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Keytruda

Generic Name: pembrolizumab
Dosage Form: injection, powder, lyophilized, for solution

Medically reviewed by Drugs.com. Last updated on May 1, 2019.

Indications and Usage for Keytruda

See also: Xeloda

Melanoma

Keytruda® (pembrolizumab) is indicated for the treatment of patients with unresectable or metastatic melanoma.

Keytruda is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

Keytruda, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

Keytruda, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

Keytruda, as a single agent, is indicated for the first-line treatment of patients with stage III NSCLC, who are not candidates for surgical resection or definitive chemoradiation, or metastatic NSCLC, and whose tumors express PD-L1 [Tumor Proportion Score (TPS) ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations [see Dosage and Administration (2.1)].

Keytruda, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test [see Dosage and Administration (2.1)], with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving Keytruda.

Head and Neck Squamous Cell Cancer

Keytruda is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.

This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.3)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Classical Hodgkin Lymphoma

Keytruda is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 3 or more prior lines of therapy.

This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.4)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Primary Mediastinal Large B-Cell Lymphoma

Keytruda is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy.

This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.5)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Limitations of Use: Keytruda is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

Keytruda is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [Combined Positive Score (CPS) ≥10] as determined by an FDA-approved test [see Dosage and Administration (2.1)], or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status.

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

Keytruda is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Microsatellite Instability-High Cancer

Keytruda is indicated for the treatment of adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient

  • solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or
  • colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.7)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Limitations of Use: The safety and effectiveness of Keytruda in pediatric patients with MSI-H central nervous system cancers have not been established.

Gastric Cancer

Keytruda is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test [see Dosage and Administration (2.1)], with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy.

This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.8)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Cervical Cancer

Keytruda is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test [see Dosage and Administration (2.1)].

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

Hepatocellular Carcinoma

Keytruda is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.

This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.10)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

Keytruda is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC).

This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.11)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

Keytruda, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC) [see Clinical Studies (14.12)].

Keytruda Dosage and Administration

Patient Selection for NSCLC, Urothelial Carcinoma, Gastric Cancer, or Cervical Cancer

Select patients for treatment with Keytruda as a single agent based on the presence of positive PD-L1 expression in:

  • stage III NSCLC, who are not candidates for surgical resection or definitive chemoradiation, or metastatic NSCLC [see Clinical Studies (14.2)].
  • metastatic urothelial carcinoma [see Clinical Studies (14.6)].
  • metastatic gastric cancer [see Clinical Studies (14.8)]. If PD-L1 expression is not detected in an archival gastric cancer specimen, evaluate the feasibility of obtaining a tumor biopsy for PD-L1 testing.
  • recurrent or metastatic cervical cancer [see Clinical Studies (14.9)].

Information on FDA-approved tests for the detection of PD-L1 expression for these indications is available at: http://www.fda.gov/CompanionDiagnostics.

Recommended Dosage for Melanoma

The recommended dose of Keytruda in patients with unresectable or metastatic melanoma is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.

The recommended dose of Keytruda for the adjuvant treatment of adult patients with melanoma is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease recurrence, unacceptable toxicity, or for up to 12 months in patients without disease recurrence.

Recommended Dosage for NSCLC

The recommended dose of Keytruda is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

When administering Keytruda in combination with chemotherapy, administer Keytruda prior to chemotherapy when given on the same day. Refer to the Prescribing Information for the chemotherapy agents administered in combination with Keytruda for recommended dosing information, as appropriate.

Recommended Dosage for HNSCC

The recommended dose of Keytruda is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Recommended Dosage for cHL

The recommended dose of Keytruda in adults is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

The recommended dose of Keytruda in pediatric patients is 2 mg/kg (up to a maximum of 200 mg), administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Recommended Dosage for PMBCL

The recommended dose of Keytruda in adults is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

The recommended dose of Keytruda in pediatric patients is 2 mg/kg (up to a maximum of 200 mg), administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Recommended Dosage for Urothelial Carcinoma

The recommended dose of Keytruda is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Recommended Dosage for MSI-H Cancer

The recommended dose of Keytruda in adults is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

The recommended dose of Keytruda in pediatric patients is 2 mg/kg (up to a maximum of 200 mg), administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Recommended Dosage for Gastric Cancer

The recommended dose of Keytruda is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Recommended Dosage for Cervical Cancer

The recommended dose of Keytruda is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Recommended Dosage for HCC

The recommended dose of Keytruda is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Recommended Dosage for MCC

The recommended dose of Keytruda in adults is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

The recommended dose of Keytruda in pediatric patients is 2 mg/kg (up to a maximum of 200 mg), administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Recommended Dosage for RCC

The recommended dose of Keytruda is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks in combination with 5 mg axitinib orally twice daily until disease progression, unacceptable toxicity, or for Keytruda, up to 24 months in patients without disease progression. When axitinib is used in combination with Keytruda, dose escalation of axitinib above the initial 5 mg dose may be considered at intervals of six weeks or longer. See also the Prescribing Information for recommended axitinib dosing information [see Clinical Studies (14.12)].

Dose Modifications

No dose reductions of Keytruda are recommended. Withhold or discontinue Keytruda to manage adverse reactions as described in Table 1.

Table 1: Recommended Dose Modifications for Adverse Reactions [see Warnings and Precautions (5.1-5.9)]
Adverse Reaction Severity* Dose Modification for Keytruda
*
Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events. Version 4.0 (NCI CTCAE v4)
Resume in patients with complete or partial resolution (Grades 0 to 1) after corticosteroid taper.
Resume in HCC patients when AST or ALT and total bilirubin recover to Grades 0-1 or to baseline.
Immune-mediated pneumonitis Grade 2 Withhold
Grades 3 or 4 or recurrent Grade 2 Permanently discontinue
Immune-mediated colitis Grades 2 or 3 Withhold
Grade 4 Permanently discontinue
Immune-mediated hepatitis in patients with HCC Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than or equal to 5 times upper limit of normal (ULN) if baseline less than 2 times ULN;
AST or ALT greater than 3 times baseline if baseline greater than or equal to 2 times ULN
Total bilirubin greater than 2.0 mg/dL if baseline less than 1.5 mg/dL; or
Total bilirubin greater than 3.0 mg/dL, regardless of baseline levels
Withhold
ALT or AST greater than 10 times ULN; or Child-Pugh score greater than or equal to 9 points;
Gastrointestinal bleeding suggestive of portal hypertension; or
New onset of clinically detectable ascites; or encephalopathy
Permanently discontinue
Immune-mediated hepatitis in patients without HCC AST or ALT greater than 3 but no more than 5 times the ULN or total bilirubin greater than 1.5 but no more than 3 times the ULN Withhold
For liver enzyme elevations in RCC patients treated with combination therapy, see dosing guidelines following this table. In patients without liver metastases, AST or ALT greater than 5 times ULN or total bilirubin greater than 3 times ULN
In patients with liver metastasis and Grade 2 AST or ALT at baseline, with an increase in AST or ALT of 50% or more relative to baseline that persists for at least 1 week
Permanently discontinue
Immune-mediated endocrinopathies Grades 3 or 4 Withhold until clinically stable
Immune-mediated nephritis Grade 2 Withhold
Grades 3 or 4 Permanently discontinue
Immune-mediated skin adverse reactions Grade 3 or suspected Stevens-Johnson Syndrome (SJS) or toxic epidermal necrolysis (TEN) Withhold
Grade 4 or confirmed SJS or TEN Permanently discontinue
Hematologic toxicity in patients with cHL or PMBCL Grade 4 Withhold until resolution to Grades 0 or 1
Other immune-mediated adverse reactions Grades 2 or 3 based on the severity and type of reaction Withhold
Grade 3 based on the severity and type of reaction or Grade 4 Permanently discontinue
Recurrent immune-mediated adverse reactions Recurrent Grade 2 pneumonitis
Recurrent Grades 3 or 4
Permanently discontinue
Inability to taper corticosteroid Requirement for 10 mg per day or greater prednisone or equivalent for more than 12 weeks after last dose of Keytruda Permanently discontinue
Persistent Grade 2 or 3 adverse reaction (excluding endocrinopathy) Grades 2 or 3 adverse reactions lasting 12 weeks or longer after last dose of Keytruda Permanently discontinue
Infusion-related reactions Grades 1 or 2 Interrupt or slow the rate of infusion
Grades 3 or 4 Permanently discontinue

In patients with RCC being treated with Keytruda in combination with axitinib:

  • If ALT or AST ≥3 times ULN but <10 times ULN without concurrent total bilirubin ≥2 times ULN, withhold both Keytruda and axitinib until these adverse reactions recover to Grades 0-1. Consider corticosteroid therapy. Consider rechallenge with a single drug or sequential rechallenge with both drugs after recovery. If rechallenging with axitinib, consider dose reduction as per the axitinib Prescribing Information.
  • If ALT or AST ≥10 times ULN or >3 times ULN with concurrent total bilirubin ≥2 times ULN, permanently discontinue both Keytruda and axitinib and consider corticosteroid therapy.

Preparation and Administration

Reconstitution of Keytruda for Injection (Lyophilized Powder)

  • Add 2.3 mL of Sterile Water for Injection, USP by injecting the water along the walls of the vial and not directly on the lyophilized powder (resulting concentration 25 mg/mL).
  • Slowly swirl the vial. Allow up to 5 minutes for the bubbles to clear. Do not shake the vial.

Preparation for Intravenous Infusion

  • Visually inspect the solution for particulate matter and discoloration. The solution is clear to slightly opalescent, colorless to slightly yellow. Discard the vial if visible particles are observed.
  • Dilute Keytruda injection (solution) or reconstituted lyophilized powder prior to intravenous administration.
  • Withdraw the required volume from the vial(s) of Keytruda and transfer into an intravenous (IV) bag containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Mix diluted solution by gentle inversion. The final concentration of the diluted solution should be between 1 mg/mL to 10 mg/mL.
  • Discard any unused portion left in the vial.

Storage of Reconstituted and Diluted Solutions

The product does not contain a preservative.

Store the reconstituted and diluted solution from the Keytruda 50 mg vial either:

  • At room temperature for no more than 6 hours from the time of reconstitution. This includes room temperature storage of reconstituted vials, storage of the diluted solution, and the duration of infusion.
  • Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of reconstitution. If refrigerated, allow the diluted solution to come to room temperature prior to administration.

Store the diluted solution from the Keytruda 100 mg/4 mL vial either:

  • At room temperature for no more than 6 hours from the time of dilution. This includes room temperature storage of the diluted solution, and the duration of infusion.
  • Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of dilution. If refrigerated, allow the diluted solution to come to room temperature prior to administration.

Discard after 6 hours at room temperature or after 24 hours under refrigeration.

Do not freeze.

Administration

  • Administer diluted solution intravenously over 30 minutes through an intravenous line containing a sterile, non-pyrogenic, low-protein binding 0.2 micron to 5 micron in-line or add-on filter.
  • Do not co-administer other drugs through the same infusion line.

Dosage Forms and Strengths

  • For injection: 50 mg white to off-white lyophilized powder in a single-dose vial for reconstitution
  • Injection: 100 mg/4 mL (25 mg/mL) clear to slightly opalescent, colorless to slightly yellow solution in a single-dose vial

Contraindications

None.

Warnings and Precautions

Immune-Mediated Pneumonitis

Keytruda can cause immune-mediated pneumonitis, including fatal cases. Monitor patients for signs and symptoms of pneumonitis. Evaluate patients with suspected pneumonitis with radiographic imaging and administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a taper) for Grade 2 or greater pneumonitis. Withhold Keytruda for moderate (Grade 2) pneumonitis, and permanently discontinue Keytruda for severe (Grade 3), life-threatening (Grade 4), or recurrent moderate (Grade 2) pneumonitis [see Dosage and Administration (2.14) and Adverse Reactions (6.1)].

In clinical studies enrolling 2799 patients with various cancers who received Keytruda as a single agent, pneumonitis occurred in 94 (3.4%) patients, including Grade 1 (0.8%), Grade 2 (1.3%), Grade 3 (0.9%), Grade 4 (0.3%), and Grade 5 (0.1%) pneumonitis. The median time to onset was 3.3 months (range: 2 days to 19.3 months), and the median duration was 1.5 months (range: 1 day to 17.2+ months). Sixty-three (67%) of the 94 patients received systemic corticosteroids, with 50 of the 63 receiving high-dose corticosteroids for a median duration of 8 days (range: 1 day to 10.1 months) followed by a corticosteroid taper. Pneumonitis occurred more frequently in patients with a history of prior thoracic radiation (6.9%) than in patients who did not receive prior thoracic radiation (2.9%). Pneumonitis led to discontinuation of Keytruda in 36 (1.3%) patients. Pneumonitis resolved in 55 (59%) of the 94 patients.

In clinical studies enrolling 790 patients with NSCLC who received Keytruda as a single agent as first-line therapy for advanced disease, pneumonitis occurred in 65 (8.2%) patients, including Grades 3-4 in 3.2% of patients. Forty-eight of the 65 patients received high-dose corticosteroids for a median duration of 5 days (range: 1 to 26 days). Pneumonitis occurred in 17% of patients with a history of prior thoracic radiation and 7.7% of patients who did not receive prior thoracic radiation. Pneumonitis led to discontinuation of Keytruda in 29 (3.7%) patients. Pneumonitis resolved in 51% of the patients.

Immune-Mediated Colitis

Keytruda can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a taper) for Grade 2 or greater colitis. Withhold Keytruda for moderate (Grade 2) or severe (Grade 3) colitis, and permanently discontinue Keytruda for life-threatening (Grade 4) colitis [see Dosage and Administration (2.14) and Adverse Reactions (6.1)].

Colitis occurred in 48 (1.7%) of 2799 patients receiving Keytruda, including Grade 2 (0.4%), Grade 3 (1.1%), and Grade 4 (<0.1%) colitis. The median time to onset was 3.5 months (range: 10 days to 16.2 months), and the median duration was 1.3 months (range: 1 day to 8.7+ months). Thirty-three (69%) of the 48 patients received systemic corticosteroids, with 27 of the 33 requiring high-dose corticosteroids for a median duration of 7 days (range: 1 day to 5.3 months) followed by a corticosteroid taper. Colitis led to discontinuation of Keytruda in 15 (0.5%) patients. Colitis resolved in 41 (85%) of the 48 patients.

Immune-Mediated Hepatitis, or Hepatotoxicity (in Combination with Axitinib)

Immune-Mediated Hepatitis

Keytruda can cause immune-mediated hepatitis. Monitor patients for changes in liver function. Administer corticosteroids (initial dose of 0.5 to 1 mg/kg/day [for Grade 2 hepatitis] and 1 to 2 mg/kg/day [for Grade 3 or greater hepatitis] prednisone or equivalent followed by a taper) and, based on severity of liver enzyme elevations, withhold or discontinue Keytruda [see Dosage and Administration (2.14) and Adverse Reactions (6.1)].

Hepatitis occurred in 19 (0.7%) of 2799 patients receiving Keytruda, including Grade 2 (0.1%), Grade 3 (0.4%), and Grade 4 (<0.1%) hepatitis. The median time to onset was 1.3 months (range: 8 days to 21.4 months), and the median duration was 1.8 months (range: 8 days to 20.9+ months). Thirteen (68%) of the 19 patients received systemic corticosteroids, with 12 of the 13 receiving high-dose corticosteroids for a median duration of 5 days (range: 1 to 26 days) followed by a corticosteroid taper. Hepatitis led to discontinuation of Keytruda in 6 (0.2%) patients. Hepatitis resolved in 15 (79%) of the 19 patients.

Hepatotoxicity (in Combination with Axitinib)

Keytruda in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of Grades 3 and 4 ALT and AST elevations compared to Keytruda alone. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are used in monotherapy. For elevated liver enzymes, interrupt Keytruda and axitinib, and consider administering corticosteroids as needed [see Dosage and Administration (2.14)].

With the combination of Keytruda and axitinib, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. The median time to onset of increased ALT was 2.3 months (range: 7 days to 19.8 months). Sixty-one percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT ≥3 times ULN (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either Keytruda (3%) or axitinib (31%) monotherapy or with both (50%), 55% had no recurrence of ALT >3 times ULN.

Immune-Mediated Endocrinopathies

Hypophysitis

Keytruda can cause hypophysitis. Monitor for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold Keytruda for moderate (Grade 2) hypophysitis and withhold or discontinue Keytruda for severe (Grade 3) or life-threatening (Grade 4) hypophysitis [see Dosage and Administration (2.14) and Adverse Reactions (6.1)].

Hypophysitis occurred in 17 (0.6%) of 2799 patients receiving Keytruda, including Grade 2 (0.2%), Grade 3 (0.3%), and Grade 4 (<0.1%) hypophysitis. The median time to onset was 3.7 months (range: 1 day to 11.9 months), and the median duration was 4.7 months (range: 8+ days to 12.7+ months). Sixteen (94%) of the 17 patients received systemic corticosteroids, with 6 of the 16 receiving high-dose corticosteroids. Hypophysitis led to discontinuation of Keytruda in 4 (0.1%) patients. Hypophysitis resolved in 7 (41%) of the 17 patients.

Thyroid Disorders

Keytruda can cause thyroid disorders, including hyperthyroidism, hypothyroidism and thyroiditis. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue Keytruda for severe (Grade 3) or life-threatening (Grade 4) hyperthyroidism [see Dosage and Administration (2.14) and Adverse Reactions (6.1)].

Hyperthyroidism occurred in 96 (3.4%) of 2799 patients receiving Keytruda, including Grade 2 (0.8%) and Grade 3 (0.1%) hyperthyroidism. The median time to onset was 1.4 months (range: 1 day to 21.9 months), and the median duration was 2.1 months (range: 3 days to 15.0+ months). Hyperthyroidism led to discontinuation of Keytruda in 2 (<0.1%) patients. Hyperthyroidism resolved in 71 (74%) of the 96 patients.

Hypothyroidism occurred in 237 (8.5%) of 2799 patients receiving Keytruda, including Grade 2 (6.2%) and Grade 3 (0.1%) hypothyroidism. The median time to onset was 3.5 months (range: 1 day to 18.9 months), and the median duration was not reached (range: 2 days to 27.7+ months). Hypothyroidism led to discontinuation of Keytruda in 1 (<0.1%) patient. Hypothyroidism resolved in 48 (20%) of the 237 patients. The incidence of new or worsening hypothyroidism was higher in patients with HNSCC occurring in 28 (15%) of 192 patients receiving Keytruda, including Grade 3 (0.5%) hypothyroidism. Of these 28 patients, 15 had no prior history of hypothyroidism.

Thyroiditis occurred in 16 (0.6%) of 2799 patients receiving Keytruda, including Grade 2 (0.3%) thyroiditis. The median time of onset was 1.2 months (range: 0.5 to 3.5 months).

Type 1 Diabetes mellitus

Keytruda can cause type 1 diabetes mellitus, including diabetic ketoacidosis, which have been reported in 6 (0.2%) of 2799 patients receiving Keytruda. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes and withhold Keytruda and administer anti-hyperglycemics in patients with severe hyperglycemia [see Dosage and Administration (2.14) and Adverse Reactions (6.1)].

Immune-Mediated Nephritis and Renal Dysfunction

Keytruda can cause immune-mediated nephritis. Monitor patients for changes in renal function. Administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a taper) for Grade 2 or greater nephritis. Withhold Keytruda for moderate (Grade 2), and permanently discontinue Keytruda for severe (Grade 3) or life-threatening (Grade 4) nephritis [see Dosage and Administration (2.14) and Adverse Reactions (6.1)].

Nephritis occurred in 9 (0.3%) of 2799 patients receiving Keytruda, including Grade 2 (0.1%), Grade 3 (0.1%), and Grade 4 (<0.1%) nephritis. The median time to onset was 5.1 months (range: 12 days to 12.8 months), and the median duration was 3.3 months (range: 12 days to 8.9+ months). Eight (89%) of the 9 patients received systemic corticosteroids, with 7 of the 8 receiving high-dose corticosteroids for a median duration of 15 days (range: 3 days to 4.0 months) followed by a corticosteroid taper. Nephritis led to discontinuation of Keytruda in 3 (0.1%) patients. Nephritis resolved in 5 (56%) of the 9 patients. Nephritis occurred in 1.7% of 405 patients receiving Keytruda in combination with pemetrexed and platinum in the KEYNOTE-189 study, including Grade 3 (1%) and Grade 4 (0.5%) nephritis. The median time to onset was 3.2 months (range: 16 days to 11.1 months) and the duration ranged from 1.6 to 16.8+ months. Six (86%) of the 7 patients received systemic corticosteroids, with all 6 receiving high-dose corticosteroids for a median duration of 3 days (range: 1 to 17 days) followed by a corticosteroid taper. Nephritis led to discontinuation of Keytruda in 5 (1.2%) patients. Nephritis resolved in 2 (29%) of the 7 patients.

Immune-Mediated Skin Adverse Reactions

Immune-mediated rashes, including SJS, TEN (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and exclude other causes. Based on the severity of the adverse reaction, withhold or permanently discontinue Keytruda and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold Keytruda and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue Keytruda [see Dosage and Administration (2.14)].

Other Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving Keytruda. While immune-mediated adverse reactions usually occur during treatment with PD-1/PD-L1 blocking antibodies, they may occur after discontinuation of treatment.

