60 to 89 mL/min/1.73 m2; n=313), moderate (eGFR 30 to 59 mL/min/1.73 m2; n=140), or severe (eGFR 15 to 29 mL/min/1.73 m2; n=3) renal impairment. No clinically important differences in the clearance of nivolumab were found between patients with renal impairment and patients with normal renal function [see Use in Specific Populations (8.6)].

Hepatic Impairment: The effect of hepatic impairment on the clearance of nivolumab was evaluated by population PK analyses in patients with mild hepatic impairment (total bilirubin [TB] less than or equal to the upper limit of normal [ULN] and AST greater than ULN or TB less than 1 to 1.5 times ULN and any AST; n=92). No clinically important differences in the clearance of nivolumab were found between patients with mild hepatic impairment and patients with normal hepatic function. Nivolumab has not been studied in patients with moderate (TB greater than 1.5 to 3 times ULN and any AST) or severe hepatic impairment (TB greater than 3 times ULN and any AST) [see Use in Specific Populations (8.7)].

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

Trial 1 was a multicenter, open-label trial that randomized (2:1) patients with unresectable or metastatic melanoma to receive either Opdivo administered intravenously at 3 mg/kg 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 every 3 weeks plus paclitaxel 175 mg/m2 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 Trial 1 and in whom the minimum duration of follow-up was 6 months. The major efficacy outcome measures in this population were confirmed objective 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, 33 patients (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 objective responses in patients with and without BRAF V600 mutation-positive melanoma.

Previously Untreated Metastatic Melanoma

Trial 4

Trial 4 was a multicenter, double-blind, randomized (1:1) trial conducted in 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 by intravenous infusion every 3 weeks until disease progression or unacceptable toxicity. Randomization was stratified by PD-L1 status (greater than or equal to 5% of tumor cell membrane staining by immunohistochemistry vs. less than 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 objective response rate (ORR) per RECIST v1.1.

A total of 418 patients were randomized to Opdivo (n=210) or dacarbazine (n=208). The median age was 65 years (range: 18 to 87), 59% were men, and 99.5% were white. Disease characteristics were M1c stage disease (61%), cutaneous melanoma (74%), mucosal melanoma (11%), elevated LDH level (37%), PD-L1 greater than or equal to 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%).

Trial 4 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. Table 14 and Figure 1 summarize the efficacy results.

Table 14:     Efficacy Results - Trial 4
a  Based on a stratified proportional hazards model.
b  Based on stratified log-rank test.
c  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)

Not Reached

10.8 (9.3, 12.1)

     Hazard ratio (95% CI)a

0.42 (0.30, 0.60)

          p-valueb,c

<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)a

0.43 (0.34, 0.56)

          p-value

<0.0001a

Objective Response Rate

34%

9%

     (95% CI)

(28, 41)

(5, 13)

     Complete response rate

4%

1%

     Partial response rate

30%

8%

Figure 1:     Kaplan-Meier Curves of Overall Survival - Trial 4

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.

Trial 6

Trial 6 was a multicenter, double-blind trial that randomized (1:1:1) patients with previously untreated, unresectable or metastatic melanoma to one of the following arms: Opdivo plus 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 every 3 weeks for 4 doses, followed by Opdivo 3 mg/kg as a single agent every 2 weeks (Opdivo plus ipilimumab arm),
Opdivo 3 mg/kg every 2 weeks (Opdivo arm), or
Ipilimumab 3 mg/kg 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 American Joint Committee on Cancer (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.

A total of 945 patients were randomized, 314 patients to the Opdivo plus ipilimumab arm, 316 to the Opdivo arm, and 315 to the ipilimumab arm. The study 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%).

Trial 6 demonstrated statistically significant improvements in PFS for patients randomized to either Opdivo-containing arm as compared with the ipilimumab arm. Efficacy results are presented in Table 15 and Figure 2.

Table 15:     Efficacy Results in Trial 6
Opdivo plus Ipilimumab
(n=314)
Opdivo
(n=316)
Ipilimumab
(n=315)
a  Based on a stratified proportional hazards model.
b  Based on stratified log-rank test.
c  p-value is compared with .005 of the allocated alpha for final PFS treatment comparisons.
d  Based on the stratified Cochran-Mantel-Haenszel test.

