On August 5, 2016, the U. S. Food and Drug Administration granted accelerated approval to pembrolizumab (KEYTRUDA injection, Merck Sharp & Dohme Corp.) 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.
The approval was based on demonstration of a durable objective response rate (ORR) in a subgroup of patients in an international, multicenter, non-randomized, open-label, multi-cohort study. This subgroup included 174 patients with recurrent or metastatic HNSCC who had disease progression on or after platinum-containing chemotherapy. Patients received intravenous pembrolizumab 10 mg/kg every 2 weeks or 200 mg every 3 weeks.
ORR was determined by an independent review committee according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The ORR for these 174 patients was 16% (95% confidence interval [CI] 11, 22). The median response duration had not been reached at the time of analysis. The range for duration of response was 2.4 months to 27.7 months (response ongoing). Among the 28 responding patients, 23 (82%) had responses of 6 months or longer.
Safety data was evaluated in 192 patients with HNSCC receiving at least one dose of pembrolizumab 10 mg/kg every 2 weeks or 200 mg every 3 weeks. The most common (greater than or equal to 20%) adverse reactions were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were similar to those occurring in patients with melanoma or NSCLC, with the exception of an increased incidence of facial edema (10% all grades, 2.1% grades 3-4) and new or worsening hypothyroidism (14.6% all grades). The most frequent (greater than or equal to 2%) serious adverse reactions were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. Clinically significant immune-mediated adverse reactions included pneumonitis, colitis, hepatitis, adrenal insufficiency, diabetes mellitus, skin toxicity, myositis, and thyroid disorders.
As a condition of the 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 an ongoing multicenter, randomized trial (KEYNOTE 040) in patients with recurrent or met HNSCC with disease progression on or after platinum-containing chemotherapy with a primary endpoint of overall survival.
The recommended dose and schedule of pembrolizumab for this indication is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks.
The current indication was approved under FDA’s accelerated approval program. This application was granted Priority Review. A description of these expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.
Full prescribing information is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125514s009lbl.pdf