For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold Keytruda and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume Keytruda when the immune-mediated adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue Keytruda for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction [see Dosage and Administration (2.14) and Adverse Reactions (6.1)].

The following clinically significant, immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients treated with Keytruda: arthritis (1.5%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other trials, including cHL, and post-marketing use.

Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with Keytruda. Treatment with Keytruda may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment with Keytruda versus the risk of possible organ rejection in these patients.

Infusion-Related Reactions

Keytruda can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 6 (0.2%) of 2799 patients receiving Keytruda. Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions, stop infusion and permanently discontinue Keytruda [see Dosage and Administration (2.14)].

Complications of Allogeneic HSCT

Allogeneic HSCT after treatment with Keytruda

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) after being treated with Keytruda. Of 23 patients with cHL who proceeded to allogeneic HSCT after treatment with Keytruda on any trial, 6 patients (26%) developed graft-versus-host-disease (GVHD), one of which was fatal, and 2 patients (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning, one of which was fatal. Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor blocking antibody before transplantation. 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.

Allogeneic HSCT prior to treatment with Keytruda

In patients with a history of allogeneic HSCT, acute GVHD, including fatal GVHD, has been reported after treatment with Keytruda. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after treatment with Keytruda. Consider the benefit of treatment with Keytruda versus the risk of possible GVHD in patients with a history of allogeneic HSCT.

Increased Mortality in Patients with Multiple Myeloma when Keytruda is Added to a Thalidomide Analogue and Dexamethasone

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

Embryo-Fetal Toxicity

Based on its mechanism of action, Keytruda can cause fetal harm when administered to a pregnant woman. Animal models link the PD-1/PD-L1 signaling pathway with maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Keytruda and for 4 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

Adverse Reactions

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

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 described in the WARNINGS AND PRECAUTIONS reflect exposure to Keytruda as a single agent in 2799 patients in three randomized, open-label, active-controlled trials (KEYNOTE-002, KEYNOTE-006, and KEYNOTE-010), which enrolled 912 patients with melanoma and 682 patients with NSCLC, and one single-arm trial (KEYNOTE-001), which enrolled 655 patients with melanoma and 550 patients with NSCLC. In addition to the 2799 patients, certain subsections in the WARNINGS AND PRECAUTIONS describe adverse reactions observed with exposure to Keytruda as a single agent in two randomized, open-label, active-controlled clinical trials (KEYNOTE-042 and KEYNOTE-024), which enrolled 790 patients with NSCLC; in a non-randomized, open-label, multi-cohort trial (KEYNOTE-012), which enrolled 192 patients with HNSCC; and in two non-randomized, open-label trials (KEYNOTE-013 and KEYNOTE-087), which enrolled 241 patients with cHL; in combination with chemotherapy in a randomized, active-controlled trial (KEYNOTE-189), which enrolled 405 patients with nonsquamous NSCLC; in combination with axitinib in a randomized, active controlled trial (KEYNOTE 426), which enrolled 429 patients with RCC; and in post-marketing use. Across all trials, Keytruda was administered at doses of 2 mg/kg intravenously every 3 weeks, 10 mg/kg intravenously every 2 weeks, 10 mg/kg intravenously every 3 weeks, or 200 mg intravenously every 3 weeks. Among the 2799 patients, 41% were exposed for 6 months or more and 21% were exposed for 12 months or more.

The data described in this section were obtained in eight randomized, controlled trials (KEYNOTE-002, KEYNOTE-006, KEYNOTE-010, KEYNOTE-042, KEYNOTE-045, KEYNOTE-189, and KEYNOTE-407, and KEYNOTE 426) and eight non-randomized, open-label trials (KEYNOTE-012, KEYNOTE-087, KEYNOTE-170, KEYNOTE-052, KEYNOTE-059, KEYNOTE-158, KEYNOTE-224, and KEYNOTE-017). The data described in this section also included a single randomized, double-blind, placebo-controlled trial (KEYNOTE-054) in which Keytruda was administered for the adjuvant treatment of 509 patients with melanoma with involvement of lymph node(s) following complete surgical resection. In these trials, Keytruda was administered at 2 mg/kg every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg every 2 or 3 weeks.

Melanoma

Ipilimumab-Naive Melanoma

The safety of Keytruda for the treatment of patients with unresectable or metastatic melanoma who had not received prior ipilimumab and who had received no more than one prior systemic therapy was investigated in KEYNOTE-006. KEYNOTE-006 was a multicenter, open-label, active-controlled trial where patients were randomized (1:1:1) and received Keytruda 10 mg/kg every 2 weeks (n=278) or Keytruda 10 mg/kg every 3 weeks (n=277) until disease progression or unacceptable toxicity or ipilimumab 3 mg/kg every 3 weeks for 4 doses unless discontinued earlier for disease progression or unacceptable toxicity (n=256) [see Clinical Studies (14.1)]. Patients with autoimmune disease, a medical condition that required systemic corticosteroids or other immunosuppressive medication; a history of interstitial lung disease; or active infection requiring therapy, including HIV or hepatitis B or C, were ineligible.

The median duration of exposure was 5.6 months (range: 1 day to 11.0 months) for Keytruda and similar in both treatment arms. Fifty-one and 46% of patients received Keytruda 10 mg/kg every 2 or 3 weeks, respectively, for ≥6 months. No patients in either arm received treatment for more than one year.

The study population characteristics were: median age of 62 years (range: 18 to 89 years), 60% male, 98% White, 32% had an elevated lactate dehydrogenase (LDH) value at baseline, 65% had M1c stage disease, 9% with history of brain metastasis, and approximately 36% had been previously treated with systemic therapy which included a BRAF inhibitor (15%), chemotherapy (13%), and immunotherapy (6%).

In KEYNOTE-006, the adverse reaction profile was similar for the every 2 week and every 3 week schedule, therefore summary safety results are provided in a pooled analysis (n=555) of both Keytruda arms. Adverse reactions leading to permanent discontinuation of Keytruda occurred in 9% of patients. Adverse reactions leading to discontinuation of Keytruda in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). Adverse reactions leading to interruption of Keytruda occurred in 21% of patients; the most common (≥1%) was diarrhea (2.5%). Tables 2 and 3 summarize selected adverse reactions and laboratory abnormalities, respectively, in patients on Keytruda in KEYNOTE-006.

Table 2: Selected* Adverse Reactions Occurring in ≥10% of Patients Receiving Keytruda in KEYNOTE-006
  Adverse Reaction Keytruda
10 mg/kg every 2 or 3 weeks
Ipilimumab
n=555 n=256
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
*
Adverse reactions occurring at same or higher incidence than in the ipilimumab arm
Graded per NCI CTCAE v4.0
Includes rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and exfoliative rash.
§
Includes skin hypopigmentation
General
  Fatigue 28 0.9 28 3.1
Skin and Subcutaneous Tissue
  Rash 24 0.2 23 1.2
  Vitiligo§ 13 0 2 0
Musculoskeletal and Connective Tissue
  Arthralgia 18 0.4 10 1.2
  Back pain 12 0.9 7 0.8
Respiratory, Thoracic and Mediastinal
  Cough 17 0 7 0.4
  Dyspnea 11 0.9 7 0.8
Metabolism and Nutrition
  Decreased appetite 16 0.5 14 0.8
Nervous System
  Headache 14 0.2 14 0.8

Other clinically important adverse reactions occurring in ≥10% of patients receiving Keytruda were diarrhea (26%), nausea (21%), and pruritus (17%).

Table 3: Selected* Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Melanoma Patients Receiving Keytruda in KEYNOTE-006
  Laboratory Test Keytruda
10 mg/kg every 2 or 3 weeks
Ipilimumab
All Grades
%
Grades 3-4
%
All Grades
%
Grades 3-4
%
*
Laboratory abnormalities occurring at same or higher incidence than in ipilimumab arm
Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Keytruda (520 to 546 patients) and ipilimumab (237 to 247 patients); hypertriglyceridemia: Keytruda n=429 and ipilimumab n=183; hypercholesterolemia: Keytruda n=484 and ipilimumab n=205.
Graded per NCI CTCAE v4.0
Chemistry
  Hyperglycemia 45 4.2 45 3.8
  Hypertriglyceridemia 43 2.6 31 1.1
  Hyponatremia 28 4.6 26 7
  Increased AST 27 2.6 25 2.5
  Hypercholesterolemia 20 1.2 13 0
Hematology
  Anemia 35 3.8 33 4.0
  Lymphopenia 33 7 25 6

Other laboratory abnormalities occurring in ≥20% of patients receiving Keytruda were increased hypoalbuminemia (27% all Grades; 2.4% Grades 3-4), increased ALT (23% all Grades; 3.1% Grades 3-4), and increased alkaline phosphatase (21% all Grades, 2% Grades 3-4).

Ipilimumab-Refractory Melanoma

The safety of Keytruda in patients with unresectable or metastatic melanoma with disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor, was investigated in KEYNOTE-002. KEYNOTE-002 was a multicenter, partially blinded (Keytruda dose), randomized (1:1:1), active-controlled trial in which 528 patients received Keytruda 2 mg/kg (n=178) or 10 mg/kg (n=179) every 3 weeks or investigator's choice of chemotherapy (n=171), consisting of dacarbazine (26%), temozolomide (25%), paclitaxel and carboplatin (25%), paclitaxel (16%), or carboplatin (8%) [see Clinical Studies (14.1)]. Patients with autoimmune disease, severe immune-related toxicity related to ipilimumab, defined as any Grade 4 toxicity or Grade 3 toxicity requiring corticosteroid treatment (greater than 10 mg/day prednisone or equivalent dose) for greater than 12 weeks; medical conditions that required systemic corticosteroids or other immunosuppressive medication; a history of interstitial lung disease; or an active infection requiring therapy, including HIV or hepatitis B or C, were ineligible.

The median duration of exposure to Keytruda 2 mg/kg every 3 weeks was 3.7 months (range: 1 day to 16.6 months) and to Keytruda 10 mg/kg every 3 weeks was 4.8 months (range: 1 day to 16.8 months). In the Keytruda 2 mg/kg arm, 36% of patients were exposed to Keytruda for ≥6 months and 4% were exposed for ≥12 months. In the Keytruda 10 mg/kg arm, 41% of patients were exposed to Keytruda for ≥6 months and 6% of patients were exposed to Keytruda for ≥12 months.

The study population characteristics were: median age of 62 years (range: 15 to 89 years), 61% male, 98% White, 41% with an elevated LDH value at baseline, 83% with M1c stage disease, 73% received two or more prior therapies for advanced or metastatic disease (100% received ipilimumab and 25% a BRAF inhibitor), and 15% with history of brain metastasis.

In KEYNOTE-002, the adverse reaction profile was similar for the 2 mg/kg dose and 10 mg/kg dose, therefore summary safety results are provided in a pooled analysis (n=357) of both Keytruda arms. Adverse reactions resulting in permanent discontinuation occurred in 12% of patients receiving Keytruda; the most common (≥1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). Adverse reactions leading to interruption of Keytruda occurred in 14% of patients; the most common (≥1%) were dyspnea (1%), diarrhea (1%), and maculo-papular rash (1%). Tables 4 and 5 summarize adverse reactions and laboratory abnormalities, respectively, in patients on Keytruda in KEYNOTE-002.

Table 4: Selected* Adverse Reactions Occurring in ≥10% of Patients Receiving Keytruda in KEYNOTE-002
  Adverse Reaction Keytruda
2 mg/kg or 10 mg/kg every 3 weeks
Chemotherapy
n=357 n=171
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
*
Adverse reactions occurring at same or higher incidence than in chemotherapy arm
Chemotherapy: dacarbazine, temozolomide, carboplatin plus paclitaxel, paclitaxel, or carboplatin
Graded per NCI CTCAE v4.0
§
Includes rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, and rash pruritic
Skin and Subcutaneous Tissue
  Pruritus 28 0 8 0
  Rash§ 24 0.6 8 0
Gastrointestinal
  Constipation 22 0.3 20 2.3
  Diarrhea 20 0.8 20 2.3
  Abdominal pain 13 1.7 8 1.2
Respiratory, Thoracic and Mediastinal
  Cough 18 0 16 0
General
  Pyrexia 14 0.3 9 0.6
  Asthenia 10 2.0 9 1.8
Musculoskeletal and Connective Tissue
  Arthralgia 14 0.6 10 1.2

Other clinically important adverse reactions occurring in patients receiving Keytruda were fatigue (43%), nausea (22%), decreased appetite (20%), vomiting (13%), and peripheral neuropathy (1.7%).

Table 5: Selected* Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Melanoma Patients Receiving Keytruda in KEYNOTE-002
  Laboratory Test Keytruda
2 mg/kg or 10 mg/kg every 3 weeks
Chemotherapy
All Grades
%
Grades 3-4
%
All Grades
%
Grades 3-4
%
*
Laboratory abnormalities occurring at same or higher incidence than in chemotherapy arm.
Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Keytruda (range: 320 to 325 patients) and chemotherapy (range: 154 to 161 patients); hypertriglyceridemia: Keytruda n=247 and chemotherapy n=116; decreased bicarbonate: Keytruda n=263 and chemotherapy n=123.
Graded per NCI CTCAE v4.0
Chemistry
  Hyperglycemia 49 6 44 6
  Hypoalbuminemia 37 1.9 33 0.6
  Hyponatremia 37 7 24 3.8
  Hypertriglyceridemia 33 0 32 0.9
  Increased alkaline phosphatase 26 3.1 18 1.9
  Increased AST 24 2.2 16 0.6
  Decreased bicarbonate 22 0.4 13 0
  Hypocalcemia 21 0.3 18 1.9
  Increased ALT 21 1.8 16 0.6

Other laboratory abnormalities occurring in ≥20% of patients receiving Keytruda were anemia (44% all Grades; 10% Grades 3-4) and lymphopenia (40% all Grades; 9% Grades 3-4).

Adjuvant Treatment of Resected Melanoma

The safety of Keytruda as a single agent was evaluated in KEYNOTE-054, a randomized (1:1) double-blind trial in which 1019 patients with completely resected stage IIIA (>1 mm lymph node metastasis), IIIB or IIIC melanoma received 200 mg of Keytruda by intravenous infusion every 3 weeks (n=509) or placebo (n=502) for up to one year [see Clinical Studies (14.1)]. Patients with active autoimmune disease or a medical condition that required immunosuppression or mucosal or ocular melanoma were ineligible. Seventy-six percent of patients received Keytruda for 6 months or longer.

The study population characteristics were: median age of 54 years (range: 19 to 88); 25% age 65 or older; 62% male; 94% ECOG PS of 0 and 6% ECOG PS of 1. Sixteen percent had stage IIIA, 46% had stage IIIB, 18% had stage IIIC (1-3 positive lymph nodes), and 20% had stage IIIC (≥4 positive lymph nodes).

Two patients treated with Keytruda died from causes other than disease progression; causes of death were drug reaction with eosinophilia and systemic symptoms and autoimmune myositis with respiratory failure. Serious adverse reactions occurred in 25% of patients receiving Keytruda. Adverse reactions leading to permanent discontinuation occurred in 14% of patients receiving Keytruda; the most common (≥1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Adverse reactions leading to interruption of Keytruda occurred in 19% of patients; the most common (≥1%) were diarrhea (2.4%), pneumonitis (2%), increased ALT (1.4%), arthralgia (1.4%), increased AST (1.4%), dyspnea (1%), and fatigue (1%). Tables 6 and 7 summarize the adverse reactions and laboratory abnormalities, respectively, in patients on Keytruda in KEYNOTE-054.

Table 6: Selected* Adverse Reactions Occurring in ≥10% of Patients Receiving Keytruda in KEYNOTE-054
  Adverse Reaction Keytruda
200 mg every 3 weeks
n=509
Placebo
n=502
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
*
Adverse reactions occurring at same or higher incidence than in placebo arm
Graded per NCI CTCAE v4.03
Gastrointestinal
  Diarrhea 28 1.2 26 1.2
  Nausea 17 0.2 15 0
Skin and Subcutaneous Tissue
  Pruritus 19 0 12 0
  Rash 13 0.2 9 0
Musculoskeletal and Connective Tissue
  Arthralgia 16 1.2 14 0
Endocrine
  Hypothyroidism 15 0 2.8 0
  Hyperthyroidism 10 0.2 1.2 0
Respiratory, Thoracic and Mediastinal
  Cough 14 0 11 0
General
  Asthenia 11 0.2 8 0
  Influenza like illness 11 0 8 0
Investigations
  Weight loss 11 0 8 0
Table 7: Selected* Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Melanoma Patients Receiving Keytruda in KEYNOTE-054
  Laboratory Test Keytruda
200 mg every 3 weeks
Placebo
All Grades
%
Grades 3-4
%
All Grades
%
Grades 3-4
%
*
Laboratory abnormalities occurring at same or higher incidence than placebo.
Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Keytruda (range:503 to 507 patients) and placebo (range: 492 to 498 patients).
Graded per NCI CTCAE v4.03
Chemistry
  Increased ALT 27 2.4 16 0.2
  Increased AST 24 1.8 15 0.4
Hematology
  Lymphopenia 24 1 16 1.2

NSCLC

First-line treatment of metastatic nonsquamous NSCLC with pemetrexed and platinum chemotherapy

The safety of Keytruda in combination with pemetrexed and investigator's choice of platinum (either carboplatin or cisplatin) was investigated in KEYNOTE-189, a multicenter, double-blind, randomized (2:1), active-controlled trial in patients with previously untreated, metastatic nonsquamous NSCLC with no EGFR or ALK genomic tumor aberrations [see Clinical Studies (14.2)]. A total of 607 patients received Keytruda 200 mg, pemetrexed and platinum every 3 weeks for 4 cycles followed by Keytruda and pemetrexed (n=405) or placebo, pemetrexed, and platinum every 3 weeks for 4 cycles followed by placebo and pemetrexed (n=202). Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.

The median duration of exposure to Keytruda 200 mg every 3 weeks was 7.2 months (range: 1 day to 20.1 months). Sixty percent of patients in the Keytruda arm were exposed to Keytruda for ≥6 months. Seventy-two percent of patients received carboplatin.

The study population characteristics were: median age of 64 years (range: 34 to 84), 49% age 65 years or older, 59% male, 94% White and 3% Asian, and 18% with history of brain metastases at baseline.

Keytruda was discontinued for adverse reactions in 20% of patients. The most common adverse reactions resulting in permanent discontinuation of Keytruda were pneumonitis (3%) and acute kidney injury (2%). Adverse reactions leading to the interruption of Keytruda occurred in 53% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of Keytruda (≥2%) were neutropenia (13%), asthenia/fatigue (7%), anemia (7%), thrombocytopenia (5%), diarrhea (4%), pneumonia (4%), increased blood creatinine (3%), dyspnea (2%), febrile neutropenia (2%), upper respiratory tract infection (2%), increased ALT (2%), and pyrexia (2%). Tables 8 and 9 summarize adverse reactions and laboratory abnormalities, respectively, in patients on Keytruda in KEYNOTE-189.

Table 8: Adverse Reactions Occurring in ≥20% of Patients in KEYNOTE-189
  Adverse Reaction Keytruda
200 mg every 3 weeks
Pemetrexed
Platinum Chemotherapy
n=405
Placebo
Pemetrexed
Platinum Chemotherapy
n=202
All Grades*
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
*
Graded per NCI CTCAE v4.03
Includes asthenia and fatigue
Includes genital rash, rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular.
Gastrointestinal
  Nausea 56 3.5 52 3.5
  Constipation 35 1.0 32 0.5
  Diarrhea 31 5 21 3.0
  Vomiting 24 3.7 23 3.0
General
  Fatigue 56 12 58 6
  Pyrexia 20 0.2 15 0
Metabolism and Nutrition
  Decreased appetite 28 1.5 30 0.5
Skin and Subcutaneous Tissue
  Rash 25 2.0 17 2.5
Respiratory, Thoracic and Mediastinal
  Cough 21 0 28 0
  Dyspnea 21 3.7 26 5
Table 9: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients in KEYNOTE-189
  Laboratory Test* Keytruda
200 mg every 3 weeks
Pemetrexed
Platinum Chemotherapy
Placebo
Pemetrexed
Platinum Chemotherapy
All Grades
%
Grades 3-4
%
All Grades
%
Grades 3-4
%
*
Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Keytruda/pemetrexed/platinum chemotherapy (range: 381 to 401 patients) and placebo/pemetrexed/platinum chemotherapy (range: 184 to 197 patients).
Graded per NCI CTCAE v4.03
Hematology
  Anemia 85 17 81 18
  Lymphopenia 64 22 64 25
  Neutropenia 48 20 41 19
  Thrombocytopenia 30 12 29 8
Chemistry
  Hyperglycemia 63 9 60 7
  Increased ALT 47 3.8 42 2.6
  Increased AST 47 2.8 40 1.0
  Hypoalbuminemia 39 2.8 39 1.1
  Increased creatinine 37 4.2 25 1.0
  Hyponatremia 32 7 23 6
  Hypophosphatemia 30 10 28 14
  Increased alkaline phosphatase 26 1.8 29 2.1
  Hypocalcemia 24 2.8 17 0.5
  Hyperkalemia 24 2.8 19 3.1
  Hypokalemia 21 5 20 5

First-line treatment of metastatic squamous NSCLC with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy

The safety of Keytruda in combination with carboplatin and investigator's choice of either paclitaxel or paclitaxel protein-bound was investigated in KEYNOTE-407, a multicenter, double-blind, randomized (1:1), placebo-controlled trial in 558 patients with previously untreated, metastatic squamous NSCLC [see Clinical Studies (14.2)]. Safety data are available for the first 203 patients who received Keytruda and chemotherapy (n=101) or placebo and chemotherapy (n=102). Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.

