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Science in the News

A Novel Immunomodulatory Biologic Agent, Pembrolizumab (Keytruda®), Gains Additional Approval for Use in Patients with Advanced Head and Neck Cancer

August 18, 2016

On August 5, 2016,1, 2 the U.S. Food and Drug Administration (FDA) granted accelerated approval for a new indication for the humanized monoclonal antibody biologic agent, pembrolizumab (Keytruda®, Merck and Co.) for use in recurrent/metastatic squamous-cell head and neck cancer (HNSCC) that has advanced during or is unresponsive to platinum-containing chemotherapy.3  Pembrolizumab has been previously FDA approved for unresectable/metastatic melanoma and for a specific type of metastatic nonsmall-cell lung cancer that has progressed during or after platinum-containing chemotherapy.3  The approved dose schedule for recurrent/metastatic HNSCC is 200 mg IV (administered as an infusion over 30 minutes) every 3 weeks.3

The biologic is a humanized immunoglobulin (IgG4/kappa) monoclonal antibody that binds an inhibitory signaling receptor expressed on the surface of activated T cells called “programmed (cell) death-1” or “PD-1.”4 PD-1 ligands overexpressed on certain cancer cells can activate the inhibitory properties of PD-1 receptors, allowing cancer cells to go unrecognized by T-cells.  By blocking the PD-1 receptor-ligand binding, pembrolizumab acts to stimulate the body’s immune system, allowing it to play a bigger role in cancer cell recognition and destruction.4, 5

Pembrolizumab’s activity in recurrent or metastatic HNSCC was evaluated as part of a multicenter Phase 1b open-label study of the drug in a variety of advanced solid tumors, including breast cancer, urothelial tract cancer, and gastric cancer titled “KEYNOTE-012.”3, 6, 7 Enrolled patients had recurrent or metastatic HNSCC who had disease progression on or after platinum-containing chemotherapy.3  Two pembrolizumab dosing schedules for HNSCC were being evaluated in KEYNOTE-12: 10 mg/kg IV every 2 weeks or 200 mg IV every 3 weeks; patients received pembrolizumab 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. The original cohort of patients enrolled (n=60) had to have disease testing positive for PD ligand 1 (PDL1) expression; patients enrolled in the expansion cohort of the study (n=132) were enrolled regardless of PDL1 status.8  Approximately 33% of patients had tumors positive for human papillomavirus (HPV).3  The primary efficacy outcome measures were objective response rate (assessed by blinded, independent central review) and duration of response; safety outcomes were also assessed.3, 7

Pembrolizumab treatment resulted in an overall response rate of 16% (95% confidence interval [CI] 11 to 22) and a complete response rate of 5%; median follow-up was 8.9 months.3  Of the 28 responding patients, median duration of response had not been reached (range 2.4+ to 27.7+ months); 23 patients had responses lasting 6 months or longer.3  Overall response rate and response duration were similar irrespective of dosage regimen (10 mg/kg every 2 weeks or 200 mg every 3 weeks) or HPV status.3  Most common adverse events in patients receiving pembrolizumab include fatigue, decreased appetite, and dyspnea; adverse event specific to patients receiving the biologic for HNSCC include increased facial edema (10%) and new or worsening hypothyroidism.3

Because this supplemental indication was approved under the FDA’s accelerated approval process, the manufacturer has committed to conducting and submitting the results of “at least one multicenter, randomized clinical trial establishing the superiority of pembrolizumab over available therapy as determined by an improvement in overall survival in patients with metastatic HNSCC].”1 This Phase III trial (KEYNOTE-040) is ongoing and registered at (NCT02252042).9


  1. U.S. Food and Drug Administration. FDA sBLA Approval Letter:  Keytruda (BLA 125514/S-5). Accessed August 12, 2016.
  2. U.S. Food and Drug Administration. FDA Approved Drugs: pembrolizumab (KEYTRUDA). Accessed August 10, 2016.
  3. Merck & Co. Inc.. Keytruda (pembrolizumab) for injection/injection, for intravenous use (rev. 8/2016). Accessed August 10, 2016.
  4. National Cancer Institute (NCI). NCI Drug Dictionary: Pembrolizumab. Accessed August 12, 2016.
  5. Machiels JP, Coulie PG. The promise of immunostimulatory antibodies in head and neck cancer. Lancet Oncol 2016;17(7):856-7.
  6. U.S. National Institutes of Health. Study of pembrolizumab (MK-3475) in participants with advanced solid tumors (MK-3475-012/KEYNOTE-012; NCT02252042). Accessed August 12, 2016.
  7. Seiwert TY, Burtness B, Mehra R, et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol 2016;17(7):956-65.
  8. American Society of Clinical Oncology. Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNHCC): pooled analyses after long-term follow-up in KEYNOTE-012 (Abstract 6012). 2016 ASCO Annual Meeting. Accessed August 10, 2016.
  9. U.S. National Institutes of Health. Pembrolizumab (MK-3475) versus standard treatment for recurrent or metastatic head and neck cancer (MK-3475-040/KEYNOTE-040; NCT02252042). Accessed August 10, 2016.

Prepared by: Center for Scientific Information, ADA Science Institute

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Science in the News is a service by the American Dental Association (ADA) to its members to present current information about science topics in the news. The ADA is a professional association of dentists committed to the public's oral health, ethics, science and professional advancement; leading a unified profession through initiatives in advocacy, education, research and the development of standards. As a science-based organization, the ADA's evaluation of the scientific evidence may change as more information becomes available. Your thoughts would be greatly appreciated.

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