FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma

• Published in: Clinical cancer research Vol. 23; no. 19; pp. 5666 - 5670
• Main Authors: Chuk, Meredith K, Chang, Jennie T, Theoret, Marc R, Sampene, Emmanuel, He, Kun, Weis, Shawna L, Helms, Whitney S, Jin, Runyan, Li, Hongshan, Yu, Jingyu, Zhao, Hong, Zhao, Liang, Paciga, Mark, Schmiel, Deborah, Rawat, Rashmi, Keegan, Patricia, Pazdur, Richard
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01.10.2017
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal, Humanized - administration & dosage; Antibodies, Monoclonal, Humanized - adverse effects; Appetite loss; Arthralgia; Cancer; Colitis; Confidence intervals; Constipation; Cough; Data processing; Diarrhea; Disease-Free Survival; Dosage; Drug Approval; Drug-Related Side Effects and Adverse Reactions - pathology; Durability; Exanthema; Fatigue; FDA approval; Female; Hepatitis; Humans; Immunotherapy; Intravenous administration; Intravenous infusion; Ipilimumab - administration & dosage; Ipilimumab - adverse effects; Male; Melanoma; Melanoma - drug therapy; Melanoma - genetics; Melanoma - pathology; Metastases; Metastasis; Middle Aged; Monoclonal antibodies; Nausea; Patients; Pneumonitis; Proto-Oncogene Proteins B-raf - genetics; Pruritus; Regulatory agencies; Side effects; Targeted cancer therapy; Thyroid
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-16-0663

On September 4, 2014, the FDA approved pembrolizumab (KEYTRUDA; Merck Sharp & Dohme Corp.) with a recommended dose of 2 mg/kg every 3 weeks by intravenous infusion for the treatment of patients with unresectable or metastatic melanoma who have progressed following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Approval was based on demonstration of objective tumor responses with prolonged response durations in 89 patients enrolled in a randomized, multicenter, open-label, dose-finding, and activity-estimating phase 1 trial. The overall response rate (ORR) by blinded independent central review per RECIST v1.1 was 24% (95% confidence interval, 15-34); with 6 months of follow-up, 86% of responses were ongoing. The most common (≥20%) adverse reactions were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea. Immune-mediated adverse reactions included pneumonitis, colitis, hepatitis, hypophysitis, and thyroid disorders. The benefits of the observed ORR with prolonged duration of responses outweighed the risks of immune-mediated adverse reactions in this life-threatening disease and represented an improvement over available therapy. Important regulatory issues in this application were role of durability of response in the evaluation of ORR for accelerated approval, reliance on data from a first-in-human trial, and strategies for dose selection. .