The median duration of exposure to Keytruda was 7 months (range: 1 day to 12 months). Sixty-one percent of patients in the Keytruda arm were exposed to Keytruda for ≥6 months. A total of 139 of 203 patients (68%) received paclitaxel and 64 patients (32%) received paclitaxel protein-bound in combination with carboplatin.

The study population characteristics were: median age of 65 years (range: 40 to 83); 52% age 65 or older; 78% male; 83% White; and 9% with history of brain metastases.

Keytruda was discontinued for adverse reactions in 15% of patients, with no single type of adverse reaction accounting for the majority. Adverse reactions leading to interruption of Keytruda occurred in 43% of patients; the most common (≥2%) were thrombocytopenia (20%), neutropenia (11%), anemia (6%), asthenia (2%), and diarrhea (2%). The most frequent (≥2%) serious adverse reactions were febrile neutropenia (6%), pneumonia (6%), and urinary tract infection (3%).

The adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs. 36%) and peripheral neuropathy (31% vs. 25%) were observed in the Keytruda and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.

Previously Untreated NSCLC

The safety of Keytruda was investigated in KEYNOTE-042, a multicenter, open-label, randomized (1:1), active-controlled trial in 1251 patients with PD-L1 expressing, previously untreated stage III NSCLC, who were not candidates for surgical resection or definitive chemoradiation, or metastatic NSCLC [see Clinical Studies (14.2)]. Patients received Keytruda 200 mg every 3 weeks (n=636) or investigator's choice of chemotherapy (n=615), consisting of pemetrexed and carboplatin followed by optional pemetrexed (n=312) or paclitaxel and carboplatin followed by optional pemetrexed (n=303) every 3 weeks. Patients with EGFR or ALK genomic tumor aberrations; autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.

The median duration of exposure to Keytruda was 5.6 months (range: 1 day to 27.3 months). Forty-eight percent of patients in the Keytruda arm were exposed to Keytruda 200 mg for ≥6 months.

The study population characteristics were: median age of 63 years (range: 25 to 90), 45% age 65 years or older; 71% male; 64% White, 30% Asian, and 2% Black. Nineteen percent were Hispanic or Latino. Eighty-seven percent had metastatic disease (stage IV), 13% with stage III disease (2% stage IIIA and 11% stage IIIB); and 5% with treated brain metastases at baseline.

Keytruda was discontinued for adverse reactions in 19% of patients. The most common adverse reactions resulting in permanent discontinuation of Keytruda were pneumonitis (3.0%), death due to unknown cause (1.6%), and pneumonia (1.4%). Adverse reactions leading to interruption of Keytruda occurred in 33% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of Keytruda (≥2%) were pneumonitis (3.1%), pneumonia (3.0%), hypothyroidism (2.2%), and increased ALT (2.0%). The most frequent (≥2%) serious adverse reactions were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%).

Tables 10 and 11 summarize the adverse reactions and laboratory abnormalities, respectively, in patients treated with Keytruda in KEYNOTE-042.

Table 10: Adverse Reactions Occurring in ≥10% of Patients in KEYNOTE-042
  Adverse Reaction Keytruda
200 mg every 3 weeks
n=636
Chemotherapy
n=615
All Grades*
(%)
Grades 3-5
(%)
All Grades
(%)
Grades 3-5
(%)
*
Graded per NCI CTCAE v4.03
Includes fatigue and asthenia
Includes rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular.
General
  Fatigue 25 3.1 33 3.9
  Pyrexia 10 0.3 8 0
Metabolism and Nutrition
  Decreased appetite 17 1.7 21 1.5
Respiratory, Thoracic and Mediastinal
  Dyspnea 17 2.0 11 0.8
  Cough 16 0.2 11 0.3
Skin and Subcutaneous Tissue
  Rash 15 1.3 8 0.2
Gastrointestinal
  Constipation 12 0 21 0.2
  Diarrhea 12 0.8 12 0.5
  Nausea 12 0.5 32 1.1
Endocrine
  Hypothyroidism 12 0.2 1.5 0
Infections
  Pneumonia 12 7 9 6
Investigations
  Weight loss 10 0.9 7 0.2
Table 11: Laboratory Abnormalities Worsened from Baseline in ≥20% of Patients in KEYNOTE-042
  Laboratory Test* Keytruda
200 mg every 3 weeks
Chemotherapy
All Grades
%
Grades 3-4
%
All Grades
%
Grades 3-4
%
*
Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Keytruda (range: 598 to 610 patients) and chemotherapy (range: 588 to 597 patients); increased prothrombin INR: Keytruda n=203 and chemotherapy n=173.
Graded per NCI CTCAE v4.03
Chemistry
  Hyperglycemia 52 4.7 51 5
  Increased ALT 33 4.8 34 2.9
  Hypoalbuminemia 33 2.2 29 1.0
  Increased AST 31 3.6 32 1.7
  Hyponatremia 31 9 32 8
  Increased alkaline phosphatase 29 2.3 29 0.3
  Hypocalcemia 25 2.5 19 0.7
  Hyperkalemia 23 3.0 20 2.2
  Increased prothrombin INR 21 2.0 15 2.9
Hematology
  Anemia 43 4.4 79 19
  Lymphopenia 30 7 41 13

Previously Treated NSCLC

The safety of Keytruda was investigated in KEYNOTE-010, a multicenter, open-label, randomized (1:1:1), active-controlled trial, in patients with advanced NSCLC who had documented disease progression following treatment with platinum-based chemotherapy and, if positive for EGFR or ALK genetic aberrations, appropriate therapy for these aberrations [see Clinical Studies (14.2)]. A total of 991 patients received Keytruda 2 mg/kg (n=339) or 10 mg/kg (n=343) every 3 weeks or docetaxel (n=309) at 75 mg/m2 every 3 weeks. Patients with autoimmune disease, medical conditions that required systemic corticosteroids or other immunosuppressive medication, or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.

The median duration of exposure to Keytruda 2 mg/kg every 3 weeks was 3.5 months (range: 1 day to 22.4 months) and to Keytruda 10 mg/kg every 3 weeks was 3.5 months (range 1 day to 20.8 months). The data described below reflect exposure to Keytruda 2 mg/kg in 31% of patients exposed to Keytruda for ≥6 months. In the Keytruda 10 mg/kg arm, 34% of patients were exposed to Keytruda for ≥6 months.

The study population characteristics were: median age of 63 years (range: 20 to 88), 42% age 65 years or older, 61% male, 72% white and 21% Asian, 8% with advanced localized disease, 91% with metastatic disease, and 15% with history of brain metastases. Twenty-nine percent received two or more prior systemic treatments for advanced or metastatic disease.

In KEYNOTE-010, the adverse reaction profile was similar for the 2 mg/kg and 10 mg/kg dose, therefore summary safety results are provided in a pooled analysis (n=682). Treatment was discontinued for adverse reactions in 8% of patients receiving Keytruda. The most common adverse events resulting in permanent discontinuation of Keytruda was pneumonitis (1.8%). Adverse reactions leading to interruption of Keytruda occurred in 23% of patients; the most common (≥1%) were diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite (1.3%), and pneumonitis (1%). Tables 12 and 13 summarize adverse reactions and laboratory abnormalities, respectively, in patients on Keytruda in KEYNOTE-010.

Table 12: Selected* Adverse Reactions Occurring in ≥10% of Patients Receiving Keytruda in KEYNOTE-010
  Adverse Reaction Keytruda
2 or 10 mg/kg every 3 weeks
n=682
Docetaxel
75 mg/m2 every 3 weeks
n=309
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
*
Adverse reactions occurring at same or higher incidence than in docetaxel arm
Graded per NCI CTCAE v4.0
Includes rash, rash erythematous, rash macular, rash maculo-papular, rash papular, and rash pruritic
Metabolism and Nutrition
  Decreased appetite 25 1.5 23 2.6
Respiratory, Thoracic and Mediastinal
  Dyspnea 23 3.7 20 2.6
  Cough 19 0.6 14 0
Gastrointestinal
  Nausea 20 1.3 18 0.6
  Constipation 15 0.6 12 0.6
  Vomiting 13 0.9 10 0.6
Skin and Subcutaneous Tissue
  Rash 17 0.4 8 0
  Pruritus 11 0 3 0.3
Musculoskeletal and Connective Tissue
  Arthralgia 11 1.0 9 0.3
  Back pain 11 1.5 8 0.3

Other clinically important adverse reactions occurring in patients receiving Keytruda were fatigue (25%), diarrhea (14%), asthenia (11%) and pyrexia (11%).

Table 13: Selected* Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of NSCLC Patients Receiving Keytruda in KEYNOTE-010
  Laboratory Test Keytruda
2 or 10 mg/kg every 3 weeks
Docetaxel
75 mg/m2 every 3 weeks
All Grades
%
Grades 3-4
%
All Grades
%
Grades 3-4
%
*
Laboratory abnormalities occurring at same or higher incidence than in docetaxel arm.
Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Keytruda (range: 631 to 638 patients) and docetaxel (range: 274 to 277 patients).
Graded per NCI CTCAE v4.0
Chemistry
  Hyponatremia 32 8 27 2.9
  Increased alkaline phosphatase 28 3.0 16 0.7
  Increased AST 26 1.6 12 0.7
  Increased ALT 22 2.7 9 0.4

Other laboratory abnormalities occurring in ≥20% of patients receiving Keytruda were hyperglycemia (44% all Grades; 4.1% Grades 3-4), anemia (37% all Grades; 3.8% Grades 3-4), hypertriglyceridemia (36% all Grades; 1.8% Grades 3-4), lymphopenia (35% all Grades; 9% Grades 3-4), hypoalbuminemia (34% all Grades; 1.6% Grades 3-4), and hypercholesterolemia (20% all Grades; 0.7% Grades 3-4).

HNSCC

Among the 192 patients with HNSCC enrolled in KEYNOTE-012 [see Clinical Studies (14.3)], the median duration of exposure to Keytruda was 3.3 months (range: 1 day to 27.9 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible for KEYNOTE-012.

The median age of patients was 60 years (range: 20 to 84), 35% were age 65 years or older, 83% were male, 77% were White, 15% were Asian, and 5% were Black. Sixty-one percent of patients had two or more lines of therapy in the recurrent or metastatic setting, and 95% had prior radiation therapy. Baseline ECOG PS was 0 (30%) or 1 (70%) and 86% had M1 disease.

Keytruda was discontinued due to adverse reactions in 17% of patients. Serious adverse reactions occurred in 45% of patients receiving Keytruda. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The incidence of adverse reactions, including serious adverse reactions, was similar between dosage regimens (10 mg/kg every 2 weeks or 200 mg every 3 weeks); therefore, summary safety results are provided in a pooled analysis. The most common adverse reactions (occurring in ≥20% of patients) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC, with the exception of increased incidences of facial edema (10% all Grades; 2.1% Grades 3-4) and new or worsening hypothyroidism [see Warnings and Precautions (5.4)].

cHL

Among the 210 patients with cHL enrolled in KEYNOTE-087 [see Clinical Studies (14.4)], the median duration of exposure to Keytruda was 8.4 months (range: 1 day to 15.2 months). Keytruda was discontinued due to adverse reactions in 5% of patients, and treatment was interrupted due to adverse reactions in 26%. Fifteen percent (15%) of patients had an adverse reaction requiring systemic corticosteroid therapy. Serious adverse reactions occurred in 16% of patients. The most frequent serious adverse reactions (≥1%) included pneumonia, pneumonitis, pyrexia, dyspnea, graft versus host disease and herpes zoster. Two patients died from causes other than disease progression; one from GVHD after subsequent allogeneic HSCT and one from septic shock. Tables 14 and 15 summarize adverse reactions and laboratory abnormalities, respectively, in patients on Keytruda in KEYNOTE-087.

Table 14: Adverse Reactions in ≥10% of Patients with cHL in KEYNOTE-087
  Adverse Reaction Keytruda
200 mg every 3 weeks
N=210
All Grades*
(%)
Grade 3
(%)
*
Graded per NCI CTCAE v4.0
Includes fatigue, asthenia
Includes cough, productive cough
§
Includes dyspnea, dyspnea exertional, wheezing
Includes back pain, myalgia, bone pain, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, musculoskeletal discomfort, neck pain
#
Includes diarrhea, gastroenteritis, colitis, enterocolitis
Þ
Includes rash, rash maculo-papular, drug eruption, eczema, eczema asteatotic, dermatitis, dermatitis acneiform, dermatitis contact, rash erythematous, rash macular, rash papular, rash pruritic, seborrhoeic dermatitis, dermatitis psoriasiform
ß
Includes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paresthesia, dysesthesia, polyneuropathy
General
  Fatigue 26 1.0
  Pyrexia 24 1.0
Respiratory, Thoracic and Mediastinal
  Cough 24 0.5
  Dyspnea§ 11 1.0
Musculoskeletal and Connective Tissue
  Musculoskeletal pain 21 1.0
  Arthralgia 10 0.5
Gastrointestinal
  Diarrhea# 20 1.4
  Vomiting 15 0
  Nausea 13 0
Skin and Subcutaneous Tissue
  Rash Þ 20 0.5
  Pruritus 11 0
Endocrine
  Hypothyroidism 14 0.5
Infections
  Upper respiratory tract infection 13 0
Nervous System
  Headache 11 0.5
  Peripheral neuropathyß 10 0

Other clinically important adverse reactions that occurred in less than 10% of patients on KEYNOTE-087 included infusion reactions (9%), hyperthyroidism (3%), pneumonitis (3%), uveitis and myositis (1% each), and myelitis and myocarditis (0.5% each).

Table 15: Selected Laboratory Abnormalities Worsened from Baseline Occurring in ≥15% of cHL Patients Receiving Keytruda in KEYNOTE-087
  Laboratory Test* Keytruda
200 mg every 3 weeks
All Grades
(%)
Grades 3-4
(%)
*
Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Keytruda (range: 208 to 209 patients)
Graded per NCI CTCAE v4.0
Includes elevation of AST or ALT
Chemistry
  Hypertransaminasemia 34 2
  Increased alkaline phosphatase 17 0
  Increased creatinine 15 0.5
Hematology
  Anemia 30 6
  Thrombocytopenia 27 4
  Neutropenia 24 7

Hyperbilirubinemia occurred in less than 15% of patients on KEYNOTE-087 (10% all Grades, 2.4% Grade 3-4).

PMBCL

Among the 53 patients with PMBCL treated in KEYNOTE-170 [see Clinical Studies (14.5)], the median duration of exposure to Keytruda was 3.5 months (range: 1 day to 22.8 months).

Keytruda was discontinued due to adverse reactions in 8% of patients, and treatment was interrupted due to adverse reactions in 15%. Twenty-five percent of patients had an adverse reaction requiring systemic corticosteroid therapy. Serious adverse reactions occurred in 26% of patients, and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. Tables 16 and 17 summarize adverse reactions and laboratory abnormalities, respectively, in patients on Keytruda in KEYNOTE-170.

Table 16: Adverse Reactions in ≥10% of Patients with PMBCL in KEYNOTE-170
  Adverse Reaction Keytruda
200 mg every 3 weeks
N=53
All Grades*
(%)
Grades 3-4
(%)
*
Graded per NCI CTCAE v4.0
Includes arthralgia, back pain, myalgia, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, bone pain, neck pain, non-cardiac chest pain
Includes nasopharyngitis, pharyngitis, rhinorrhea, rhinitis, sinusitis, upper respiratory tract infection
§
Includes fatigue, asthenia
Includes allergic cough, cough, productive cough
#
Includes diarrhea, gastroenteritis
Þ
Includes abdominal pain, abdominal pain upper
ß
Includes atrial fibrillation, sinus tachycardia, supraventricular tachycardia, tachycardia
Musculoskeletal and Connective Tissue
  Musculoskeletal pain 30 0
Infections
  Upper respiratory tract infection 28 0
General
  Pyrexia 28 0
  Fatigue§ 23 2
Respiratory, Thoracic and Mediastinal
  Cough 26 2
  Dyspnea 21 11
Gastrointestinal
  Diarrhea# 13 2
  Abdominal pain Þ 13 0
  Nausea 11 0
Cardiac
  Arrhythmia ß 11 4
Nervous System
  Headache 11 0

Other clinically important adverse reactions that occurred in less than 10% of patients in KEYNOTE-170 included hypothyroidism (8%), hyperthyroidism and pericarditis (4% each), and thyroiditis, pericardial effusion, pneumonitis, arthritis and acute kidney injury (2% each).

Table 17: Laboratory Abnormalities Worsened from Baseline Occurring in ≥15% of PMBCL Patients Receiving Keytruda in KEYNOTE-170
  Laboratory Test* Keytruda
200 mg every 3 weeks
All Grades
(%)
Grades 3-4
(%)
*
Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Keytruda (range: 44 to 48 patients)
Graded per NCI CTCAE v4.0
Includes elevation of AST or ALT
Hematology
  Anemia 47 0
  Leukopenia 35 9
  Lymphopenia 32 18
  Neutropenia 30 11
Chemistry
  Hyperglycemia 38 4
  Hypophosphatemia 29 10
  Hypertransaminasemia 27 4
  Hypoglycemia 19 0
  Increased alkaline phosphatase 17 0
  Increased creatinine 17 0
  Hypocalcemia 15 4
  Hypokalemia 15 4

Urothelial Carcinoma

Cisplatin Ineligible Patients with Urothelial Carcinoma

The safety of Keytruda was investigated in KEYNOTE-052, a single-arm trial that enrolled 370 patients with locally advanced or metastatic urothelial carcinoma who were not eligible for cisplatin-containing chemotherapy. Patients with autoimmune disease or medical conditions that required systemic corticosteroids or other immunosuppressive medications were ineligible [see Clinical Studies (14.6)]. Patients received Keytruda 200 mg every 3 weeks until unacceptable toxicity or either radiographic or clinical disease progression.

The median duration of exposure to Keytruda was 2.8 months (range: 1 day to 15.8 months).

Keytruda was discontinued due to adverse reactions in 11% of patients. Eighteen patients (5%) died from causes other than disease progression. Five patients (1.4%) who were treated with Keytruda experienced sepsis which led to death, and three patients (0.8%) experienced pneumonia which led to death. Adverse reactions leading to interruption of Keytruda occurred in 22% of patients; the most common (≥1%) were liver enzyme increase, diarrhea, urinary tract infection, acute kidney injury, fatigue, joint pain, and pneumonia. Serious adverse reactions occurred in 42% of patients. The most frequent serious adverse reactions (≥2%) were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis.

Immune-related adverse reactions that required systemic glucocorticoids occurred in 8% of patients, use of hormonal supplementation due to an immune-related adverse reaction occurred in 8% of patients, and 5% of patients required at least one steroid dose ≥40 mg oral prednisone equivalent.

Table 18 summarizes adverse reactions in patients on Keytruda in KEYNOTE-052.

Table 18: Adverse Reactions Occurring in ≥10% of Patients Receiving Keytruda in KEYNOTE-052
Adverse Reaction Keytruda
200 mg every 3 weeks
N=370
All Grades*
(%)
Grades 3–4
(%)
*
Graded per NCI CTCAE v4.0
Includes fatigue, asthenia
Includes abdominal pain, pelvic pain, flank pain, abdominal pain lower, tumor pain, bladder pain, hepatic pain, suprapubic pain, abdominal discomfort, abdominal pain upper
§
Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, pain in extremity, spinal pain
Includes diarrhea, colitis, enterocolitis, gastroenteritis, frequent bowel movements
#
Includes autoimmune hepatitis, hepatitis, hepatitis toxic, liver injury, increased transaminases, hyperbilirubinemia, increased blood bilirubin, increased alanine aminotransferase, increased aspartate aminotransferase, increased hepatic enzymes, increased liver function tests
Þ
Includes dermatitis, dermatitis bullous, eczema, erythema, rash, rash macular, rash maculo-papular, rash pruritic, rash pustular, skin reaction, dermatitis acneiform, seborrheic dermatitis, palmar-plantar erythrodysesthesia syndrome, rash generalized
General
Fatigue 38 6
Pyrexia 11 0.5
Weight loss 10 0
Musculoskeletal and Connective Tissue
  Musculoskeletal pain§ 24 4.9
  Arthralgia 10 1.1
Metabolism and Nutrition
Decreased appetite 22 1.6
Hyponatremia 10 4.1
Gastrointestinal
  Constipation 21 1.1
  Diarrhea 20 2.4
  Nausea 18 1.1
  Abdominal pain 18 2.7
  Elevated LFTs# 13 3.5
  Vomiting 12 0
Skin and Subcutaneous Tissue
  RashÞ 21 0.5
  Pruritus 19 0.3
  Edema peripheral 14 1.1
Infections
  Urinary tract infection 19 9
Blood and Lymphatic System
  Anemia 17 7
Respiratory, Thoracic, and Mediastinal
  Cough 14 0
  Dyspnea 11 0.5
Renal and Urinary
Increased blood creatinine 11 1.1
Hematuria 13 3.0

Previously Treated Urothelial Carcinoma

The safety of Keytruda for the treatment of patients with locally advanced or metastatic urothelial carcinoma with disease progression following platinum-containing chemotherapy was investigated in KEYNOTE-045. KEYNOTE-045 was a multicenter, open-label, randomized (1:1), active-controlled trial in which 266 patients received Keytruda 200 mg every 3 weeks or investigator's choice of chemotherapy (n=255), consisting of paclitaxel (n=84), docetaxel (n=84) or vinflunine (n=87) [see Clinical Studies (14.6)]. Patients with autoimmune disease or a medical condition that required systemic corticosteroids or other immunosuppressive medications were ineligible.

