Pembrolizumab Benefits Patients With Recurrent Metastatic Head and Neck Cancer, Mainly High PD-L1–Expressing Tumors

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Pembrolizumab (Keytruda) may be a better choice than standard of care for patients with recurrent or metastatic head and neck squamous cell carcinoma, especially those whose tumors express programmed cell death ligand 1 (PD-L1) in 50% or more of cells, suggest results of the phase III KEYNOTE-040 trial.1

In the overall population, the study did not meet its primary endpoint of statistical significance for overall survival for pembrolizumab vs standard of care. Pembrolizumab reduced the risk of death by 19% compared with standard of care, but the P value of .0204 was slightly higher than the prespecified value. Median overall survival was 8.4 months with pembrolizumab vs 7.1 months for standard of care.

Corey Langer, MD

Corey Langer, MD

During a question-and-answer session after the presentation at the European Society for Medical Oncology (ESMO) 2017 Congress, audience member Corey Langer, MD, Director of Thoracic Oncology and Professor of Medicine at the Hospital of the University of Pennsylvania, asked: “Why isn’t a P value of .02 not statistically significant?”

Ezra Cohen, MD, Associate Director, Translational Science, University of California San Diego Moore Cancer Center in La Jolla, who presented these late-breaking results, said: “Although the study did not meet its primary endpoint because we used statistical rigor, I still think it is a positive trial. I think the difference is clinically meaningful for this population with a devastating disease. From a clinician’s perspective, this is a meaningful therapy that improves survival. Pembrolizumab should continue to be offered as an important option for all patients with this devastating disease.”

Overall survival was significantly superior with pembrolizumab in the subgroup of patients whose tumors expressed PD-L1. For those with PD-L1 expression of 1% or greater (n = 196 for pembrolizumab and n = 191 for standard of care), median overall survival was 8.7 months vs 7.1% for standard of care (P = .0078), whereas for a smaller subgroup with a higher bar of PD-L1 expression of 50% or greater (n = 64 and 65, respectively), median overall survival was 11.6 months vs 7.9 months, respectively (P = .0017).

ESMO Expert Speaks

Commenting on this study, ESMO spokesperson Amanda Psyrri, MD, PhD, Chief of Medical Oncology and Professor of Medicine, National Kapodistrian University of Athens Medical School, Attikon University Hospital, Athens, Greece, said: -“KEYNOTE-040 did not reach its primary endpoint of overall survival; however, pembrolizumab was superior to investigator’s choice in terms of toxicity, an important consideration in

treatment decisions for these poor-prognosis patients with recurrent/metastatic platinum-refractory head and neck squamous cell carcinoma. As the authors pointed out, subsequent immunotherapy in the standard-of-care arm may have confounded the overall survival analysis. The magnitude of treatment effect was greater in patients with a PD-L1 combined positive score ≥ 1%, especially those with a tumor proportion score ≥ 50%, suggesting pembrolizumab may represent the preferable option for this subset of patients.”

Study Details

Pembrolizumab is a programmed cell death protein 1 (PD-1) checkpoint inhibitor approved by the U.S. Food and Drug Administration for recurrent and metastatic head and neck squamous cell carcinoma. The global, open-label phase III study enrolled 495 patients with recurrent or progressive disease after receiving a platinum-based regimen. Patients were randomized 1:1 to receive pembrolizumab at 200 mg every 3 weeks for 24 months or investigator’s choice of standard therapy (methotrexate at 40 mg/m2 weekly, docetaxel at 75 mg/m2 every 3 weeks, or cetuximab at 250 mg/m2 weekly). Tissue samples were collected for PD-L1 assessment. Patients were stratified according to Eastern Cooperative Oncology Group performance status (0 vs 1), human papillomavirus status (p16-positive or -negative), and PD-L1 tumor proportion score (tumor proportion score, ≥ 50% vs < 50%).

Amanda Psyrri, MD, PhD

Amanda Psyrri, MD, PhD

The primary endpoint was overall survival in an intent-to-treat analysis. Secondary endpoints included overall survival according to biomarker analysis, progression-free survival, objective response rate, duration of response, and safety and tolerability.

At a median follow-up of 7.3 months, treatment was ongoing for 22 of the 246 patients randomized to treatment with pembrolizumab vs 2 of the 234 randomized to treatment with the standard of care. The majority of patients were male, the median age was 60 years, and about 25% had tumors with PD-L1 tumor proportion score ≥ 50%.

The objective response rate was higher with pembrolizumab in the intent-to-treat analysis: 14% for pembrolizumab vs 10% for the standard of care, rising to 17% vs 9.9%, respectively, for PD-L1 combined positive score ≥ 1%, and more than 26% vs 9.2% for PD-L1 tumor proportion score ≥ 50%. “All the complete responses and almost all the partial responses were observed in patients whose tumors expressed some degree of PD-L1,” Dr. Cohen said. The median duration of response stood out for pembrolizumab: 18.4 months vs 5 months with the standard of care.

Immunotherapy for Head and Neck Cancer

  • Pembrolizumab extended survival modestly compared with the standard of care, with fewer side effects.
  • Although KEYNOTE 040 failed to meet its primary endpoint in the overall population, pembrolizumab reduced the risk of death by 19%, and this benefit was more pronounced in patients with PD-L1–expressing tumors.
  • In patients who respond to pembrolizumab, the duration of response is “remarkable.”
  • These findings suggest pembrolizumab is an important option in this setting.

In an exploratory analysis of all patients randomized to receive the standard of care who went on to subsequent therapy, those who received a checkpoint inhibitor “appeared to benefit tremendously,” Dr. Cohen said. Median overall survival for that group was 20 months compared with 9.8 months for those who received other subsequent therapy and 4.6 months for those who had no other therapy. “Crossover confounded survival results,” Dr. Cohen explained.

Pembrolizumab-treated patients had a lower rate of all adverse events as well as serious adverse events compared with those treated with the standard of care. The rate of treatment-emergent adverse events was 63% vs 93%, respectively. Grades 3 to 5 adverse events were reported in 13.4% vs 36.3%, respectively. Hypothyroidism was the only adverse event occurring more frequently with pembrolizumab (13% vs 1%, respectively). ■

DISCLOSURE: Dr. Langer has served as an advisor and consultant for Merck, and Merck has sponsored several trials at the University of Pennsylvania as well as investigator-initiated trials. Drs. Cohen and Psyrri reported no conflicts of interest.


1. Cohen EEW, Harrington KJ, Le Tourneau C, et al: Pembrolizumab versus standard of care for recurrent or metastatic head and neck squamous cell carcinoma: Phase 3 KEYNOTE-040 trial. 2017 ESMO Congress. Abstract LBA45_PR. Presented September 11, 2017.

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