Progression-free Survival

     Disease progression or death

151

174

234

     Median in months (95% CI)

11.5
(8.9, 16.7)

6.9
(4.3, 9.5)

2.9
(2.8, 3.4)

     Hazard ratioa (vs. ipilimumab)

0.42

0.57

          (95% CI)

(0.34, 0.51)

(0.47, 0.69)

          p-valueb,c

<0.0001

<0.0001

Confirmed Objective Response Rate

50%

40%

14%

          (95% CI)

(44, 55)

(34, 46)

(10, 18)

          p-valued

<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 2:     Progression-free Survival: Unresectable or Metastatic Melanoma - Trial 6

Figures 3 and 4 present exploratory efficacy subgroup analyses of PFS based on defined PD-L1 expression levels determined in archival tumor specimens using the PD-L1 IHC 28-8 pharmDx assay. Tumor samples were available for retrospective assessment for 97% of the study population; PD-L1 expression status was ascertained for 89% of the study population while in 6% of patients, melanin precluded evaluation of PD-L1 expression status. PD-L1 expression status was unknown for 5% of the study population due to consent withdrawal or missing samples.

Figure 3:     Progression-free Survival by PD-L1 Expression (<1%) - Trial 6

Figure 4:     Progression-free Survival by PD-L1 Expression (≥1%) - Trial 6

The data presented in the figure below summarize the results of exploratory analyses comparing the two Opdivo-containing arms in subgroups defined by PD-L1 tumor expression.

Figure 5:     Forest Plot: PFS Based on PD-L1 Expression Comparing Opdivo-Containing Arms - Trial 6

Metastatic Non-Small Cell Lung Cancer

Second-line Treatment of Metastatic Squamous NSCLC

Trial 2 was a randomized (1:1), open-label study enrolling 272 patients with metastatic squamous NSCLC who had experienced disease progression during or after one prior platinum doublet-based chemotherapy regimen. Patients received Opdivo (n=135) administered intravenously at 3 mg/kg every 2 weeks or docetaxel (n=137) administered intravenously at 75 mg/m2 every 3 weeks. Randomization was stratified by prior paclitaxel vs other prior treatment and region (US/Canada vs. Europe vs. Rest of World). This study 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.

In Trial 2, the 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) (Table 16 and Figure 6).

Table 16:     Efficacy Results in Trial 2
Opdivo
(n=135)
Docetaxel
(n=137)
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.

Overall Survival

Deaths (%)

86 (64%)

113 (82%)

Median (months)

9.2

6.0

     (95% CI)

(7.3, 13.3)

(5.1, 7.3)

Hazard ratio (95% CI)a

0.59 (0.44, 0.79)

p-valueb,c

0.0002

Objective Response Rate

27 (20%)

12 (9%)

 
(95% CI)

(14 , 28)

(5, 15)

 
p-value d

0.0083

 
Complete response

1 (0.7%)

0

 
Median duration of response, months
(95% CI)

NR
(9.8, NR)

8.4
(3.6, 10.8)

Progression-free Survival

Disease progression or death (%)

105 (78%)

122 (89%)

Median (months)

3.5

2.8

p-valuea

0.0004

Hazard ratio (95% CI)c

0.62 (0.47, 0.81)

Figure 6:     Overall Survival - Trial 2

Archival tumor specimens were retrospectively evaluated for PD-L1 expression. Across the study population, 17% (47/272) of patients had non-quantifiable results. Among the 225 patients with quantifiable results, 47% (106/225) had PD-L1 negative squamous NSCLC, defined as <1% of tumor cells expressing PD-L1, and 53% (119/225) had PD-L1 positive squamous NSCLC, defined as ≥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 NSCLC subgroup.

Second-line Treatment of Metastatic Non-Squamous NSCLC

Trial 3 was a randomized (1:1), open-label study of 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 (n=292) administered intravenously at 3 mg/kg every 2 weeks or docetaxel (n=290) administered intravenously at 75 mg/m2 every 3 weeks. 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.