The median duration of exposure was 3.5 months (range: 1 day to 20 months) in patients who received Keytruda and 1.5 months (range: 1 day to 14 months) in patients who received chemotherapy.

Keytruda was discontinued due to adverse reactions in 8% of patients. The most common adverse reaction resulting in permanent discontinuation of Keytruda was pneumonitis (1.9%). Adverse reactions leading to interruption of Keytruda occurred in 20% of patients; the most common (≥1%) were urinary tract infection (1.5%), diarrhea (1.5%), and colitis (1.1%). Serious adverse reactions occurred in 39% of Keytruda-treated patients. The most frequent serious adverse reactions (≥2%) in Keytruda-treated patients were urinary tract infection, pneumonia, anemia, and pneumonitis. Tables 19 and 20 summarize adverse reactions and laboratory abnormalities, respectively, in patients on Keytruda in KEYNOTE-045.

Table 19: Adverse Reactions Occurring in ≥10% of Patients Receiving Keytruda in KEYNOTE-045
  Adverse Reaction Keytruda
200 mg every 3 weeks
Chemotherapy*
n=266 n=255
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
*
Chemotherapy: paclitaxel, docetaxel, or vinflunine
Graded per NCI CTCAE v4.0
Includes asthenia, fatigue, malaise lethargy
§
Includes back pain, myalgia, bone pain, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, musculoskeletal discomfort, neck pain
Includes rash maculo-papular, rash, genital rash, rash erythematous, rash papular, rash pruritic, rash pustular, erythema, drug eruption, eczema, eczema asteatotic, dermatitis contact, dermatitis acneiform, dermatitis, seborrhoeic keratosis, lichenoid keratosis
#
Includes diarrhea, gastroenteritis, colitis, enterocolitis
Þ
Includes cough, productive cough
ß
Includes dyspnea, dyspnea exertional, wheezing
à
Includes blood urine present, hematuria, chromaturia
General
  Fatigue 38 4.5 56 11
  Pyrexia 14 0.8 13 1.2
Musculoskeletal and Connective Tissue
  Musculoskeletal pain§ 32 3.0 27 2.0
Skin and Subcutaneous Tissue
  Pruritus 23 0 6 0.4
  Rash 20 0.4 13 0.4
Gastrointestinal
  Nausea 21 1.1 29 1.6
  Constipation 19 1.1 32 3.1
  Diarrhea# 18 2.3 19 1.6
  Vomiting 15 0.4 13 0.4
  Abdominal pain 13 1.1 13 2.7
Infections
  Urinary tract infection 15 4.9 14 4.3
Metabolism and Nutrition
  Decreased appetite 21 3.8 21 1.2
Respiratory, Thoracic and Mediastinal
  CoughÞ 15 0.4 9 0
  Dyspneaß 14 1.9 12 1.2
Renal and Urinary
  Hematuria à 12 2.3 8 1.6
Table 20: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Urothelial Carcinoma Patients Receiving Keytruda in KEYNOTE-045
  Laboratory Test* Keytruda
200 mg every 3 weeks
Chemotherapy
All Grades
%
Grades 3-4
%
All Grades
%
Grades 3-4
%
*
Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Keytruda (range: 240 to 248 patients) and chemotherapy (range: 238 to 244 patients); phosphate decreased: Keytruda n=232 and chemotherapy n=222.
Graded per NCI CTCAE v4.0
Chemistry
  Hyperglycemia 52 8 60 7
  Anemia 52 13 68 18
  Lymphopenia 45 15 53 25
  Hypoalbuminemia 43 1.7 50 3.8
  Hyponatremia 37 9 47 13
  Increased alkaline phosphatase 37 7 33 4.9
  Increased creatinine 35 4.4 28 2.9
  Hypophosphatemia 29 8 34 14
  Increased AST 28 4.1 20 2.5
  Hyperkalemia 28 0.8 27 6
  Hypocalcemia 26 1.6 34 2.1

Gastric Cancer

Among the 259 patients with gastric cancer enrolled in KEYNOTE-059 [see Clinical Studies (14.8)], the median duration of exposure to Keytruda was 2.1 months (range: 1 day to 21.4 months). Patients with autoimmune disease or a medical condition that required immunosuppression or with clinical evidence of ascites by physical exam were ineligible. Adverse reactions occurring in patients with gastric cancer were similar to those occurring in patients with melanoma or NSCLC.

Cervical Cancer

Among the 98 patients with cervical cancer enrolled in Cohort E of KEYNOTE-158 [see Clinical Studies (14.9)], the median duration of exposure to Keytruda was 2.9 months (range: 1 day to 22.1 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible.

Keytruda was discontinued due to adverse reactions in 8% of patients. Serious adverse reactions occurred in 39% of patients receiving Keytruda. The most frequent serious adverse reactions reported included anemia (7%), fistula (4.1%), hemorrhage (4.1%), and infections [except UTIs] (4.1%). Tables 21 and 22 summarize adverse reactions and laboratory abnormalities, respectively, in patients on Keytruda in KEYNOTE-158.

Table 21: Adverse Reactions Occurring in ≥10% of Patients with Cervical Cancer in KEYNOTE-158
  Adverse Reaction Keytruda
200 mg every 3 weeks
N=98
All Grades*
(%)
Grades 3–4
(%)
*
Graded per NCI CTCAE v4.0
Includes asthenia, fatigue, lethargy, malaise
Includes breast pain, cancer pain, dysesthesia, dysuria, ear pain, gingival pain, groin pain, lymph node pain, oropharyngeal pain, pain, pain of skin, pelvic pain, radicular pain, stoma site pain, toothache
§
Includes edema peripheral, peripheral swelling
Includes arthralgia, back pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, myositis, neck pain, non-cardiac chest pain, pain in extremity
#
Includes colitis, diarrhea, gastroenteritis
Þ
Includes abdominal discomfort, abdominal distension, abdominal pain, abdominal pain lower, abdominal pain upper
ß
Includes epistaxis, hematuria, hemoptysis, metrorrhagia, rectal hemorrhage, uterine hemorrhage, vaginal hemorrhage
à
Includes bacterial pyelonephritis, pyelonephritis acute, urinary tract infection, urinary tract infection bacterial, urinary tract infection pseudomonal, urosepsis
è
Includes cellulitis, clostridium difficile infection, device-related infection, empyema, erysipelas, herpes virus infection, infected neoplasm, infection, influenza, lower respiratory tract congestion, lung infection, oral candidiasis, oral fungal infection, osteomyelitis, pseudomonas infection, respiratory tract infection, tooth abscess, upper respiratory tract infection, uterine abscess, vulvovaginal candidiasis
ð
Includes dermatitis, drug eruption, eczema, erythema, palmar-plantar erythrodysesthesia syndrome, rash, rash generalized, rash maculo-papular
General
  Fatigue 43 5
  Pain 22 2.0
  Pyrexia 19 1.0
  Edema peripheral§ 15 2.0
Musculoskeletal and Connective Tissue
  Musculoskeletal pain 27 5
Gastrointestinal
  Diarrhea# 23 2.0
  Abdominal painÞ 22 3.1
  Nausea 19 0
  Vomiting 19 1.0
  Constipation 14 0
Metabolism and Nutrition
  Decreased appetite 21 0
Vascular
  Hemorrhageß 19 5
Infections
  UTIà 18 6
  Infection (except UTI)è 16 4.1
Skin and Subcutaneous Tissue
  Rashð 17 2.0
Endocrine
  Hypothyroidism 11 0
Nervous System
  Headache 11 2.0
Respiratory, Thoracic and Mediastinal
  Dyspnea 10 1.0
Table 22: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients with Cervical Cancer in KEYNOTE-158
  Laboratory Test* Keytruda
200 mg every 3 weeks
All Grades
(%)
Grades 3-4
(%)
*
Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Keytruda (range: 76 to 79 patients)
Graded per NCI CTCAE v4.0
Hematology
  Anemia 54 24
  Lymphopenia 47 9
Chemistry
  Hypoalbuminemia 44 5
  Increased alkaline phosphatase 42 2.6
  Hyponatremia 38 13
  Hyperglycemia 38 1.3
  Increased AST 34 3.9
  Increased creatinine 32 5
  Hypocalcemia 27 0
  Increased ALT 21 3.9
  Hypokalemia 20 6

Other laboratory abnormalities occurring in ≥10% of patients receiving Keytruda were hypophosphatemia (19% all Grades; 6% Grades 3-4), increased INR (19% all Grades; 0% Grades 3-4), hypercalcemia (14% all Grades; 2.6% Grades 3-4), platelet count decreased (14% all Grades; 1.3% Grades 3-4), activated partial thromboplastin time prolonged (14% all Grades; 0% Grades 3-4), hypoglycemia (13% all Grades; 1.3% Grades 3-4), white blood cell decreased (13% all Grades; 2.6% Grades 3-4), and hyperkalemia (13% all Grades; 1.3% Grades 3-4).

HCC

Among the 104 patients with HCC who received Keytruda in KEYNOTE-224 [see Clinical Studies (14.10)], the median duration of exposure to Keytruda was 4.2 months (range: 1 day to 1.5 years). Adverse reactions occurring in patients with HCC were generally similar to those in patients with melanoma or NSCLC, with the exception of increased incidences of ascites (8% Grades 3-4) and immune-mediated hepatitis (2.9%). Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (20%), ALT (9%), and hyperbilirubinemia (10%).

MCC

Among the 50 patients with MCC enrolled in KEYNOTE-017 [see Clinical Studies (14.11)], the median duration of exposure to Keytruda was 6.6 months (range 1 day to 23.6 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Adverse reactions occurring in patients with MCC were similar to those occurring in patients with melanoma or NSCLC. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (11%) and hyperglycemia (19%).

RCC

The safety of Keytruda in combination with axitinib was investigated in KEYNOTE-426 [see Clinical Studies (14.12)]. Patients with medical conditions that required systemic corticosteroids or other immunosuppressive medications or had a history of severe autoimmune disease other than type 1 diabetes, vitiligo, Sjogren's syndrome, and hypothyroidism stable on hormone replacement were ineligible. Patients received Keytruda 200 mg intravenously every 3 weeks and axitinib 5 mg orally twice daily, or sunitinib 50 mg once daily for 4 weeks and then off treatment for 2 weeks. The median duration of exposure to the combination therapy of Keytruda and axitinib was 10.4 months (range: 1 day to 21.2 months).

The median age of patients treated with Keytruda in combination with axitinib was 62 years (range: 30 to 89), 40% of patients were 65 years or older, 71% were male, 80% were White, and the performance status as assessed by the Karnofsky Performance Status (KPS) was KPS 90-100 in 80% and KPS 70-80 in 20% of patients.

Fatal adverse reactions occurred in 3.3% of patients receiving Keytruda in combination with axitinib. These included 3 cases of cardiac arrest, 2 cases of pulmonary embolism and 1 case each of cardiac failure, death due to unknown cause, myasthenia gravis, myocarditis, Fournier's gangrene, plasma cell myeloma, pleural effusion, pneumonitis, and respiratory failure.

Serious adverse reactions occurred in 40% of patients receiving Keytruda in combination with axitinib. Serious adverse reactions in ≥1% of patients receiving Keytruda in combination with axitinib included hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%).

Permanent discontinuation due to an adverse reaction of either Keytruda or axitinib occurred in 31% of patients; 13% Keytruda only, 13% axitinib only, and 8% both drugs. The most common adverse reaction (>1%) resulting in permanent discontinuation of Keytruda, axitinib, or the combination was hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%).

Dose interruptions or reductions due to an adverse reaction, excluding temporary interruptions of Keytruda infusions due to infusion-related reactions, occurred in 76% of patients receiving Keytruda in combination with axitinib. This includes interruption of Keytruda in 50% of patients. Axitinib was interrupted in 64% of patients and dose reduced in 22% of patients. The most common adverse reactions (>10%) resulting in interruption of Keytruda were hepatotoxicity (14%) and diarrhea (11%), and the most common adverse reactions (>10%) resulting in either interruption or reduction of axitinib were hepatotoxicity (21%), diarrhea (19%), and hypertension (18%).

The most common adverse reactions (≥20%) in patients receiving Keytruda and axitinib were diarrhea, fatigue/asthenia, hypertension, hypothyroidism, decreased appetite, hepatotoxicity, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation.

Twenty-seven percent (27%) of patients treated with Keytruda in combination with axitinib received an oral prednisone dose equivalent to ≥40 mg daily for an immune-mediated adverse reaction.

Tables 23 and 24 summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in at least 20% of patients treated with Keytruda and axitinib in KEYNOTE-426.

Table 23: Adverse Reactions Occurring in ≥20% of Patients Receiving Keytruda with Axitinib in KEYNOTE-426
  Adverse Reaction Keytruda and Axitinib
n=429
Sunitinib
n=425
All Grades*
(%)
Grade 3-4
(%)
All Grades
(%)
Grade 3-4
(%)
*
Graded per NCI CTCAE v4.03
Includes diarrhea, colitis, enterocolitis, gastroenteritis, enteritis, enterocolitis hemorrhagic
Includes hypertension, blood pressure increased, hypertensive crisis, labile hypertension
§
Includes ALT increased, AST increased, autoimmune hepatitis, blood bilirubin increased, drug-induced liver injury, hepatic enzyme increased, hepatic function abnormal, hepatitis, hepatitis fulminant, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, immune-mediated hepatitis, liver function test increased, liver injury, transaminases increased
Includes rash, butterfly rash, dermatitis, dermatitis acneform, dermatitis atopic, dermatitis bullous, dermatitis contact, exfoliative rash, genital rash, rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, seborrhoeric dermatitis, skin discoloration, skin exfoliation, perineal rash
Gastrointestinal
  Diarrhea 56 11 45 5
  Nausea 28 0.9 32 0.9
  Constipation 21 0 15 0.2
General
  Fatigue/Asthenia 52 5 51 10
Vascular
  Hypertension 48 24 48 20
Hepatobiliary
  Hepatotoxicity§ 39 20 25 4.9
Endocrine
  Hypothyroidism 35 0.2 32 0.2
Metabolism and Nutrition
  Decreased appetite 30 2.8 29 0.7
Skin and Subcutaneous Tissue
  Palmar-plantar erythrodysaesthesia syndrome 28 5 40 3.8
  Stomatitis/Mucosal inflammation 27 1.6 41 4
  Rash 25 1.4 21 0.7
Respiratory, Thoracic and Mediastinal
  Dysphonia 25 0.2 3.3 0
  Cough 21 0.2 14 0.5
Table 24: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving Keytruda with Axitinib in KEYNOTE-426
  Laboratory Test* Keytruda and Axitinib Sunitinib
All Grades
%
Grades 3-4
%
All Grades
%
Grades 3-4
%
*
Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Keytruda/axitinib (range: 342 to 425 patients) and sunitinib (range: 345 to 422 patients).
Graded per NCI CTCAE v4.03
Corrected for albumin
§
Two patients with a Grade 3 elevated activated partial thromboplastin time prolonged (aPTT) were also reported as having an adverse reaction of hepatotoxicity.
Chemistry
  Hyperglycemia 62 9 54 3.2
  Increased ALT 60 20 44 5
  Increased AST 57 13 56 5
  Increased creatinine 43 4.3 40 2.4
  Hyponatremia 35 8 29 8
  Hyperkalemia 34 6 22 1.7
  Hypoalbuminemia 32 0.5 34 1.7
  Hypercalcemia 27 0.7 15 1.9
  Hypophosphatemia 26 6 49 17
  Increased alkaline phosphatase 26 1.7 30 2.7
  Hypocalcemia 22 0.2 29 0.7
  Blood bilirubin increased 22 2.1 21 1.9
  Activated partial thromboplastin time prolonged§ 22 1.2 14 0
Hematology
  Lymphopenia 33 11 46 8
  Anemia 29 2.1 65 8
  Thrombocytopenia 27 1.4 78 14

Immunogenicity

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

Trough levels of pembrolizumab interfere with the electrochemiluminescent (ECL) assay results; therefore, a subset analysis was performed in the patients with a concentration of pembrolizumab below the drug tolerance level of the anti-product antibody assay. In clinical studies in patients treated with pembrolizumab at a dose of 2 mg/kg every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg every 2 or 3 weeks, 27 (2.1%) of 1289 evaluable patients tested positive for treatment-emergent anti-pembrolizumab antibodies of whom six (0.5%) patients had neutralizing antibodies against pembrolizumab. There was no evidence of an altered pharmacokinetic profile or increased infusion reactions with anti-pembrolizumab binding antibody development.

USE IN SPECIFIC POPULATIONS

Pregnancy

Risk Summary

Based on its mechanism of action, Keytruda can cause fetal harm when administered to a pregnant woman. There are no available human data informing the risk of embryo-fetal toxicity. In animal models, the PD-1/PD-L1 signaling pathway is important in the maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue (see Data). Human IgG4 (immunoglobulins) are known to cross the placenta; therefore, pembrolizumab has the potential to be transmitted from the mother to the developing fetus. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

Animal reproduction studies have not been conducted with Keytruda to evaluate its effect on reproduction and fetal development. A literature-based assessment of the effects of the PD-1 pathway on reproduction demonstrated that 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 result in an increase in fetal loss; therefore, potential risks of administering Keytruda during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 knockout mice. Based on its mechanism of action, fetal exposure to pembrolizumab may increase the risk of developing immune-mediated disorders or of altering the normal immune response.

Lactation

Risk Summary

There are no data on the presence of pembrolizumab in either animal or human milk or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with Keytruda and for 4 months after the final dose.

Females and Males of Reproductive Potential

Pregnancy Testing

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

Contraception

Keytruda can cause fetal harm when administered to a pregnant woman [see Warnings and Precautions (5.11), Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with Keytruda and for at least 4 months following the final dose.

Pediatric Use

The safety and effectiveness of Keytruda have been established in pediatric patients with cHL, PMBCL, and MSI-H cancer. Use of Keytruda in pediatric patients with cHL, PMBCL, and MSI-H cancers is supported by evidence from adequate and well-controlled studies of Keytruda in adults with additional pharmacokinetic and safety data in pediatric patients [see Adverse Reactions (6.1), Clinical Studies (14,4, 14.5, 14.7), Clinical Pharmacology (12.3)].

There is limited experience with Keytruda in pediatric patients. In a trial (NCT02332668), 40 pediatric patients (16 children ages 2 years to less than 12 years and 24 adolescents ages 12 years to 18 years) with various cancers, including unapproved usages, were administered Keytruda 2 mg/kg every 3 weeks. Patients received Keytruda for a median of 3 doses (range: 1-17 doses), with 34 patients (85%) receiving Keytruda for 2 doses or more.

The safety profile in these pediatric patients was similar to that seen in adults; adverse reactions that occurred at a higher rate (≥15% difference) in pediatric patients when compared to adults <65 years of age were fatigue (45%), vomiting (38%), abdominal pain (28%), increased transaminases (28%) and hyponatremia (18%).

The concentrations of pembrolizumab in pediatric patients were comparable to those observed in adult patients at the same dose regimen of 2 mg/kg every 3 weeks.

The safety and effectiveness of Keytruda in pediatric patients have not been established in the other approved indications [see Indications and Usage (1)].

Geriatric Use

Of 3991 patients with melanoma, NSCLC, HNSCC, cHL or urothelial carcinoma who were treated with Keytruda in clinical studies, 46% were 65 years and over and 16% were 75 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients.

Keytruda Description

Pembrolizumab is a programmed death receptor-1 (PD 1)-blocking antibody. Pembrolizumab is a humanized monoclonal IgG4 kappa antibody with an approximate molecular weight of 149 kDa. Pembrolizumab is produced in recombinant Chinese hamster ovary (CHO) cells.

Keytruda (pembrolizumab) for injection is a sterile, preservative-free, white to off-white lyophilized powder in single-dose vials for intravenous use. Each 2 mL of reconstituted solution contains 50 mg of pembrolizumab and is formulated in L-histidine (3.1 mg), polysorbate 80 (0.4 mg), and sucrose (140 mg). May contain hydrochloric acid/sodium hydroxide to adjust pH to 5.5.

Keytruda (pembrolizumab) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution for intravenous use. Each vial contains 100 mg of pembrolizumab in 4 mL of solution. Each 1 mL of solution contains 25 mg of pembrolizumab and is formulated in: L-histidine (1.55 mg), polysorbate 80 (0.2 mg), sucrose (70 mg), and Water for Injection, USP.

Keytruda - 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. Pembrolizumab is a 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.

