On September 4, 2014, the U. S. Food and Drug Administration granted accelerated approval to pembrolizumab (KEYTRUDA, Merck Sharp & Dohme Corp.) for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 
Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby releasing PD-1 pathway-mediated inhibition of the immune response, including anti-tumor immune response.  
Approval was based on the results of a multicenter, open-label, randomized (1:1), dose-comparative, activity-estimating cohort conducted within Trial P001. In this cohort, 173 patients with unresectable or metastatic melanoma with disease progression within 24 weeks of the last dose of ipilimumab and, if BRAF V600 mutation positive, prior treatment with a BRAF inhibitor, were randomized to receive pembrolizumab 2 mg/kg (n=89) or 10 mg/kg (n=84) intravenously once every 3 weeks until disease progression or unacceptable toxicity.
Key exclusion criteria were an autoimmune disease, a medical condition that required immunosuppression, and/or a history of severe immune-mediated adverse reactions from treatment with ipilimumab.  Severe immune-mediated adverse reactions were defined as any CTCAE Grade 4 toxicity requiring treatment with corticosteroids or Grade 3 toxicity requiring corticosteroid treatment (greater than 10 mg/day prednisone or equivalent dose) for greater than 12 weeks.
Among the 173 patients, the median age was 61 years (64% less than age 65); 40% female; 97% White; and 66% and 34% with an ECOG performance status 0 and 1, respectively.  Disease characteristics were BRAF V600 mutation  positive (17%), elevated lactate dehydrogenase (39%), M1c (82%), brain metastases (9%), and two or more prior therapies for advanced or metastatic disease (73%).
The major efficacy endpoints were confirmed overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as assessed by a blinded independent review committee and duration of response (DOR).  The ORR was 24% (95% CI: 15, 34) in the 2 mg/kg arm, consisting of one complete response and 20 partial responses.  Among the 21 patients with an objective response, 3 (14%) had disease progression at 2.8, 2.9, and 8.2 months after initial response. The remaining 18 patients (86%) have ongoing responses, ranging from 1.4+ to 8.5+ months;  8 patients have ongoing responses of 6 months or longer.  Similar ORR results were observed in the 10 mg/kg arm. 
The most common (greater than or equal to 20%) adverse reactions among patients receiving pembrolizumab 2 mg/kg every 3 weeks were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea.
The most frequent (greater than or equal to 2%) serious adverse drug reactions observed with pembrolizumab were renal failure, dyspnea, pneumonia, and cellulitis.  Additional clinically significant immune-mediated adverse reactions included pneumonitis, colitis, hypophysitis, hyperthyroidism, hypothyroidism, nephritis, and hepatitis.
As a condition of this accelerated approval, Merck is required to conduct a multicenter, randomized trial establishing the superiority of pembrolizumab over standard therapy to verify and describe the clinical benefit of pembrolizumab.  Merck has two ongoing multicenter, randomized, controlled, therapeutic confirmatory trials in patients with unresectable or metastatic melanoma, either ipilimumab refractory (Trial P002) or ipilimumab naïve (Trial P006), each with co-primary endpoints of progression-free survival and overall survival.
FDA granted pembrolizumab breakthrough therapy designation for pembrolizumab for this indication in January 2013 based on preliminary evidence of clinical activity in patients with unresectable or metastatic melanoma, previously untreated with or refractory to ipilimumab.
The recommended dose of pembrolizumab is 2 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks.
Full prescribing information is available at: 
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


Page Last Updated: 09/01/2015
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