In Trial 3, the 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%).

Trial 3 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) (Table 17 and Figure 7).

Table 17:     Efficacy Results in Trial 3
Opdivo
(n=292)
Docetaxel
(n=290)
a  Based on stratified log-rank test.
b  p-value is compared with .0408 of the allocated alpha for this interim analysis.
c  Based on a stratified Cox proportional hazards model.
d  Based on the stratified Cochran-Mantel-Haenszel test.

Overall Survival

Deaths (%)

190 (65%)

223 (77%)

Median (months)
     (95% CI)

12.2
(9.7, 15.0)

9.4
(8.0, 10.7)

p-valuea,b

0.0015

Hazard ratio (95% CI)c

0.73 (0.60, 0.89)

Objective 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, NR)

6
(4.4, 7.0)

Progression-free Survival

Disease progression or death (%)

234 (80%)

245 (84%)

Median (months)

2.3

4.2

p-valuea

0.39

Hazard ratio (95% CI)c

0.92 (0.77, 1.11)

Figure 7:     Overall Survival - Trial 3

Archival tumor specimens were evaluated for PD-L1 expression following completion of the trial. Across the study population, 22% (127/582) of 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% (209/455) PD-L1 negative, defined as <1% of tumor cells expressing PD-L1 and 54% (246/455) had PD-L1 expression, defined as ≥1% of tumor cells expressing PD-L1. Among the 246 patients with tumors expressing PD-L1, 26% (65/246) had ≥1%, but <5% tumor cells with positive staining, 7% (16/246) had ≥5% but <10% tumor cells with positive staining, and 67% (165/246) had greater than or equal to 10% tumor cells with positive staining. Figure 8 summarizes the results of prespecified analyses of survival in subgroups determined by percentage of tumor cells expressing PD-L1. Figure 9 summarizes the results of prespecified analyses of progression-free survival in subgroups determined by percentage of tumor cells expressing PD-L1.

Figure 8:     Forest Plot: OS Based on PD-L1 Expression - Trial 3

Figure 9:     Forest Plot: PFS Based on PD-L1 Expression - Trial 3

Renal Cell Carcinoma

Trial 5 was a randomized (1:1), open-label study 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. Trial 5 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 to Opdivo (n=410) administered intravenously at 3 mg/kg every 2 weeks or everolimus (n=411) administered orally 10 mg daily. The 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 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 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) (Table 18 and Figure 10). OS benefit was observed regardless of PD-L1 expression level.

Other endpoints include confirmed objective response rates, which are also presented in Table 18.

Table 18:     Efficacy Results - Trial 5
Opdivo
(n=410)
Everolimus
(n=411)
a  Based on a stratified proportional hazards model.
b  Based on a stratified log rank test.
c  p-value is compared with .0148 of the allocated alpha for this interim analysis

Overall Survival

Deaths (%)

183 (45)

215 (52)

Median survival in months (95% CI)

25.0 (21.7, NE)

19.6 (17.6, 23.1)

Hazard ratio (95% CI)a

0.73 (0.60, 0.89)

     p-valueb,c

0.0018

Confirmed Objective Response Rate (95% CI)

21.5% (17.6, 25.8)

3.9% (2.2, 6.2)

Median duration of response in months (95% CI)

23.0 (12.0, NE)

13.7 (8.3, 21.9)

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

3.0 (1.4, 13.0)

3.7 (1.5, 11.2)

Figure 10:     Overall Survival - Trial 5

Classical Hodgkin Lymphoma

Two studies evaluated the efficacy of Opdivo as a single agent in patients with cHL after failure of autologous HSCT and post-transplantation brentuximab vedotin.

Trial 7 was a single-arm, open-label, multicenter, multicohort study in cHL. Trial 8 was an open-label, multicenter, dose escalation study 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 less than 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 3 mg/kg of Opdivo administered intravenously over 60 minutes 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 objective response rate (ORR) as determined by an independent radiographic review committee (IRRC). Additional outcome measures included duration of response. Efficacy was evaluated in 95 patients in Trials 7 and 8 combined who had received brentuximab vedotin after failure of autologous HSCT. 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: 3 to 15).