Pharmacodynamics

Based on dose/exposure efficacy and safety relationships, there are no clinically significant differences in efficacy and safety between pembrolizumab doses of 200 mg or 2 mg/kg every 3 weeks in patients with melanoma or NSCLC.

Pharmacokinetics

The pharmacokinetics (PK) of pembrolizumab was characterized using a population PK analysis with concentration data collected from 2993 patients with various cancers who received pembrolizumab doses of 1 to 10 mg/kg every 2 weeks, 2 to 10 mg/kg every 3 weeks, or 200 mg every 3 weeks.

Steady-state concentrations of pembrolizumab were reached by 16 weeks of repeated dosing with an every 3-week regimen and the systemic accumulation was 2.1-fold. The peak concentration (Cmax), trough concentration (Cmin), and area under the plasma concentration versus time curve at steady state (AUCss) of pembrolizumab increased dose proportionally in the dose range of 2 to 10 mg/kg every 3 weeks.

Distribution

The geometric mean value (CV%) for volume of distribution at steady state is 6.0 L (20%).

Elimination

Pembrolizumab clearance (CV%) is approximately 23% lower [geometric mean, 195 mL/day (40%)] at steady state than that after the first dose [252 mL/day (37%)]; this decrease in clearance with time is not considered clinically important. The terminal half-life (t1/2) is 22 days (32%).

Specific Populations

The following factors had no clinically important effect on the CL of pembrolizumab: age (range: 15 to 94 years), sex, race (89% White), renal impairment (eGFR ≥ 15 mL/min/1.73 m2), mild hepatic impairment (total bilirubin ≤ upper limit of normal (ULN) and AST > ULN or total bilirubin between 1 and 1.5 times ULN and any AST), or tumor burden. The impact of moderate or severe hepatic impairment on the pharmacokinetics of pembrolizumab is unknown.

Pediatric Patients: Pembrolizumab concentrations with weight-based dosing at 2 mg/kg every 3 weeks in pediatric patients (2 to 17 years) are comparable to those of adults at the same dose.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been performed to test the potential of pembrolizumab for carcinogenicity or genotoxicity.

Fertility studies have not been conducted with pembrolizumab. In 1-month and 6-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 resulted in an increased 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 (LCMV). Administration of pembrolizumab in chimpanzees with naturally occurring chronic hepatitis B infection resulted in two out of four animals with significantly increased levels of serum ALT, AST, and GGT, which persisted for at least 1 month after discontinuation of pembrolizumab.

Clinical Studies

Melanoma

Ipilimumab-Naive Melanoma

The efficacy of Keytruda was investigated in KEYNOTE-006 (NCT01866319), a randomized (1:1:1), open-label, multicenter, active-controlled trial in 834 patients. Patients were randomized to receive Keytruda at a dose of 10 mg/kg every 2 weeks or 10 mg/kg every 3 weeks intravenously until disease progression or unacceptable toxicity or to ipilimumab 3 mg/kg every 3 weeks intravenously for 4 doses unless discontinued earlier for disease progression or unacceptable toxicity. Patients with disease progression could receive additional doses of treatment unless disease progression was symptomatic, was rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at 4 to 6 weeks with repeat imaging. Randomization was stratified by line of therapy (0 vs. 1), ECOG PS (0 vs. 1), and PD-L1 expression (≥1% of tumor cells [positive] vs. <1% of tumor cells [negative]) according to an investigational use only (IUO) assay. Key eligibility criteria were unresectable or metastatic melanoma; no prior ipilimumab; and no more than one prior systemic treatment for metastatic melanoma. Patients with BRAF V600E mutation-positive melanoma were not required to have received prior BRAF inhibitor therapy. Patients with autoimmune disease; a medical condition that required immunosuppression; previous severe hypersensitivity to other monoclonal antibodies; and HIV, hepatitis B or hepatitis C infection, were ineligible. Assessment of tumor status was performed at 12 weeks, then every 6 weeks through Week 48, followed by every 12 weeks thereafter. The major efficacy outcome measures were overall survival (OS) and progression-free survival (PFS; as assessed by blinded independent central review [BICR] using Response Evaluation Criteria in Solid Tumors [RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ]). Additional efficacy outcome measures were overall response rate (ORR) and response duration.

The study population characteristics were: median age of 62 years (range: 18 to 89 years), 60% male, 98% White, 66% had no prior systemic therapy for metastatic disease, 69% ECOG PS of 0, 80% had PD-L1 positive melanoma, 18% had PD-L1 negative melanoma, and 2% had unknown PD-L1 status using the IUO assay, 65% had M1c stage disease, 68% with normal LDH, 36% with reported BRAF mutation-positive melanoma, and 9% with a history of brain metastases. Among patients with BRAF mutation-positive melanoma, 139 (46%) were previously treated with a BRAF inhibitor.

The study demonstrated statistically significant improvements in OS and PFS for patients randomized to Keytruda as compared to ipilimumab. Among the 91 patients randomized to Keytruda 10 mg/kg every 3 weeks with an objective response, response durations ranged from 1.4+ to 8.1+ months. Among the 94 patients randomized to Keytruda 10 mg/kg every 2 weeks with an objective response, response durations ranged from 1.4+ to 8.2 months. Efficacy results are summarized in Table 25 and Figure 1.

Table 25: Efficacy Results in KEYNOTE-006
Endpoint Keytruda
10 mg/kg every 3 weeks
n=277
Keytruda
10 mg/kg every 2 weeks
n=279
Ipilimumab
3 mg/kg every 3 weeks
n=278
*
Hazard ratio (Keytruda compared to ipilimumab) based on the stratified Cox proportional hazard model
OS
  Deaths (%) 92 (33%) 85 (30%) 112 (40%)
  Hazard ratio* (95% CI) 0.69 (0.52, 0.90) 0.63 (0.47, 0.83) ---
  p-Value (stratified log-rank) 0.004 <0.001 ---
PFS by BICR
  Events (%) 157 (57%) 157 (56%) 188 (68%)
  Median in months (95% CI) 4.1 (2.9, 6.9) 5.5 (3.4, 6.9) 2.8 (2.8, 2.9)
  Hazard ratio* (95% CI) 0.58 (0.47, 0.72) 0.58 (0.46, 0.72) ---
  p-Value (stratified log-rank) <0.001 <0.001 ---
Best overall response by BICR
  ORR (95% CI) 33% (27, 39) 34% (28, 40) 12% (8, 16)
    Complete response rate 6% 5% 1%
    Partial response rate 27% 29% 10%
Figure 1: Kaplan-Meier Curve for Overall Survival in KEYNOTE-006*
*
based on the final analysis with an additional follow-up of 9 months (total of 383 deaths as pre-specified in the protocol)

Ipilimumab-Refractory Melanoma

The efficacy of Keytruda was investigated in KEYNOTE-002 (NCT01704287), a multicenter, randomized (1:1:1), active-controlled trial in 540 patients randomized to receive one of two doses of Keytruda in a blinded fashion or investigator's choice chemotherapy. The treatment arms consisted of Keytruda 2 mg/kg or 10 mg/kg intravenously every 3 weeks or investigator's choice of any of the following chemotherapy regimens: dacarbazine 1000 mg/m2 intravenously every 3 weeks (26%), temozolomide 200 mg/m2 orally once daily for 5 days every 28 days (25%), carboplatin AUC 6 intravenously plus paclitaxel 225 mg/m2 intravenously every 3 weeks for four cycles then carboplatin AUC of 5 plus paclitaxel 175 mg/m2 every 3 weeks (25%), paclitaxel 175 mg/m2 intravenously every 3 weeks (16%), or carboplatin AUC 5 or 6 intravenously every 3 weeks (8%). Randomization was stratified by ECOG performance status (0 vs. 1), LDH levels (normal vs. elevated [≥110% ULN]) and BRAF V600 mutation status (wild-type [WT] or V600E). The trial included patients with unresectable or metastatic melanoma with progression of disease; refractory to two or more doses of ipilimumab (3 mg/kg or higher) and, if BRAF V600 mutation-positive, a BRAF or MEK inhibitor; and disease progression within 24 weeks following the last dose of ipilimumab. The trial excluded patients with uveal melanoma and active brain metastasis. Patients received Keytruda until unacceptable toxicity; disease progression that was symptomatic, was rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at 4 to 6 weeks with repeat imaging; withdrawal of consent; or physician's decision to stop therapy for the patient. Assessment of tumor status was performed at 12 weeks after randomization, then every 6 weeks through week 48, followed by every 12 weeks thereafter. Patients on chemotherapy who experienced progression of disease were offered Keytruda. The major efficacy outcomes were progression-free survival (PFS) as assessed by BICR per RECIST v1.1 and overall survival (OS). Additional efficacy outcome measures were confirmed overall response rate (ORR) as assessed by BICR per RECIST v1.1 and duration of response.

The study population characteristics were: median age was 62 years (range: 15 to 89 years), with 43% age 65 or older; 61% male; 98% White; and ECOG performance score was 0 (55%) and 1 (45%). Twenty-three percent of patients were BRAF V600 mutation positive, 40% had elevated LDH at baseline, 82% had M1c disease, and 73% had two or more prior therapies for advanced or metastatic disease.

The study demonstrated a statistically significant improvement in PFS for patients randomized to Keytruda as compared to control arm. There was no statistically significant difference between Keytruda 2 mg/kg and chemotherapy or between Keytruda 10 mg/kg and chemotherapy in the OS analysis in which 55% of the patients who had been randomized to receive chemotherapy had crossed over to receive Keytruda. Among the 38 patients randomized to Keytruda 2 mg/kg with an objective response, response durations ranged from 1.3+ to 11.5+ months. Among the 46 patients randomized to Keytruda 10 mg/kg with an objective response, response durations ranged from 1.1+ to 11.1+ months. Efficacy results are summarized in Table 26.

Table 26: Efficacy Results in KEYNOTE-002
Endpoint Keytruda
2 mg/kg every 3 weeks
Keytruda
10 mg/kg every 3 weeks
Chemotherapy
n=180 n=181 n=179
*
Hazard ratio (Keytruda compared to chemotherapy) based on the stratified Cox proportional hazard model
With additional follow-up of 18 months after the PFS analysis
Not statistically significant compared to multiplicity adjusted significance level of 0.01
PFS
  Number of Events, n (%) 129 (72%) 126 (70%) 155 (87%)
  Progression, n (%) 105 (58%) 107 (59%) 134 (75%)
  Death, n (%) 24 (13%) 19 (10%) 21 (12%)
  Median in months (95% CI) 2.9 (2.8, 3.8) 2.9 (2.8, 4.7) 2.7 (2.5, 2.8)
  p-Value (stratified log-rank) <0.001 <0.001 ---
  Hazard ratio* (95% CI) 0.57 (0.45, 0.73) 0.50 (0.39, 0.64) ---
OS
  Deaths (%) 123 (68%) 117 (65%) 128 (72%)
  Hazard ratio* (95% CI) 0.86 (0.67, 1.10) 0.74 (0.57, 0.96) ---
  p-Value (stratified log-rank) 0.117 0.011 ---
  Median in months (95% CI) 13.4 (11.0, 16.4) 14.7 (11.3, 19.5) 11.0 (8.9, 13.8)
Objective Response Rate
  ORR (95% CI) 21% (15, 28) 25% (19, 32) 4% (2, 9)
    Complete response rate 2% 3% 0%
    Partial response rate 19% 23% 4%
Figure 2: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-002

Adjuvant Treatment of Resected Melanoma

The efficacy of Keytruda was evaluated in KEYNOTE-054 (NCT02362594), a multicenter, randomized (1:1), double-blind, placebo-controlled trial in patients with completely resected stage IIIA (>1 mm lymph node metastasis), IIIB or IIIC melanoma. Patients were randomized to Keytruda 200 mg every three weeks or placebo for up to one year until disease recurrence or unacceptable toxicity. Randomization was stratified by American Joint Committee on Cancer 7th edition (AJCC) stage (IIIA vs. IIIB vs. IIIC 1-3 positive lymph nodes vs. IIIC ≥4 positive lymph nodes) and geographic region (North America, European countries, Australia, and other countries as designated). Patients must have undergone lymph node dissection and, if indicated, radiotherapy within 13 weeks prior to starting treatment. The major efficacy outcome measure was investigator-assessed recurrence-free survival (RFS) in the whole population and in the population with PD-L1 positive tumors where RFS was defined as the time between the date of randomization and the date of first recurrence (local, regional, or distant metastasis) or death, whichever occurs first. Patients underwent imaging every 12 weeks after the first dose of Keytruda for the first two years, then every 6 months from year 3 to 5, and then annually.

The study population characteristics were: median age of 54 years (range: 19 to 88); 25% age 65 or older; 62% male; 94% ECOG PS of 0 and 6% ECOG PS of 1. Sixteen percent had stage IIIA, 46% had stage IIIB, 18% had stage IIIC (1-3 positive lymph nodes), and 20% had stage IIIC (≥4 positive lymph nodes); 50% were BRAF V600 mutation positive and 44% were BRAF wild-type; and 84% had PD-L1 positive melanoma with tumor proportion score (TPS ≥1%) according to an investigational use only assay.

The trial demonstrated a statistically significant improvement in RFS for patients randomized to the Keytruda arm compared with placebo. Efficacy results are summarized in Table 27 and Figure 3.

Table 27: Efficacy Results in KEYNOTE-054
Endpoint Keytruda
200 mg every 3 weeks
n=514
Placebo
n=505
NR = not reached
*
Based on the stratified Cox proportional hazard model
Stratified by American Joint Committee on Cancer 7th edition (AJCC) stage
p-Value is compared with 0.008 of the allocated alpha for this interim analysis.
RFS
  Number (%) of patients with event 135 (26%) 216 (43%)
  Median in months (95% CI) NR 20.4 (16.2, NR)
  Hazard ratio* (95% CI) 0.57 (0.46, 0.70)
  p-Value (log-rank) <0.001

For patients with PD-L1 positive tumors, the HR was 0.54 (95% CI: 0.42, 0.69); p<0.001. The RFS benefit for Keytruda compared to placebo was observed regardless of tumor PD-L1 expression.

Figure 3: Kaplan-Meier Curve for Recurrence-Free Survival in KEYNOTE-054

Non-Small Cell Lung Cancer

First-line treatment of metastatic nonsquamous NSCLC with pemetrexed and platinum chemotherapy

The efficacy of Keytruda in combination with pemetrexed and platinum chemotherapy was investigated in KEYNOTE-189 (NCT02578680), a randomized, multicenter, double-blind, active-controlled trial conducted in 616 patients with metastatic nonsquamous NSCLC, regardless of PD-L1 tumor expression status, who had not previously received systemic therapy for metastatic disease and in whom there were no EGFR or ALK genomic tumor aberrations. Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Randomization was stratified by smoking status (never vs. former/current), choice of platinum (cisplatin vs. carboplatin), and tumor PD-L1 status (TPS <1% [negative] vs. TPS ≥1%). Patients were randomized (2:1) to one of the following treatment arms:

  • Keytruda 200 mg, pemetrexed 500 mg/m2, and investigator's choice of cisplatin 75 mg/m2 or carboplatin AUC 5 mg/mL/min intravenously on Day 1 of each 21-day cycle for 4 cycles followed by Keytruda 200 mg and pemetrexed 500 mg/m2 intravenously every 3 weeks. Keytruda was administered prior to chemotherapy on Day 1.
  • Placebo, pemetrexed 500 mg/m2, and investigator's choice of cisplatin 75 mg/m2 or carboplatin AUC 5 mg/mL/min intravenously on Day 1 of each 21-day cycle for 4 cycles followed by placebo and pemetrexed 500 mg/m2 intravenously every 3 weeks.

Treatment with Keytruda continued until RECIST v1.1-defined progression of disease as determined by the investigator, unacceptable toxicity, or a maximum of 24 months. Administration of Keytruda was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Patients randomized to placebo and chemotherapy were offered Keytruda as a single agent at the time of disease progression. Assessment of tumor status was performed at Week 6, Week 12, and then every 9 weeks thereafter. The main efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1. Additional efficacy outcome measures were ORR and duration of response, as assessed by the BICR according to RECIST v1.1.

The study population characteristics were: median age of 64 years (range: 34 to 84); 49% age 65 or older; 59% male; 94% White and 3% Asian; 56% ECOG performance status of 1; and 18% with history of brain metastases. Thirty-one percent had tumor PD-L1 expression TPS <1% [negative]. Seventy-two percent received carboplatin and 12% were never smokers. A total of 85 patients in the placebo and chemotherapy arm received an anti-PD-1/PD-L1 monoclonal antibody at the time of disease progression.

The trial demonstrated a statistically significant improvement in OS and PFS for patients randomized to Keytruda in combination with pemetrexed and platinum chemotherapy compared with placebo, pemetrexed, and platinum chemotherapy. Table 28 and Figure 4 summarize the efficacy results for KEYNOTE-189.

Table 28: Efficacy Results in KEYNOTE-189
Endpoint Keytruda
Pemetrexed
Platinum Chemotherapy
n=410
Placebo
Pemetrexed
Platinum Chemotherapy
n=206
NR = not reached
*
Based on the stratified Cox proportional hazard model
Based on stratified log-rank test.
Response: Best objective response as confirmed complete response or partial response
§
Based on Miettinen and Nurminen method stratified by PD-L1 status, platinum chemotherapy and smoking status
OS
  Number (%) of patients with event 127 (31%) 108 (52%)
  Median in months (95% CI) NR
(NR, NR)
11.3
(8.7, 15.1)
  Hazard ratio* (95% CI) 0.49 (0.38, 0.64)
  p-Value <0.0001
PFS
  Number of patients with event (%) 244 (60%) 166 (81%)
  Median in months (95% CI) 8.8 (7.6, 9.2) 4.9 (4.7, 5.5)
  Hazard ratio* (95% CI) 0.52 (0.43, 0.64)
  p-Value <0.0001
Objective Response Rate
  ORR (95% CI) 48% (43, 53) 19% (14, 25)
    Complete response 0.5% 0.5%
    Partial response 47% 18%
  p-Value§ <0.0001
Duration of Response
  Median in months (range) 11.2 (1.1+, 18.0+) 7.8 (2.1+, 16.4+)
Figure 4: Kaplan-Meier Curve for Overall Survival in KEYNOTE-189

First-line treatment of metastatic squamous NSCLC with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy

The efficacy of Keytruda in combination with carboplatin and investigator's choice of either paclitaxel or paclitaxel protein-bound was investigated in KEYNOTE-407 (NCT02775435), a randomized, multi-center, double-blind, placebo-controlled trial conducted in 559 patients with metastatic squamous NSCLC, regardless of PD-L1 tumor expression status, who had not previously received systemic therapy for metastatic disease. Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Randomization was stratified by tumor PD-L1 status (TPS <1% [negative] vs. TPS ≥1%), choice of paclitaxel or paclitaxel protein-bound, and geographic region (East Asia vs. non-East Asia). Patients were randomized (1:1) to one of the following treatment arms; all study medications were administered via intravenous infusion.

  • Keytruda 200 mg and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for 4 cycles, and paclitaxel 200 mg/m2 on Day 1 of each 21-day cycle for 4 cycles or paclitaxel protein-bound 100 mg/m2 on Days 1, 8 and 15 of each 21-day cycle for 4 cycles, followed by Keytruda 200 mg every 3 weeks. Keytruda was administered prior to chemotherapy on Day 1.
  • Placebo and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for 4 cycles and paclitaxel 200 mg/m2 on Day 1 of each 21-day cycle for 4 cycles or paclitaxel protein-bound 100 mg/m2 on Days 1, 8 and 15 of each 21-day cycle for 4 cycles, followed by placebo every 3 weeks.

Treatment with Keytruda and chemotherapy or placebo and chemotherapy continued until RECIST v1.1-defined progression of disease as determined by BICR, unacceptable toxicity, or a maximum of 24 months. Administration of Keytruda was permitted beyond RECIST-defined disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator. Patients randomized to the placebo and chemotherapy arm were offered Keytruda as a single agent at the time of disease progression. Assessment of tumor status was performed every 6 weeks through Week 18, every 9 weeks through Week 45 and every 12 weeks thereafter. The main efficacy outcome measures were PFS and ORR as assessed by BICR using RECIST v1.1 and OS. An additional efficacy outcome measure was DOR as assessed by BICR according to RECIST v1.1.

The study population characteristics were: median age of 65 years (range: 29 to 88); 55% age 65 or older; 81% male; 77% White; 71% ECOG performance status of 1; and 8% with a history of brain metastases. Thirty-five percent had tumor PD-L1 expression TPS <1%; 19% were from the East Asian region; and 60% received paclitaxel.

The trial demonstrated a statistically significant improvement in OS, PFS and ORR in patients randomized to Keytruda in combination with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy compared with patients randomized to placebo with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy. Table 29 and Figure 5 summarize the efficacy results for KEYNOTE-407.

Table 29: Efficacy Results in KEYNOTE-407
Endpoint Keytruda
Carboplatin
Paclitaxel/Paclitaxel protein-bound
n=278
Placebo
Carboplatin
Paclitaxel/Paclitaxel protein-bound
n=281
NE = not estimable
*
Based on the stratified Cox proportional hazard model
Based on a stratified log-rank test
ORR primary analysis and DOR analysis were conducted with the first 204 patients enrolled.
§
Based on a stratified Miettinen-Nurminen test
OS
  Number of events (%) 85 (31%) 120 (43%)
  Median in months (95% CI) 15.9 (13.2, NE) 11.3 (9.5, 14.8)
  Hazard ratio* (95% CI) 0.64 (0.49, 0.85)
  p-Value 0.0017
PFS
  Number of events (%) 152 (55%) 197 (70%)
  Median in months (95% CI) 6.4 (6.2, 8.3) 4.8 (4.3, 5.7)
  Hazard ratio* (95% CI) 0.56 (0.45, 0.70)
  p-Value <0.0001
n=101 n=103
Objective Response Rate
  ORR (95% CI) 58% (48, 68) 35% (26, 45)
  Difference (95% CI) 23.6% (9.9, 36.4)
  p-Value§ 0.0008
Duration of Response
  Median duration of response in months (range) 7.2 (2.4, 12.4+) 4.9 (2.0, 12.4+)
Figure 5: Kaplan-Meier Curve for Overall Survival in KEYNOTE-407

First-line treatment of metastatic NSCLC as a single agent

KEYNOTE-042

The efficacy of Keytruda was investigated in KEYNOTE-042 (NCT02220894), a randomized, multicenter, open-label, active-controlled trial conducted in 1274 patients with stage III NSCLC, who were not candidates for surgical resection or definitive chemoradiation, or metastatic NSCLC, whose tumors expressed PD-L1 (TPS ≥1%) by an immunohistochemistry assay using the PD-L1 IHC 22C3 pharmDx Kit, and who had not received prior systemic treatment for metastatic NSCLC. Patients with EGFR or ALK genomic tumor aberrations; autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of radiation in the thoracic region within the prior 26 weeks of initiation of study were ineligible. Randomization was stratified by ECOG performance status (0 vs. 1), histology (squamous vs. nonsquamous), geographic region (East Asia vs. non-East Asia), and PD-L1 expression (TPS ≥50% vs. TPS 1 to 49%). Patients were randomized (1:1) to receive Keytruda 200 mg intravenously every 3 weeks or investigator's choice of either of the following platinum-containing chemotherapy regimens:

  • Pemetrexed 500 mg/m2 every 3 weeks and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for a maximum of 6 cycles followed by optional pemetrexed 500 mg/m2 every 3 weeks for patients with nonsquamous histologies;
  • Paclitaxel 200 mg/m2 every 3 weeks and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for a maximum of 6 cycles followed by optional pemetrexed 500 mg/m2 every 3 weeks for patients with nonsquamous histologies.

Treatment with Keytruda continued until RECIST v1.1-defined progression of disease, unacceptable toxicity, or a maximum of 24 months. Administration of Keytruda was permitted beyond RECIST-defined disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator. Treatment with Keytruda could be reinitiated at the time of subsequent disease progression and administered for up to 12 months. Assessment of tumor status was performed every 9 weeks. The main efficacy outcome measure was OS in the subgroup of patients with TPS ≥50% NSCLC, the subgroup of patients with TPS ≥20% NSCLC, and the overall population with TPS ≥1% NSCLC. Additional efficacy outcome measures were PFS and ORR in the subgroup of patients with TPS ≥50% NSCLC, the subgroup of patients with TPS ≥20% NSCLC, and the overall population with TPS ≥1% NSCLC as assessed by a BICR review according to RECIST v1.1.

The study population characteristics were: median age of 63 years (range: 25 to 90), 45% age 65 or older; 71% male; 64% White, 30% Asian, and 2% Black. Nineteen percent were Hispanic or Latino. Sixty-nine percent had ECOG performance status of 1; 39% with squamous and 61% with nonsquamous histology; 87% with M1 disease and 13% with Stage IIIA (2%) or Stage IIIB (11%) who were not candidates for surgical resection or definitive chemoradiation per investigator assessment; and 5% with treated brain metastases at baseline. Forty-seven percent of patients had TPS ≥50% NSCLC and 53% had TPS 1 to 49% NSCLC.

The trial demonstrated a statistically significant improvement in OS for patients (PD-L1 TPS ≥50%, TPS ≥20%, TPS ≥1%) randomized to Keytruda as compared with chemotherapy. Table 30 and Figure 6 summarize the efficacy results in the subgroup of patients with TPS ≥50% and in all randomized patients with TPS ≥1%.

Table 30: Efficacy Results of All Randomized Patients (TPS ≥1% and TPS ≥50%) in KEYNOTE-042
TPS ≥1% TPS ≥50%
Endpoint Keytruda
200 mg every 3 weeks
Chemotherapy Keytruda
200 mg every 3 weeks
Chemotherapy
n=637 n=637 n=299 n=300
*
Based on the stratified Cox proportional hazard model
Based on a stratified log-rank test; compared to a p-Value boundary of 0.0291
Not evaluated for statistical significance as a result of the sequential testing procedure for the secondary endpoints
§
Not significant compared to a p-Value boundary of 0.0291
Based on observed duration of response
OS
  Number of events (%) 371 (58%) 438 (69%) 157 (53%) 199 (66%)
  Median in months (95% CI) 16.7 (13.9, 19.7) 12.1 (11.3, 13.3) 20.0 (15.4, 24.9) 12.2 (10.4, 14.2)
  Hazard ratio* (95% CI) 0.81 (0.71, 0.93) 0.69 (0.56, 0.85)
  p-Value 0.0036 0.0006
PFS
  Number of events (%) 507 (80%) 506 (79%) 221 (74%) 233 (78%)
  Median in months (95% CI) 5.4 (4.3, 6.2) 6.5 (6.3, 7.0) 7.1 (5.9, 9.0) 6.4 (6.1, 6.9)
  Hazard ratio*, (95% CI) 1.07
(0.94, 1.21)
0.81
(0.67, 0.99)
  p-Value - NS§
Objective Response Rate
  ORR (95% CI) 27% (24, 31) 27% (23, 30) 39% (33.9, 45.3) 32% (26.8, 37.6)
    Complete response rate 0.5% 0.5% 0.7% 0.3%
    Partial response rate 27% 26% 39% 32%
Duration of Response
  % with duration ≥12 months 47% 16% 42% 17%
  % with duration ≥18 months 26% 6% 25% 5%

The results of all efficacy outcome measures in the subgroup of patients with PD-L1 TPS ≥20% NSCLC were intermediate between the results of those with PD-L1 TPS ≥1% and those with PD-L1 TPS ≥50%. In a pre-specified exploratory subgroup analysis for patients with TPS 1-49% NSCLC, the median OS was 13.4 months (95% CI: 10.7, 18.2) for the pembrolizumab group and 12.1 months (95% CI: 11.0, 14.0) in the chemotherapy group, with an HR of 0.92 (95% CI: 0.77, 1.11).

Figure 6: Kaplan-Meier Curve for Overall Survival in all Randomized Patients in KEYNOTE-042 (TPS ≥1%)

KEYNOTE-024

The efficacy of Keytruda was also investigated in KEYNOTE-024 (NCT02142738), a randomized, multicenter, open-label, active-controlled trial in 305 previously untreated patients with metastatic NSCLC. The study design was similar to that of KEYNOTE-042, except that only patients whose tumors had high PD-L1 expression (TPS of 50% or greater) by an immunohistochemistry assay using the PD-L1 IHC 22C3 pharmDx Kit were eligible. Patients were randomized (1:1) to receive Keytruda 200 mg intravenously every 3 weeks or investigator's choice of any of the following platinum-containing chemotherapy regimens:

  • Pemetrexed 500 mg/m2 every 3 weeks and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for 4 to 6 cycles followed by optional pemetrexed 500 mg/m2 every 3 weeks for patients with nonsquamous histologies;
  • Pemetrexed 500 mg/m2 every 3 weeks and cisplatin 75 mg/m2 every 3 weeks on Day 1 for 4 to 6 cycles followed by optional pemetrexed 500 mg/m2 every 3 weeks for patients with nonsquamous histologies;
  • Gemcitabine 1250 mg/m2 on days 1 and 8 and cisplatin 75 mg/m2 every 3 weeks on Day 1 for 4 to 6 cycles;
  • Gemcitabine 1250 mg/m2 on Days 1 and 8 and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for 4 to 6 cycles;
  • Paclitaxel 200 mg/m2 every 3 weeks and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for 4 to 6 cycles followed by optional pemetrexed maintenance (for nonsquamous histologies).

Patients randomized to chemotherapy were offered Keytruda at the time of disease progression.

The main efficacy outcome measure was PFS as assessed by a blinded independent central radiologists' (BICR) review according to RECIST v1.1. Additional efficacy outcome measures were OS and ORR as assessed by the BICR according to RECIST v1.1.

The study population characteristics were: median age of 65 years (range: 33 to 90), 54% age 65 or older; 61% male; 82% White and 15% Asian; 65% with ECOG performance status of 1; 18% with squamous and 82% with nonsquamous histology and 9% with history of brain metastases. A total of 66 patients in the chemotherapy arm received Keytruda at the time of disease progression.

The trial demonstrated a statistically significant improvement in both PFS and OS for patients randomized to Keytruda as compared with chemotherapy. Table 31 and Figure 7 summarize the efficacy results for KEYNOTE-024.

Table 31: Efficacy Results in KEYNOTE-024
Endpoint Keytruda
200 mg every 3 weeks
Chemotherapy
n=154 n=151
NR = not reached
*
Based on the stratified Cox proportional hazard model for the interim analysis
Based on the protocol-specified final OS analysis conducted at 169 events, which occurred 14 months after the interim analysis.
p-Value is compared with 0.0118 of the allocated alpha for the interim analysis
PFS
  Number (%) of patients with event 73 (47%) 116 (77%)
  Median in months (95% CI) 10.3 (6.7, NR) 6.0 (4.2, 6.2)
  Hazard ratio* (95% CI) 0.50 (0.37, 0.68)
  p-Value (stratified log-rank) <0.001
OS
  Number (%) of patients with event 44 (29%) 64 (42%)
  Median in months (95% CI) 30.0
(18.3, NR)
14.2
(9.8, 19.0)
  Hazard ratio* (95% CI) 0.60 (0.41, 0.89)
  p-Value (stratified log-rank) 0.005
Objective Response Rate
  ORR (95% CI) 45% (37, 53) 28% (21, 36)
    Complete response rate 4% 1%
    Partial response rate 41% 27%
  p-Value (Miettinen-Nurminen) 0.001
  Median duration of response in months (range) NR
(1.9+, 14.5+)
6.3
(2.1+, 12.6+)
Figure 7: Kaplan-Meier Curve for Overall Survival in KEYNOTE-024*
*
Based on the protocol-specified final OS analysis conducted at 169 events, which occurred 14 months after the interim analysis.

Previously treated NSCLC

The efficacy of Keytruda was investigated in KEYNOTE-010 (NCT01905657), a randomized, multicenter, open-label, active-controlled trial conducted in 1033 patients with metastatic NSCLC that had progressed following platinum-containing chemotherapy, and if appropriate, targeted therapy for EGFR or ALK genomic tumor aberrations. Eligible patients had PD-L1 expression TPS of 1% or greater by an immunohistochemistry assay using the PD-L1 IHC 22C3 pharmDx Kit. Patients with autoimmune disease; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Randomization was stratified by tumor PD-L1 expression (PD-L1 expression TPS ≥50% vs. PD-L1 expression TPS=1-49%), ECOG performance scale (0 vs. 1), and geographic region (East Asia vs. non-East Asia). Patients were randomized (1:1:1) to receive Keytruda 2 mg/kg intravenously every 3 weeks, Keytruda 10 mg/kg intravenously every 3 weeks or docetaxel intravenously 75 mg/m2 every 3 weeks until unacceptable toxicity or disease progression. Patients randomized to Keytruda were permitted to continue until disease progression that was symptomatic, rapidly progressive, required urgent intervention, occurred with a decline in performance status, or confirmation of progression at 4 to 6 weeks with repeat imaging or for up to 24 months without disease progression. Assessment of tumor status was performed every 9 weeks. The main efficacy outcome measures were OS and PFS as assessed by the BICR according to RECIST v1.1 in the subgroup of patients with TPS ≥50% and the overall population with TPS ≥1%. Additional efficacy outcome measures were ORR and response duration in the subgroup of patients with TPS ≥50% and the overall population with TPS ≥1%.

The study population characteristics were: median age 63 years (range: 20 to 88), 42% age 65 or older; 61% male; 72% White and 21% Asian; 66% ECOG performance status 1; 43% with high PD-L1 tumor expression; 21% with squamous, 70% with nonsquamous, and 8% with mixed, other or unknown histology; 91% metastatic (M1) disease; 15% with history of brain metastases; and 8% and 1% with EGFR and ALK genomic aberrations, respectively. All patients had received prior therapy with a platinum-doublet regimen, 29% received two or more prior therapies for their metastatic disease.

Tables 32 and 33 and Figure 8 summarize efficacy results in the subgroup with TPS ≥50% population and in all patients, respectively.

Table 32: Efficacy Results of the Subgroup of Patients with TPS ≥50% in KEYNOTE-010
Endpoint Keytruda
2 mg/kg every 3 weeks
n=139
Keytruda
10 mg/kg every 3 weeks
n=151
Docetaxel
75 mg/m2 every 3 weeks
n=152
NR = not reached
*
Hazard ratio (Keytruda compared to docetaxel) based on the stratified Cox proportional hazard model
All responses were partial responses
OS
  Deaths (%) 58 (42%) 60 (40%) 86 (57%)
  Median in months (95% CI) 14.9 (10.4, NR) 17.3 (11.8, NR) 8.2 (6.4, 10.7)
  Hazard ratio* (95% CI) 0.54 (0.38, 0.77) 0.50 (0.36, 0.70) ---
  p-Value (stratified log-rank) <0.001 <0.001 ---
PFS
  Events (%) 89 (64%) 97 (64%) 118 (78%)
  Median in months (95% CI) 5.2 (4.0, 6.5) 5.2 (4.1, 8.1) 4.1 (3.6, 4.3)
  Hazard ratio* (95% CI) 0.58 (0.43, 0.77) 0.59 (0.45, 0.78) ---
  p-Value (stratified log-rank) <0.001 <0.001 ---
Objective Response Rate
  ORR (95% CI) 30% (23, 39) 29% (22, 37) 8% (4, 13)
  p-Value (Miettinen-Nurminen) <0.001 <0.001 ---
  Median duration of response in months (range) NR
(0.7+, 16.8+)
NR
(2.1+, 17.8+)
8.1
(2.1+, 8.8+)
Table 33: Efficacy Results of All Randomized Patients (TPS ≥1%) in KEYNOTE-010
Endpoint Keytruda
2 mg/kg every 3 weeks
n=344
Keytruda
10 mg/kg every 3 weeks
n=346
Docetaxel
75 mg/m2 every 3 weeks
n=343
NR = not reached
*
Hazard ratio (Keytruda compared to docetaxel) based on the stratified Cox proportional hazard model
All responses were partial responses
OS
  Deaths (%) 172 (50%) 156 (45%) 193 (56%)
  Median in months (95% CI) 10.4 (9.4, 11.9) 12.7 (10.0, 17.3) 8.5 (7.5, 9.8)
  Hazard ratio* (95% CI) 0.71 (0.58, 0.88) 0.61 (0.49, 0.75) ---
  p-Value (stratified log-rank) <0.001 <0.001 ---
PFS
  Events (%) 266 (77%) 255 (74%) 257 (75%)
  Median in months (95% CI) 3.9 (3.1, 4.1) 4.0 (2.6, 4.3) 4.0 (3.1, 4.2)
  Hazard ratio* (95% CI) 0.88 (0.73, 1.04) 0.79 (0.66, 0.94) ---
  p-Value (stratified log-rank) 0.068 0.005 ---
Objective Response Rate
  ORR (95% CI) 18% (14, 23) 19% (15, 23) 9% (7, 13)
  p-Value (Miettinen-Nurminen) <0.001 <0.001 ---
  Median duration of response in months (range) NR
(0.7+, 20.1+)
NR
(2.1+, 17.8+)
6.2
(1.4+, 8.8+)
Figure 8: Kaplan-Meier Curve for Overall Survival in all Randomized Patients in KEYNOTE-010 (TPS ≥1%)

Head and Neck Squamous Cell Cancer

The efficacy of Keytruda was investigated in KEYNOTE-012 (NCT01848834), a multicenter, non-randomized, open-label, multi-cohort study that enrolled 174 patients with recurrent or metastatic HNSCC who had disease progression on or after platinum-containing chemotherapy administered for recurrent or metastatic HNSCC or following platinum-containing chemotherapy administered as part of induction, concurrent, or adjuvant therapy. Patients with active autoimmune disease, a medical condition that required immunosuppression, evidence of interstitial lung disease, or ECOG PS ≥2 were ineligible.

Patients received Keytruda 10 mg/kg every 2 weeks (n=53) or 200 mg every 3 weeks (n=121) until unacceptable toxicity or disease progression that was symptomatic, was rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at least 4 weeks later with repeat imaging. Patients without disease progression were treated for up to 24 months. Treatment with pembrolizumab could be reinitiated for subsequent disease progression and administered for up to 1 additional year. Assessment of tumor status was performed every 8 weeks. The major efficacy outcome measures were ORR according to RECIST v1.1, as assessed by blinded independent central review, and duration of response.

The study population characteristics were median age 60 years (32% age 65 or older); 82% male; 75% White, 16% Asian, and 6% Black; 87% had M1 disease; 33% had HPV positive tumors; 63% had prior cetuximab; 29% had an ECOG PS of 0 and 71% had an ECOG PS of 1; and the median number of prior lines of therapy administered for the treatment of HNSCC was 2.

The ORR was 16% (95% CI: 11, 22) with a complete response rate of 5%. The median follow-up time was 8.9 months. Among the 28 responding patients, the median duration of response had not been reached (range: 2.4+ to 27.7+ months), with 23 patients having responses of 6 months or longer. The ORR and duration of response were similar irrespective of dosage regimen (10 mg/kg every 2 weeks or 200 mg every 3 weeks) or HPV status.

Classical Hodgkin Lymphoma

The efficacy of Keytruda was investigated in KEYNOTE-087 (NCT02453594), a multicenter, non-randomized, open-label trial in 210 patients with relapsed or refractory cHL. Patients with active, non-infectious pneumonitis, an allogeneic HSCT within the past 5 years (or > 5 years but with symptoms of GVHD), active autoimmune disease, a medical condition that required immunosuppression, or an active infection requiring systemic therapy were ineligible for the trial. Patients received Keytruda 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression, or for up to 24 months in patients who did not progress. Disease assessment was performed every 12 weeks. The major efficacy outcome measures (ORR, CRR, and duration of response) were assessed by blinded independent central review according to the 2007 revised International Working Group (IWG) criteria.

The study population characteristics were: median age of 35 years (range: 18 to 76), 9% age 65 or older; 54% male; 88% White; 49% had an ECOG performance status (PS) of 0 and 51% had an ECOG PS of 1. The median number of prior lines of therapy administered for the treatment of cHL was 4 (range: 1 to 12). Fifty-eight percent were refractory to the last prior therapy, including 35% with primary refractory disease and 14% whose disease was chemo-refractory to all prior regimens. Sixty-one percent of patients had undergone prior auto-HSCT, 83% had received prior brentuximab vedotin and 36% of patients had prior radiation therapy.

Efficacy results for KEYNOTE-087 are summarized in Table 34.

Table 34: Efficacy Results in KEYNOTE-087
Endpoint Keytruda
200 mg every 3 weeks
n=210*
*
Median follow-up time of 9.4 months
Based on patients (n=145) with a response by independent review
Objective Response Rate
  ORR (95% CI) 69% (62, 75)
    Complete response 22%
    Partial response 47%
Response Duration
  Median in months (range) 11.1 (0.0+, 11.1)

Primary Mediastinal Large B-Cell Lymphoma

The efficacy of Keytruda was investigated in KEYNOTE-170 (NCT02576990), a multicenter, open-label, single-arm trial in 53 patients with relapsed or refractory PMBCL. Patients were not eligible if they had active non-infectious pneumonitis, allogeneic HSCT within the past 5 years (or >5 years but with symptoms of GVHD), active autoimmune disease, a medical condition that required immunosuppression, or an active infection requiring systemic therapy. The patients were treated with Keytruda 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression, or for up to 24 months for patients who did not progress. Disease assessments were performed every 12 weeks and assessed by blinded independent central review according to the 2007 revised IWG criteria. The efficacy outcome measures were overall response rate (ORR) and duration of response.

The study population characteristics were: median age 33 years (range: 20 to 61 years), 43% male; 92% White; 43% had an ECOG performance status (PS) of 0 and 57% had an ECOG PS of 1. The median number of prior lines of therapy administered for the treatment of PMBCL was 3 (range 2 to 8). Thirty-six percent had primary refractory disease, 49% had relapsed disease refractory to the last prior therapy, and 15% had untreated relapse. Twenty-six percent of patients had undergone prior autologous HSCT, and 32% of patients had prior radiation therapy. All patients had received rituximab as part of a prior line of therapy.

For the 24 responders, the median time to first objective response (complete or partial response) was 2.8 months (range 2.1 to 8.5 months). Efficacy results for KEYNOTE-170 are summarized in Table 35.