Results are shown in Table 19. Patients received a median of 17 doses of Opdivo (range 3 to 48), with a median duration of therapy of 8.3 months (range 1.9 to 24 months).

Table 19:     Efficacy in cHL after Autologous HSCT and Brentuximab Vedotin
a  Per 2007 revised International Working Group criteria.

Trial 7 and Trial

(n=95)

Objective Response Rate, n (%)a

      (95% CI)

62 (65%)
(55, 75)

   Complete Remission Rate

      (95% CI)

7 (7%)
(3, 15)

   Partial Remission Rate

      (95% CI)

55 (58%)
(47, 68)

Median Duration of Response (months)

      (95% CI)

      Range

8.7
(6.8, NE)
0.0+, 23.1+

Median Time to Response (months)

      Range

2.1
0.7, 5.7

Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN)

Trial 9 was a randomized (2:1), active-controlled, open-label study 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 administered intravenously (IV) at 3 mg/kg every 2 weeks or investigator’s choice of:

cetuximab 400 mg/m2 loading dose IV followed by 250 mg/m2 weekly,
methotrexate 40 to 60 mg/m2 IV weekly, or
docetaxel 30 to 40 mg/m2 IV 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.

In Trial 9, total of 361 patients were randomized; 240 patients to Opdivo and 121 patients to investigator’s choice (45% received docetaxel, 43% received methotrexate, and 12% received cetuximab). The 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). The survival results are displayed in Table 20 and Figure 11. 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).

Table 20:     Overall Survival in Trial 9
Opdivo
(n=240)
Everolimus
(n=121)
a  Based on stratified proportional hazards model.
b  Based on stratified log rank test.
c  p-value is compared with .0227 of the allocated alpha for this interim analysis

Overall Survival

Deaths (%)

133 (55)

85 (70)

Median (months)
     (95% CI)

25.0
(5.5, 9.1)

19.6
(4.0, 6.0)

Hazard ratio (95% CI)a

0.70 (0.53, 0.92)

p-valueb,c

0.0101

Figure 11:     Overall Survival - Trial 9

Archival tumor specimens were retrospectively evaluated for PD-L1 expression using the PD-L1 IHC 28-8 pharmDx assay. Across the study 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.

How Supplied/Storage and Handling

Opdivo® (nivolumab) 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

Store Opdivo under refrigeration at 2°C to 8°C (36°F to 46°F). Protect Opdivo 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).

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 (5.2)].
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 (5.3)].
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 (5.4)].
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 (5.5)].
Skin Adverse Reactions: Advise patients to contact their healthcare provider immediately for rash [see Warnings and Precautions (5.6)].
Encephalitis: Advise patients to contact their healthcare provider immediately for neurological signs or symptoms of encephalitis [see Warnings and Precautions (5.7)].
Infusion Reactions: Advise patients of the potential risk of infusion reaction [see Warnings and Precautions (5.9)].
Complications of allogeneic HSCT after Opdivo: Advise patients of potential risk of post-transplant complications [see Warnings and Precautions (5.10)].
Females of Reproductive Potential: 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 (5.11), 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 of Opdivo [see Use in Specific Populations (8.3)].
Lactation: Advise women not to breastfeed while taking Opdivo [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. 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 your melanoma, lung cancer, kidney cancer, blood cancer, or head and neck cancer by working with your immune system. Opdivo can cause your immune system to attack normal organs and tissues in many areas of your body and can affect the way they work. These problems can sometimes become serious or life-threatening and can lead to death. These problems may happen anytime during treatment or even after your treatment has ended. Some of these problems may happen more often when Opdivo is used in combination with ipilimumab.