Table 35: Efficacy Results in KEYNOTE-170
Endpoint Keytruda
200 mg every 3 weeks
n=53*
NR = not reached
*
Median follow-up time of 9.7 months
Based on patients (n=24) with a response by independent review
Objective Response Rate
  ORR (95% CI) 45% (32, 60)
    Complete response 11%
    Partial response 34%
Response Duration
  Median in months (range) NR (1.1+, 19.2+)

Urothelial Carcinoma

Cisplatin Ineligible Patients with Urothelial Carcinoma

The efficacy of Keytruda was investigated in KEYNOTE-052 (NCT02335424), a multicenter, open-label, single-arm trial in 370 patients with locally advanced or metastatic urothelial carcinoma who were not eligible for cisplatin-containing chemotherapy. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression. Patients received Keytruda 200 mg every 3 weeks until unacceptable toxicity or disease progression. Patients with initial radiographic disease progression could receive additional doses of treatment during confirmation of progression unless disease progression was symptomatic, was rapidly progressive, required urgent intervention, or occurred with a decline in performance status. Patients without disease progression could be treated for up to 24 months. Tumor response assessments were performed at 9 weeks after the first dose, then every 6 weeks for the first year, and then every 12 weeks thereafter. The major efficacy outcome measures were ORR according to RECIST v1.1, as assessed by independent radiology review, and duration of response.

The study population characteristics were: median age was 74 years, 77% were male, and 89% were White. Eighty-seven percent had M1 disease, and 13% had M0 disease. Eighty-one percent had a primary tumor in the lower tract, and 19% of patients had a primary tumor in the upper tract. Eighty-five percent of patients had visceral metastases, including 21% with liver metastases. Reasons for cisplatin ineligibility included: 50% with baseline creatinine clearance of <60 mL/min, 32% with ECOG performance status of 2, 9% with ECOG 2 and baseline creatinine clearance of <60 mL/min, and 9% with other reasons (Class III heart failure, Grade 2 or greater peripheral neuropathy, and Grade 2 or greater hearing loss). Ninety percent of patients were treatment naïve, and 10% received prior adjuvant or neoadjuvant platinum-based chemotherapy.

Among the 370 patients, 30% (n = 110) had tumors that expressed PD-L1 with a combined positive score (CPS) of ≥ 10. PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx Kit. The study population characteristics of these 110 patients were: median age 73 years, 68% male, and 87% White. Eighty-two percent had M1 disease, and 18% had M0 disease. Eighty-one percent had a primary tumor in the lower tract, and 18% of patients had a primary tumor in the upper tract. Seventy-six percent of patients had visceral metastases, including 11% with liver metastases. Reasons for cisplatin ineligibility included: 45% with baseline creatinine clearance of <60 mL/min, 37% with ECOG performance status of 2, 10% with ECOG 2 and baseline creatinine clearance of <60 mL/min, and 8% with other reasons (Class III heart failure, Grade 2 or greater peripheral neuropathy, and Grade 2 or greater hearing loss). Ninety percent of patients were treatment naïve, and 10% received prior adjuvant or neoadjuvant platinum-based chemotherapy.

The median follow-up time for 370 patients treated with Keytruda was 7.8 months (range 0.1 to 20 months). Efficacy results are summarized in Table 36.

Table 36: Efficacy Results in KEYNOTE-052
Endpoint Keytruda
200 mg every 3 weeks
All Subjects
n=370
PD-L1 CPS <10
n=260*
PD-L1 CPS ≥10
n=110
+ Denotes ongoing
NR = not reached
*
Includes 9 subjects with unknown PD-L1 status
Objective Response Rate
  ORR (95% CI) 29% (24, 34) 21% (16, 26) 47% (38, 57)
    Complete response rate 7% 3% 15%
    Partial response rate 22% 18% 32%
Duration of Response
  Median in months (range) NR
(1.4+, 17.8+)
NR
(1.4+, 16.3+)
NR
(1.4+, 17.8+)

Previously Untreated Urothelial Carcinoma

KEYNOTE-361 (NCT02853305) is an ongoing, multicenter, randomized study in previously untreated patients with metastatic urothelial carcinoma who are eligible for platinum-containing chemotherapy. The study compares Keytruda with or without platinum-based chemotherapy (i.e., cisplatin or carboplatin with gemcitabine) to platinum-based chemotherapy alone. The trial also enrolled a third arm of monotherapy with Keytruda to compare to platinum-based chemotherapy alone. The independent Data Monitoring Committee (iDMC) for the study conducted a review of early data and found that in patients classified as having low PD-L1 expression (CPS <10), those treated with Keytruda monotherapy had decreased survival compared to those who received platinum-based chemotherapy. The iDMC recommended to stop further accrual of patients with low PD-L1 expression in the monotherapy arm, however, no other changes were recommended, including any change of therapy for patients who had already been randomized to and were receiving treatment in the monotherapy arm.

Previously Treated Urothelial Carcinoma

The efficacy of Keytruda was investigated in KEYNOTE-045 (NCT02256436), a multicenter, randomized (1:1), active-controlled trial in 542 patients with locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression.

Patients were randomized to receive either Keytruda 200 mg every 3 weeks (n=270) or investigator's choice of any of the following chemotherapy regimens all given intravenously every 3 weeks (n=272): paclitaxel 175 mg/m2 (n=90), docetaxel 75 mg/m2 (n=92), or vinflunine 320 mg/m2 (n=90). Treatment continued until unacceptable toxicity or disease progression. Patients with initial radiographic disease progression could receive additional doses of treatment during confirmation of progression unless disease progression was symptomatic, was rapidly progressive, required urgent intervention, or occurred with a decline in performance status. Patients without disease progression could be treated for up to 24 months. Assessment of tumor status was performed at 9 weeks after randomization, then every 6 weeks through the first year, followed by every 12 weeks thereafter. The major efficacy outcomes were OS and PFS as assessed by BICR per RECIST v1.1. Additional efficacy outcome measures were ORR as assessed by BICR per RECIST v1.1.

The study population characteristics were: median age 66 years (range: 26 to 88), 58% age 65 or older; 74% male; 72% White and 23% Asian; 42% with ECOG status of 0 and 56% with ECOG performance status of 1; and 96% M1 disease and 4% M0 disease. Eighty-seven percent of patients had visceral metastases, including 34% with liver metastases. Eighty-six percent had a primary tumor in the lower tract and 14% had a primary tumor in the upper tract. Fifteen percent of patients had disease progression following prior platinum-containing neoadjuvant or adjuvant chemotherapy. Twenty-one percent had received 2 or more prior systemic regimens in the metastatic setting. Seventy-six percent of patients received prior cisplatin, 23% had prior carboplatin, and 1% were treated with other platinum-based regimens.

The study demonstrated statistically significant improvements in OS and ORR for patients randomized to Keytruda as compared to chemotherapy. There was no statistically significant difference between Keytruda and chemotherapy with respect to PFS. The median follow-up time for this trial was 9.0 months (range: 0.2 to 20.8 months). Table 37 and Figure 9 summarize the efficacy results for KEYNOTE-045.

Table 37: Efficacy Results in KEYNOTE-045
Keytruda
200 mg every 3 weeks
Chemotherapy
n=270 n=272
+ Denotes ongoing
NR = not reached
*
Hazard ratio (Keytruda compared to chemotherapy) based on the stratified Cox proportional hazard model
OS
  Deaths (%) 155 (57%) 179 (66%)
  Median in months (95% CI) 10.3 (8.0, 11.8) 7.4 (6.1, 8.3)
  Hazard ratio* (95% CI) 0.73 (0.59, 0.91)
  p-Value (stratified log-rank) 0.004
PFS by BICR
  Events (%) 218 (81%) 219 (81%)
  Median in months (95% CI) 2.1 (2.0, 2.2) 3.3 (2.3, 3.5)
  Hazard ratio* (95% CI) 0.98 (0.81, 1.19)
  p-Value (stratified log-rank) 0.833
Objective Response Rate
  ORR (95% CI) 21% (16, 27) 11% (8, 16)
    Complete response rate 7% 3%
    Partial response rate 14% 8%
    p-Value (Miettinen-Nurminen) 0.002
    Median duration of response in months (range) NR
(1.6+, 15.6+)
4.3
(1.4+, 15.4+)
Figure 9: Kaplan-Meier Curve for Overall Survival in KEYNOTE-045

Microsatellite Instability-High Cancer

The efficacy of Keytruda was investigated in patients with MSI-H or mismatch repair deficient (dMMR), solid tumors enrolled in one of five uncontrolled, open-label, multi-cohort, multi-center, single-arm trials. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible across the five trials. Patients received either Keytruda 200 mg every 3 weeks or Keytruda 10 mg/kg every 2 weeks. Treatment continued until unacceptable toxicity or disease progression that was either symptomatic, rapidly progressive, required urgent intervention, or occurred with a decline in performance status. A maximum of 24 months of treatment with Keytruda was administered. For the purpose of assessment of anti-tumor activity across these 5 trials, the major efficacy outcome measures were ORR as assessed by blinded independent central radiologists' (BICR) review according to RECIST v1.1, and duration of response.

Table 38: MSI-H Trials
Study Design and Patient Population Number of Patients MSI-H/dMMR Testing Dosage Prior Therapy
CRC = colorectal cancer
PCR = polymerase chain reaction
IHC = immunohistochemistry
KEYNOTE-016
NCT01876511
  • prospective, investigator-initiated
  • 6 sites
  • patients with CRC and other tumors
28 CRC
30 non-CRC
local PCR or IHC 10 mg/kg every 2 weeks
  • CRC: ≥ 2 prior regimens
  • Non-CRC: ≥1 prior regimen
KEYNOTE-164
NCT02460198
  • prospective international multi-center
  • CRC
61 local PCR or IHC 200 mg every 3 weeks Prior fluoropyrimidine, oxaliplatin, and irinotecan +/- anti-VEGF/EGFR mAb
KEYNOTE-012
NCT01848834
  • retrospectively identified patients with PD-L1-positive gastric, bladder, or triple-negative breast cancer
6 central PCR 10 mg/kg every 2 weeks ≥1 prior regimen
KEYNOTE-028
NCT02054806
  • retrospectively identified patients with PD-L1-positive esophageal, biliary, breast, endometrial, or CRC
5 central PCR 10 mg/kg every 2 weeks ≥1 prior regimen
KEYNOTE-158
NCT02628067
  • prospective international multi-center enrollment of patients with MSI-H/dMMR non-CRC
  • retrospectively identified patients who were enrolled in specific rare tumor non-CRC cohorts
19 local PCR or IHC (central PCR for patients in rare tumor non-CRC cohorts) 200 mg every 3 weeks ≥1 prior regimen
Total 149

A total of 149 patients with MSI-H or dMMR cancers were identified across the five trials. Among these 149 patients, the baseline characteristics were: median age 55 years (36% age 65 or older); 56% male; 77% White, 19% Asian, 2% Black; and ECOG PS 0 (36%) or 1 (64%). Ninety-eight percent of patients had metastatic disease and 2% had locally advanced, unresectable disease. The median number of prior therapies for metastatic or unresectable disease was two. Eighty-four percent of patients with metastatic CRC and 53% of patients with other solid tumors received two or more prior lines of therapy.

The identification of MSI-H or dMMR tumor status for the majority of patients (135/149) was prospectively determined using local laboratory-developed, polymerase chain reaction (PCR) tests for MSI-H status or immunohistochemistry (IHC) tests for dMMR. Fourteen of the 149 patients were retrospectively identified as MSI-H by testing tumor samples from a total of 415 patients using a central laboratory developed PCR test. Forty-seven patients had dMMR cancer identified by IHC, 60 had MSI-H identified by PCR, and 42 were identified using both tests.

Efficacy results are summarized in Tables 39 and 40.

Table 39: Efficacy Results for Patients with MSI-H/dMMR Cancer
Endpoint Keytruda
n=149
NR = not reached
Objective Response Rate
  ORR (95% CI) 39.6% (31.7, 47.9)
    Complete response rate 7.4%
    Partial response rate 32.2%
Response duration
  Median in months (range) NR (1.6+, 22.7+)
  % with duration ≥6 months 78%
Table 40: Response by Tumor Type
Objective response rate DOR range
N n (%) 95% CI (months)
CR = complete response
PR = partial response
SD = stable disease
PD = progressive disease
NE = not evaluable
CRC 90 32 (36%) (26%, 46%) (1.6+, 22.7+)
Non-CRC 59 27 (46%) (33%, 59%) (1.9+, 22.1+)
  Endometrial cancer 14 5 (36%) (13%, 65%) (4.2+, 17.3+)
  Biliary cancer 11 3 (27%) (6%, 61%) (11.6+, 19.6+)
  Gastric or GE junction cancer 9 5 (56%) (21%, 86%) (5.8+, 22.1+)
  Pancreatic cancer 6 5 (83%) (36%, 100%) (2.6+, 9.2+)
  Small intestinal cancer 8 3 (38%) (9%, 76%) (1.9+, 9.1+)
  Breast cancer 2 PR, PR (7.6, 15.9)
  Prostate cancer 2 PR, SD 9.8+
  Bladder cancer 1 NE
  Esophageal cancer 1 PR 18.2+
  Sarcoma 1 PD
  Thyroid cancer 1 NE
  Retroperitoneal adenocarcinoma 1 PR 7.5+
  Small cell lung cancer 1 CR 8.9+
  Renal cell cancer 1 PD

Gastric Cancer

The efficacy of Keytruda was investigated in KEYNOTE-059 (NCT02335411), a multicenter, non-randomized, open-label multi-cohort trial that enrolled 259 patients with gastric or gastroesophageal junction (GEJ) adenocarcinoma who progressed on at least 2 prior systemic treatments for advanced disease. Previous treatment must have included a fluoropyrimidine and platinum doublet. HER2/neu positive patients must have previously received treatment with approved HER2/neu-targeted therapy. Patients with active autoimmune disease or a medical condition that required immunosuppression or with clinical evidence of ascites by physical exam were ineligible. Patients received Keytruda 200 mg every 3 weeks until unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at least 4 weeks later with repeat imaging. Patients without disease progression were treated for up to 24 months. Assessment of tumor status was performed every 6 to 9 weeks. The major efficacy outcome measures were ORR according to RECIST v1.1, as assessed by blinded independent central review, and duration of response.

Among the 259 patients, 55% (n = 143) had tumors that expressed PD-L1 with a combined positive score (CPS) of ≥ 1 and microsatellite stable (MSS) tumor status or undetermined MSI or MMR status. PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx Kit. The baseline characteristics of these 143 patients were: median age 64 years (47% age 65 or older); 77% male; 82% White, 11% Asian; and ECOG PS of 0 (43%) and 1 (57%). Eighty-five percent had M1 disease and 7% had M0 disease. Fifty-one percent had two and 49% had three or more prior lines of therapy in the recurrent or metastatic setting.

For the 143 patients, the ORR was 13.3% (95% CI: 8.2, 20.0); 1.4% had a complete response and 11.9% had a partial response. Among the 19 responding patients, the duration of response ranged from 2.8+ to 19.4+ months, with 11 patients (58%) having responses of 6 months or longer and 5 patients (26%) having responses of 12 months or longer.

Among the 259 patients enrolled in KEYNOTE-059, 7 (3%) had tumors that were determined to be MSI-H. An objective response was observed in 4 patients, including 1 complete response. The duration of response ranged from 5.3+ to 14.1+ months.

Cervical Cancer

The efficacy of Keytruda was investigated in 98 patients with recurrent or metastatic cervical cancer enrolled in a single cohort (Cohort E) in KEYNOTE-158 (NCT02628067), a multicenter, non-randomized, open-label, multi-cohort trial. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression. Patients received Keytruda 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression. Patients with initial radiographic disease progression could receive additional doses of treatment during confirmation of progression unless disease progression was symptomatic, was rapidly progressive, required urgent intervention, or occurred with a decline in performance status. Patients without disease progression could be treated for up to 24 months. Assessment of tumor status was performed every 9 weeks for the first 12 months, and every 12 weeks thereafter. The major efficacy outcome measures were ORR according to RECIST v1.1, as assessed by blinded independent central review, and duration of response.

Among the 98 patients in Cohort E, 77 (79%) had tumors that expressed PD-L1 with a CPS ≥ 1 and received at least one line of chemotherapy in the metastatic setting. PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx Kit. The baseline characteristics of these 77 patients were: median age was 45 years (range: 27 to 75 years); 81% were White, 14% Asian, 3% Black; ECOG PS was 0 (32%) or 1 (68%); 92% had squamous cell carcinoma, 6% adenocarcinoma, and 1% adenosquamous histology; 95% had M1 disease and 5% had recurrent disease; 35% had one and 65% had two or more prior lines of therapy in the recurrent or metastatic setting.

No responses were observed in patients whose tumors did not have PD-L1 expression (CPS <1). Efficacy results are summarized in Table 41 for patients with PD-L1 expression (CPS ≥1).

Table 41: Efficacy Results in Patients with Recurrent or Metastatic Cervical Cancer (CPS ≥1) in KEYNOTE-158
Endpoint Keytruda
200 mg every 3 weeks
n=77*
+ Denotes ongoing
NR = not reached
*
Median follow-up time of 11.7 months (range 0.6 to 22.7 months)
Based on patients (n=11) with a response by independent review
Objective Response Rate
  ORR (95% CI) 14.3% (7.4, 24.1)
    Complete response rate 2.6%
    Partial response rate 11.7%
Response duration
  Median in months (range) NR (4.1, 18.6+)
  % with duration ≥6 months 91%

Hepatocellular Carcinoma

The efficacy of Keytruda was investigated in KEYNOTE-224 (NCT02702414), a single-arm, multicenter trial in 104 patients with HCC who had disease progression on or after sorafenib or were intolerant to sorafenib; had measurable disease; and Child-Pugh class A liver impairment. Patients with active autoimmune disease, greater than one etiology of hepatitis, a medical condition that required immunosuppression, or clinical evidence of ascites by physical exam were ineligible for the trial. Patients received Keytruda 200 mg intravenously every 3 weeks until unacceptable toxicity, investigator-assessed confirmed disease progression (based on repeat scan at least 4 weeks from the initial scan showing progression), or completion of 24 months of Keytruda. Assessment of tumor status was performed every 9 weeks. The major efficacy outcome measures were ORR and duration of response according to RECIST v1.1, as assessed by blinded independent central review committee (BICR).

The study population characteristics were: median age 68 years (67% age 65 or older); 83% male; 81% White; 14% Asian; ECOG PS of 0 (61%) or 1 (39%). Child-Pugh class and score were A5 for 72%, A6 for 22%, B7 for 5%, and B8 for 1% of patients. Twenty-one percent of the patients were HBV seropositive and 25% HCV seropositive. There were 9 patients (9%) who were seropositive for both HBV and HCV. For these 9 patients, all of the HBV cases and three of the HCV cases were inactive. Sixty-four percent (64%) of patients had extrahepatic disease, 17% had vascular invasion, and 9% had both. Thirty-eight percent (38%) of patients had alpha-fetoprotein (AFP) levels ≥400 mcg/L. All patients received prior sorafenib; of whom 20% were unable to tolerate sorafenib. No patient received more than one prior systemic therapy (sorafenib).

Efficacy results are summarized in Table 42.

Table 42: Efficacy Results in KEYNOTE-224
Endpoint Keytruda
200 mg every 3 weeks
n=104
*
Based on patients (n=18) with a confirmed response by independent review
BICR-Assessed Objective Response Rate (RECIST v1.1)
  ORR (95% CI)* 17% (11, 26)
    Complete response rate 1%
    Partial response rate 16%
BICR-Assessed Response Duration
  % with duration ≥6 months 89%
  % with duration ≥12 months 56%

Merkel Cell Carcinoma

The efficacy of Keytruda was investigated in KEYNOTE-017 (NCT02267603), a multicenter, non-randomized, open-label trial that enrolled 50 patients with recurrent locally advanced or metastatic MCC who had not received prior systemic therapy for their advanced disease. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible.

Patients received Keytruda 2 mg/kg every 3 weeks until unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at least 4 weeks later with repeat imaging. Patients without disease progression were treated for up to 24 months. Assessment of tumor status was performed at 13 weeks followed by every 9 weeks for the first year and every 12 weeks thereafter. The major efficacy outcome measures were ORR and duration of response as assessed by BICR per RECIST v1.1.

The study population characteristics were: median age was 71 years (range: 46 to 91 years), with 80% age 65 or older; 68% male; 90% White; and ECOG performance score was 0 (48%) and 1 (52%). Fourteen percent had stage IIIB disease and 86% had stage IV. Eighty-four percent of patients had prior surgery and 70% had prior radiation therapy.

Efficacy results are summarized in Table 43.

Table 43: Efficacy Results in KEYNOTE-017
Endpoint Keytruda
2 mg/kg every 3 weeks
n=50
*
The median duration of response was not reached
Objective Response Rate
  ORR (95% CI) 56% (41, 70)
    Complete response (CR) rate (95% CI) 24% (13, 38)
    Partial response (PR) rate (95% CI) 32% (20, 47)
Duration of Response
  Range in months* 5.9-34.5+
  Patients with duration ≥6 months, n (%) 27 (96%)
  Patients with duration ≥12 months, n (%) 15 (54%)

Renal Cell Carcinoma

The efficacy of Keytruda in combination with axitinib was investigated in KEYNOTE-426 (NCT02853331), a randomized, multicenter, open-label trial conducted in 861 patients who had not received systemic therapy for advanced RCC. Patients were enrolled regardless of PD-L1 tumor expression status. Patients with active autoimmune disease requiring systemic immunosuppression within the last 2 years were ineligible. Randomization was stratified by International Metastatic RCC Database Consortium (IMDC) risk categories (favorable versus intermediate versus poor) and geographic region (North America versus Western Europe versus "Rest of the World").