Call or see your healthcare provider right away if you develop any symptoms of the following problems or these symptoms get worse:

Lung problems (pneumonitis). Symptoms of pneumonitis may include:

new or worsening cough
chest pain
shortness of breath

Intestinal problems (colitis) that can lead to tears or holes in your intestine. Signs and symptoms of colitis may include:

diarrhea (loose stools) or more bowel movements than usual
blood in your stools or dark, tarry, sticky stools
severe stomach-area (abdomen) pain or tenderness

Liver problems (hepatitis). Signs and symptoms of hepatitis may include:

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

Hormone gland problems (especially the thyroid, pituitary, adrenal glands, and pancreas). Signs and symptoms that your hormone glands are not working properly may include:

headaches that will not go away or unusual headaches
extreme tiredness
weight gain or weight loss
dizziness or fainting
hair loss
changes in mood or behavior, such as decreased sex drive, irritability, or forgetfulness
feeling cold
constipation
voice gets deeper
excessive thirst or lots of urine

Kidney problems, including nephritis and kidney failure. Signs of kidney problems may include:

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

Skin Problems. Signs of these problems may include:

rash
itching
skin blistering
ulcers in mouth or other mucous membranes

Inflammation of the brain (encephalitis). Signs and symptoms of encephalitis may include:

headache
fever
tiredness or weakness
confusion
memory problems
sleepiness
seeing or hearing things that are not really there (hallucinations)
seizures
stiff neck

Problems in other organs. Signs of these problems may include:

changes in eyesight
severe or persistent muscle or joint pains
severe muscle weakness

Getting medical treatment right away may 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:

a type of skin cancer called melanoma that has spread or cannot be removed by surgery (advanced melanoma). You may receive Opdivo alone or in combination with ipilimumab.
a type of advanced stage lung cancer (called non-small cell lung cancer)
 
Opdivo may be used when your lung cancer:
o
has spread or grown, and
o
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.
kidney cancer (renal cell carcinoma)
o
Opdivo may be used when your cancer has spread or grown after treatment with other cancer medications.
a type of blood cancer that affects white blood cells known as lymphocytes (called classical Hodgkin lymphoma)
 
Opdivo may be used if:
o
your cancer has come back or spread after a type of stem cell transplant that uses your own stem cells (autologous), and
o
you used the drug brentuximab vedotin (Adcetris®) after your stem cell transplant.
head and neck cancer

Opdivo may be used when your head and neck cancer:

 
o
has come back or spread, and
o
you have tried chemotherapy that contains platinum and it did not work or is no longer working.
 
It is not known if Opdivo is safe and effective in children less than 18 years of age.

What should I tell my healthcare provider before receiving Opdivo?

Before you receive Opdivo, tell your healthcare provider if you:

have immune system problems such as Crohn’s disease, ulcerative colitis, or lupus
have had an organ transplant
have lung or breathing problems
have liver problems
have any other medical conditions
are pregnant or plan to become pregnant. Opdivo can harm your unborn baby.
Females who are able to become pregnant 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.
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.

Know the medicines you take. Keep a list of them to show your healthcare providers and pharmacist when you get a new medicine.

How will I receive Opdivo?

Your healthcare provider will give you Opdivo into your vein through an intravenous (IV) line over 60 minutes.
Opdivo is usually given every 2 weeks.
When used in combination with ipilimumab, 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.
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 doctor or nurse right away if you get these symptoms during an infusion of Opdivo:
chills or shaking
itching or rash
flushing
difficulty breathing
dizziness
fever
feeling like passing out
Complications of stem cell transplant that uses donor stem cells (allogeneic) after treatment with Opdivo. These complications can be severe and can lead to death. 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
pain in muscles, bones, and joints
diarrhea
cough
constipation
back pain
fever
rash
itchy skin
nausea
shortness of breath
decreased appetite
upper respiratory tract infection
weakness

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

feeling tired
diarrhea
fever
shortness of breath
rash
nausea
vomiting

These are not all the possible side effects of Opdivo. For more information, ask your healthcare provider or pharmacist. 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. If you would like more information about Opdivo, talk with your healthcare provider. You can ask your 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.

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

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

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: November 2016

1363787A2

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 
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
Labeler - E.R. Squibb & Sons, L.L.C. (011550092)
Revised: 11/2016
 
E.R. Squibb & Sons, L.L.C.
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