Patients were randomized (1:1) to one of the following treatment arms:

  • Keytruda 200 mg intravenously every 3 weeks up to 24 months in combination with axitinib 5 mg orally, twice daily. Patients who tolerated axitinib 5 mg twice daily for 2 consecutive cycles (6 weeks) could increase to 7 mg and then subsequently to 10 mg twice daily. Axitinib could be interrupted or reduced to 3 mg twice daily and subsequently to 2 mg twice daily to manage toxicity.
  • Sunitinib 50 mg orally, once daily for 4 weeks and then off treatment for 2 weeks.

Treatment with Keytruda and axitinib continued until RECIST v1.1-defined progression of disease or unacceptable toxicity. Administration of Keytruda and axitinib was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed at baseline, after randomization at Week 12, then every 6 weeks thereafter until Week 54, and then every 12 weeks thereafter.

The study population characteristics were: median age of 62 years (range: 26 to 90); 38% age 65 or older; 73% male; 79% White and 16% Asian; 19% and 80% of patients had a baseline KPS of 70 to 80 and 90 to 100, respectively; and patient distribution by IMDC risk categories was 31% favorable, 56% intermediate and 13% poor.

The main efficacy outcome measures were OS and PFS as assessed by BICR according to modified RECIST v1.1. Additional efficacy outcome measures included ORR, as assessed by BICR. A statistically significant improvement in OS was demonstrated at the pre-specified interim analysis in patients randomized to Keytruda in combination with axitinib compared with sunitinib. The trial also demonstrated statistically significant improvements in PFS and ORR. Table 44 and Figure 10 summarize the efficacy results for KEYNOTE-426. The median follow-up time was 12.8 months (range 0.1 to 22.0 months).Consistent results were observed across pre-specified subgroups, IMDC risk categories and PD-L1 tumor expression status.

Table 44: Efficacy Results in KEYNOTE-426
Endpoint Keytruda with axitinib
n=432
Sunitinib
n=429
NR = not reached
*
Based on the stratified Cox proportional hazard model
Based on stratified log-rank test
p-Value (one-sided) is compared with the allocated alpha of 0.0001 for this interim analysis (with 39% of the planned number of events for final analysis).
§
p-Value (one-sided) is compared with the allocated alpha of 0.0013 for this interim analysis (with 81% of the planned number of events for final analysis).
Based on Miettinen and Nurminen method stratified by IMDC risk group and geographic region
OS
  Number of patients with event (%) 59 (14%) 97 (23%)
  Median in months (95% CI) NR (NR, NR) NR (NR, NR)
  Hazard ratio* (95% CI) 0.53 (0.38, 0.74)
  p-Value <0.0001
  12-month OS rate 90% (86, 92) 78% (74, 82)
PFS
  Number of patients with event (%) 183 (42%) 212 (49%)
  Median in months (95% CI) 15.1 (12.6, 17.7) 11.1 (8.7, 12.5)
  Hazard ratio* (95% CI) 0.69 (0.57, 0.84)
  p-Value 0.0001§
ORR
  Overall confirmed response rate (95% CI) 59% (54, 64) 36% (31, 40)
    Complete response 6% 2%
    Partial response 53% 34%
  p-Value <0.0001
Figure 10: Kaplan-Meier Curve for Overall Survival in KEYNOTE-426

How Supplied/Storage and Handling

Keytruda for injection (white to off-white lyophilized powder):

Carton containing one 50 mg single-dose vial (NDC 0006-3029-02)

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

Keytruda injection (clear to slightly opalescent, colorless to slightly yellow solution):

Carton containing one 100 mg/4 mL (25 mg/mL), single-dose vial (NDC 0006-3026-02)

Carton containing two 100 mg/4 mL (25 mg/mL), single-dose vials (NDC 0006-3026-04)

Store vials under refrigeration at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not freeze. Do not shake.

Patient Counseling Information

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

Immune-Mediated Adverse Reactions

  • Inform patients of the risk of immune-mediated adverse reactions that may be severe or fatal, may occur after discontinuation of treatment, and may require corticosteroid treatment and interruption or discontinuation of Keytruda. These reactions may include:
    • Pneumonitis: Advise patients to contact their healthcare provider immediately for 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, or easy bruising or bleeding [see Warnings and Precautions (5.3)].
    • Hypophysitis: Advise patients to contact their healthcare provider immediately for persistent or unusual headache, extreme weakness, dizziness or fainting, or vision changes [see Warnings and Precautions (5.4)].
    • Hyperthyroidism and Hypothyroidism: Advise patients to contact their healthcare provider immediately for signs or symptoms of hyperthyroidism and hypothyroidism [see Warnings and Precautions (5.4)].
    • Type 1 Diabetes Mellitus: Advise patients to contact their healthcare provider immediately for signs or symptoms of type 1 diabetes [see Warnings and Precautions (5.4)].
    • Nephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis [see Warnings and Precautions (5.5)].
    • Severe skin reactions: Advise patients to contact their healthcare provider immediately for any signs or symptoms of severe skin reactions, SJS or TEN [see Warnings and Precautions (5.6)].
    • Other immune-mediated adverse reactions:
      • Advise patients that immune-mediated adverse reactions can occur and may involve any organ system, and to contact their healthcare provider immediately for any new signs or symptoms [see Warnings and Precautions (5.7)].
      • Advise patients of the risk of solid organ transplant rejection and to contact their healthcare provider immediately for signs or symptoms of organ transplant rejection [see Warnings and Precautions (5.7)].

Infusion-Related Reactions

  • Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.8)].

Complications of Allogeneic HSCT

Embryo-Fetal Toxicity

Lactation

Laboratory Tests

Manufactured by: Merck Sharp & Dohme Corp., a subsidiary of
MERCK & CO., INC., Whitehouse Station, NJ 08889, USA
U.S. License No. 0002

For Keytruda for injection, at:
MSD International GmbH,
County Cork, Ireland

For Keytruda injection, at:
MSD Ireland (Carlow)
County Carlow, Ireland

For patent information: www.merck.com/product/patent/home.html

The trademarks depicted herein are owned by their respective companies.

uspi-mk3475-iv-1904r026

MEDICATION GUIDE
Keytruda® (key-true-duh)
(pembrolizumab)
for injection
Keytruda® (key-true-duh)
(pembrolizumab)
injection
This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: April 2019
What is the most important information I should know about Keytruda?
Keytruda is a medicine that may treat certain cancers by working with your immune system. Keytruda can cause your immune system to attack normal organs and tissues in any area of your body and can affect the way they work. These problems can sometimes become severe or life-threatening and can lead to death. These problems may happen anytime during treatment or even after your treatment has ended.
Call or see your doctor right away if you develop any symptoms of the following problems or these symptoms get worse:
Lung problems (pneumonitis). Symptoms of pneumonitis may include:
  • shortness of breath
  • chest pain
  • new or worse cough
Intestinal problems (colitis) that can lead to tears or holes in your intestine. Signs and symptoms of colitis may include:
  • diarrhea or more bowel movements than usual
  • stools that are black, tarry, sticky, or have blood or mucus
  • severe stomach-area (abdomen) pain or tenderness
Liver problems, including hepatitis. Signs and symptoms of liver problems may include:
  • yellowing of your skin or the whites of your eyes
  • nausea or vomiting
  • pain on the right side of your stomach area (abdomen)
  • dark urine
  • bleeding or bruising more easily than normal
Hormone gland problems (especially the thyroid, pituitary, adrenal glands, and pancreas). Signs and symptoms that your hormone glands are not working properly may include:
  • rapid heart beat
  • weight loss or weight gain
  • increased sweating
  • feeling more hungry or thirsty
  • urinating more often than usual
  • hair loss
  • feeling cold
  • constipation
  • your voice gets deeper
  • muscle aches
  • dizziness or fainting
  • headaches that will not go away or unusual headache
Kidney problems, including nephritis and kidney failure. Signs of kidney problems may include:
  • change in the amount or color of your urine
Skin problems. Signs of skin problems may include:
  • rash
  • itching
  • blisters, peeling or skin sores
  • painful sores or ulcers in your mouth or in your nose, throat, or genital area
Problems in other organs. Signs and symptoms of these problems may include:
  • changes in eyesight
  • severe or persistent muscle or joint pains
  • severe muscle weakness
  • low red blood cells (anemia)
  • swollen lymph nodes, rash or tender lumps on skin, cough, shortness of breath, vision changes, or eye pain (sarcoidosis)
  • confusion, fever, muscle weakness, balance problems, nausea, vomiting, stiff neck, memory problems, or seizures (encephalitis)
  • shortness of breath, irregular heartbeat, feeling tired, or chest pain (myocarditis)
Infusion (IV) reactions that can sometimes be severe and life-threatening. Signs and symptoms of infusion reactions may include:
  • chills or shaking
  • shortness of breath or wheezing
  • itching or rash
  • flushing
  • dizziness
  • fever
  • feeling like passing out
Rejection of a transplanted organ. People who have had an organ transplant may have an increased risk of organ transplant rejection. Your doctor should tell you what signs and symptoms you should report and monitor you, depending on the type of organ transplant that you have had.
Complications, including graft-versus-host-disease (GVHD), in people who have received a bone marrow (stem cell) transplant that uses donor stem cells (allogeneic). These complications can be severe and can lead to death. These complications may happen if you underwent transplantation either before or after being treated with Keytruda. Your doctor will monitor you for the following signs and symptoms: skin rash, liver inflammation, stomach-area (abdominal) pain, and diarrhea.
Getting medical treatment right away may help keep these problems from becoming more serious.
Your doctor will check you for these problems during treatment with Keytruda. Your doctor may treat you with corticosteroid or hormone replacement medicines. Your doctor may also need to delay or completely stop treatment with Keytruda, if you have severe side effects.
What is Keytruda?
Keytruda is a prescription medicine used to treat:
  • a kind of skin cancer called melanoma. Keytruda may be used:
    • when your melanoma has spread or cannot be removed by surgery (advanced melanoma), or
    • to help prevent melanoma from coming back after it and lymph nodes that contain cancer have been removed by surgery.
  • a kind of lung cancer called non-small cell lung cancer (NSCLC).
    • Keytruda may be used with the chemotherapy medicines pemetrexed and a platinum as your first treatment when your lung cancer:
      • has spread (advanced NSCLC), and
      • is a type called "nonsquamous", and
      • your tumor does not have an abnormal "EGFR" or "ALK" gene.
    • Keytruda may be used with the chemotherapy medicines carboplatin and either paclitaxel or paclitaxel protein-bound as your first treatment when your lung cancer:
      • has spread (advanced NSCLC), and
      • is a type called "squamous".
    • Keytruda may be used alone as your first treatment when your lung cancer:
      • has not spread outside your chest (stage III) and you cannot have surgery or chemotherapy with radiation or
      • your NSCLC has spread to other areas of your body (advanced NSCLC), and
      • your tumor tests positive for "PD-L1", and
      • does not have an abnormal "EGFR" or "ALK" gene.
    • Keytruda may also be used alone when:
      • you have received chemotherapy that contains platinum to treat your advanced NSCLC, and it did not work or it is no longer working, and
      • your tumor tests positive for "PD-L1", and
      • if your tumor has an abnormal "EGFR" or "ALK" gene, you have also received an EGFR or ALK inhibitor medicine and it did not work or is no longer working.
  • a kind of cancer called head and neck squamous cell cancer (HNSCC) that:
    • has returned or spread and
    • you have received chemotherapy that contains platinum and it did not work or is no longer working.
  • a kind of cancer called classical Hodgkin lymphoma (cHL) in adults and children when:
    • you have tried a treatment and it did not work or
    • your cHL has returned after you received 3 or more types of treatment.
  • a kind of cancer called primary mediastinal B-cell lymphoma (PMBCL) in adults and children when:
    • you have tried a treatment and it did not work or
    • your PMBCL has returned after you received 2 or more types of treatment.
  • a kind of bladder and urinary tract cancer called urothelial carcinoma. Keytruda may be used when your bladder or urinary tract cancer:
    • has spread or cannot be removed by surgery (advanced urothelial cancer) and,
    • you are not able to receive chemotherapy that contains a medicine called cisplatin, and your tumor tests positive for "PD-L1", or
    • you are not able to receive a medicine called cisplatin or carboplatin, or
    • you have received chemotherapy that contains platinum, and it did not work or is no longer working.
  • a kind of cancer that is shown by a laboratory test to be a microsatellite instability-high (MSI-H) or a mismatch repair deficient (dMMR) solid tumor. Keytruda may be used in adults and children to treat:
    • cancer that has spread or cannot be removed by surgery (advanced cancer), and
    • has progressed following treatment, and you have no satisfactory treatment options, or
    • you have colon or rectal cancer, and you have received chemotherapy with fluoropyrimidine, oxaliplatin, and irinotecan but it did not work or is no longer working.
    It is not known if Keytruda is safe and effective in children with MSI-H cancers of the brain or spinal cord (central nervous system cancers).
  • a kind of stomach cancer called gastric or gastroesophageal junction (GEJ) adenocarcinoma that tests positive for "PD-L1." Keytruda may be used when your stomach cancer:
    • has returned or spread (advanced gastric cancer), and
    • you have received 2 or more types of chemotherapy including fluoropyrimidine and chemotherapy that contains platinum, and it did not work or is no longer working, and
    • if your tumor has an abnormal "HER2/neu" gene, you also received a HER2/neu-targeted medicine and it did not work or is no longer working.
  • a kind of cancer called cervical cancer that tests positive for "PD-L1." Keytruda may be used when your cervical cancer:
    • has returned, or has spread or cannot be removed by surgery (advanced cervical cancer), and
    • you have received chemotherapy, and it did not work or is no longer working.
  • a kind of liver cancer called hepatocellular carcinoma, after you have received the medicine sorafenib.
  • a kind of skin cancer called Merkel cell carcinoma (MCC) in adults and children. Keytruda may be used to treat your skin cancer when it has spread or returned.
  • a kind of kidney cancer called renal cell carcinoma (RCC). Keytruda may be used with the medicine axitinib as your first treatment when your kidney cancer has spread or cannot be removed by surgery (advanced RCC).
What should I tell my doctor before receiving Keytruda?
Before you receive Keytruda, tell your doctor if you:
  • have immune system problems such as Crohn's disease, ulcerative colitis, or lupus
  • have received an organ transplant, such as a kidney or liver
  • have received or plan to receive a stem cell transplant that uses donor stem cells (allogeneic)
  • have lung or breathing problems
  • have liver problems
  • have any other medical problems
  • are pregnant or plan to become pregnant
    • Keytruda can harm your unborn baby.
    Females who are able to become pregnant:
    • Your doctor will give you a pregnancy test before you start treatment with Keytruda.
    • You should use an effective method of birth control during and for at least 4 months after the final dose of Keytruda. Talk to your doctor about birth control methods that you can use during this time.
    • Tell your doctor right away if you think you may be pregnant or if you become pregnant during treatment with Keytruda.
  • are breastfeeding or plan to breastfeed.
    • It is not known if Keytruda passes into your breast milk.
    • Do not breastfeed during treatment with Keytruda and for 4 months after your final dose of Keytruda.
Tell your doctor 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 doctor and pharmacist when you get a new medicine.
How will I receive Keytruda?
  • Your doctor will give you Keytruda into your vein through an intravenous (IV) line over 30 minutes.
  • Keytruda is usually given every 3 weeks.
  • Your doctor will decide how many treatments you need.
  • Your doctor will do blood tests to check you for side effects.
  • If you miss any appointments, call your doctor as soon as possible to reschedule your appointment.
What are the possible side effects of Keytruda?
Keytruda can cause serious side effects. See "What is the most important information I should know about Keytruda?"
Common side effects of Keytruda when used alone include: feeling tired, pain, including pain in muscles, bones or joints and stomach-area (abdominal) pain, decreased appetite, itching, diarrhea, nausea, rash, fever, cough, shortness of breath, and constipation.
Common side effects of Keytruda when given with certain chemotherapy medicines include: feeling tired or weak, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, trouble breathing, fever, hair loss, and inflammation of the nerves that may cause pain, weakness, and paralysis in the arms and legs.
Common side effects of Keytruda when given with axitinib include: diarrhea, feeling tired or weak, high blood pressure, liver problems, low levels of thyroid hormone, decreased appetite, blisters or rash on the palms of your hands and soles of your feet, nausea, mouth sores or swelling of the lining of the mouth, nose, eyes, throat, intestines, or vagina, hoarseness, rash, cough, and constipation.
In children, feeling tired, vomiting and stomach-area (abdominal) pain, and increased levels of liver enzymes and decreased levels of salt (sodium) in the blood are more common than in adults.
These are not all the possible side effects of Keytruda. For more information, ask your doctor or pharmacist.
Tell your doctor if you have any side effect that bothers you or that does not go away.
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 Keytruda
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. If you would like more information about Keytruda, talk with your doctor. You can ask your doctor or nurse for information about Keytruda that is written for healthcare professionals. For more information, go to www.Keytruda.com.
What are the ingredients in Keytruda?
Active ingredient: pembrolizumab
Inactive ingredients:
Keytruda for injection: L-histidine, polysorbate 80, and sucrose. May contain hydrochloric acid/sodium hydroxide.
Keytruda injection: L-histidine, polysorbate 80, sucrose, and Water for Injection, USP.
Manufactured by: Merck Sharp & Dohme Corp., a subsidiary of
MERCK & CO., INC., Whitehouse Station, NJ 08889, USA
For Keytruda for injection, at:
MSD International GmbH, County Cork, Ireland
For Keytruda injection, at:
MSD Ireland (Carlow), County Carlow, Ireland
U.S. License No. 0002
For patent information: www.merck.com/product/patent/home.html
Copyright © 2014-2019 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
All rights reserved.
usmg-mk3475-iv-1904r023

PRINCIPAL DISPLAY PANEL - 50 mg Vial Carton

NDC 0006-3029-02

Keytruda®
(pembrolizumab)
for Injection

50 mg / vial

For Intravenous Infusion Only

Dispense the enclosed Medication Guide to each patient.

Sterile lyophilized powder must be reconstituted with Sterile Water for
Injection, USP. Reconstituted solution requires further dilution prior
to administration.

Rx only

Single-dose vial. Discard unused portion.

PRINCIPAL DISPLAY PANEL - 100 mg/4 mL Vial Carton

NDC 0006-3026-02

Keytruda®
(pembrolizumab)
Injection

100 mg/4 mL
(25 mg/mL)

For Intravenous Infusion Only

Dispense the enclosed Medication
Guide to each patient.

Requires dilution prior to administration.

Rx only
Single-dose vial. Discard unused portion.

Keytruda 
pembrolizumab injection, powder, lyophilized, for solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0006-3029
Route of Administration INTRAVENOUS DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
pembrolizumab (pembrolizumab) pembrolizumab 50 mg  in 2 mL
Inactive Ingredients
Ingredient Name Strength
HISTIDINE 3.1 mg  in 2 mL
SUCROSE 140 mg  in 2 mL
POLYSORBATE 80 0.4 mg  in 2 mL
SODIUM HYDROXIDE  
HYDROCHLORIC ACID  
Packaging
# Item Code Package Description
1 NDC:0006-3029-02 1 VIAL in 1 CARTON
1 NDC:0006-3029-01 15 mL in 1 VIAL
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
BLA BLA125514 09/04/2014
Keytruda 
pembrolizumab injection, solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0006-3026
Route of Administration INTRAVENOUS DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
pembrolizumab (pembrolizumab) pembrolizumab 25 mg  in 1 mL
Inactive Ingredients
Ingredient Name Strength
HISTIDINE 1.55 mg  in 1 mL
SUCROSE 70 mg  in 1 mL
POLYSORBATE 80 0.2 mg  in 1 mL
WATER  
Packaging
# Item Code Package Description
1 NDC:0006-3026-02 1 VIAL in 1 CARTON
1 NDC:0006-3026-01 10 mL in 1 VIAL
2 NDC:0006-3026-04 2 VIAL in 1 CARTON
2 NDC:0006-3026-01 10 mL in 1 VIAL
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
BLA BLA125514 01/15/2015
Labeler - Merck Sharp & Dohme Corp. (001317601)
Establishment
Name Address ID/FEI Operations
Merck Sharp & Dohme Corp. 101740835 PACK(0006-3029, 0006-3026), LABEL(0006-3029, 0006-3026)
Establishment
Name Address ID/FEI Operations
MSD International GmbH 985655572 MANUFACTURE(0006-3029), ANALYSIS(0006-3029, 0006-3026)
Establishment
Name Address ID/FEI Operations
MSD Ireland (Carlow) 985084764 MANUFACTURE(0006-3026), ANALYSIS(0006-3026)
Establishment
Name Address ID/FEI Operations
N.V. Organon 404467722 ANALYSIS(0006-3029, 0006-3026)
Establishment
Name Address ID/FEI Operations
Covance Laboratories 213137276 ANALYSIS(0006-3029, 0006-3026)
 
Merck Sharp & Dohme Corp.
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