Improved Survival Shown With First-Line Pembrolizumab in Advanced Head and Neck Cancer

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In the final analysis of KEYNOTE-048, first-line pembrolizumab monotherapy led to a significant improvement in overall survival, vs standard chemotherapy with targeted therapy (EXTREME regimen), in patients with recurrent or metastatic head and neck squamous cell carcinoma expressing programmed cell death ligand 1 (PD-L1).1 In the total population as well, the combination of pembrolizumab plus chemotherapy improved overall survival, and single-agent pembrolizumab was noninferior to chemotherapy.

Danny Rischin, MD

Danny Rischin, MD

“The data from KEYNOTE-048 support pembrolizumab plus platinum-based chemotherapy and pembrolizumab monotherapy as new first-line standard-of-care therapies for recurrent head and neck squamous cell carcinoma,” said Danny Rischin, MD, of Peter MacCallum Cancer Centre in Melbourne, speaking at the 2019 ASCO Annual Meeting.

In the first-line setting for recurrent or metastatic disease, the EXTREME regimen was the standard of treatment for more than 10 years, but median overall survival with this regimen is only about 10 months, and the incidence of grade 3 to 4 toxicity is high. Immunotherapy could improve upon outcomes in terms of both efficacy and toxicity, KEYNOTE-048 investigators suggested.

The previous interim analysis of KEYNOTE-048, presented by principal investigator Barbara Burtness, MD, of Yale School of Medicine, New Haven, Connecticut, at the European Society for Medical Oncology (ESMO) 2018 Congress found a survival benefit for pembrolizumab with or without chemotherapy.2 That benefit was seen in the total population with pembrolizumab and chemotherapy in patients with a PD-L1 combined positive score (CPS) ≥ 1 and ≥ 20 with pembrolizumab monotherapy.

Barbara Burtness, MD

Barbara Burtness, MD

The study provided the first evidence of prolonged survival with immunotherapy in the first-line recurrent or metastatic setting for advanced head and neck cancer, and the data were submitted to the U.S. Food and Drug Administration (FDA). After the ASCO meeting, pembrolizumab was approved by the FDA for the first-line treatment of patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma—as monotherapy in patients whose tumors express PD-L1 (with a CPS ≥1) or in combination with a platinum and fluorouracil for this population irrespective of PD-L1 expression.

KEYNOTE-048 Details

The phase III trial included 882 patients with recurrent or metastatic head and neck squamous cell carcinoma who were tested for PD-L1 expression. Patients were randomly assigned 1:1:1 to the following three regimens:

  • 200 mg of pembrolizumab every 3 weeks for 24 months (n = 301)
  • Pembrolizumab for 24 months plus six cycles of chemotherapy consisting of cisplatin at 100 mg/m2 or ­carboplatin at AUC 5 every 3 weeks plus fluorouracil at 1,000 mg/m2/d for 4 days every 3 weeks (n = 281)
  • EXTREME regimen: cetuximab at a 400 mg/m2 loading dose followed by 250 mg/m2 once a week plus six cycles of chemotherapy (n = 300).

The study followed a hierarchic design, testing a number of initial hypotheses, with the remaining hypotheses tested for statistical significance only if the initial one was positive. Hypotheses tested in the final analysis included the superiority of pembrolizumab alone in the total population, superiority of pembrolizu­mab plus chemotherapy in the CPS ≥ 20 population, and superiority of pembrolizumab plus chemotherapy in the CPS ≥ 1 population (only if superiority in the CPS ≥ 20 population was demonstrated).

“The data from KEYNOTE-048 support pembrolizumab plus platinum-based chemotherapy and pembrolizumab monotherapy as new first-line standard-of-care therapies for recurrent head and neck squamous cell carcinoma.”
— Danny Rischin, MD

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Overall Survival Improved

Overall survival was improved by both pembrolizumab monotherapy and pembrolizumab plus chemotherapy, with some nuances. In the total population, median overall survival was 11.5 months with pembrolizumab vs 10.7 with the EXTREME regimen (hazard ratio = 0.83; P = .0199). Median overall survival was 13.0 months with pembrolizumab plus chemotherapy, for a hazard ratio of 0.72 compared with the EXTREME regimen.

Dr. Burtness noted that although the trial was not designed to compare the two investigational arms, the median overall survival and hazard ratios suggest there is no added survival benefit of chemotherapy for the CPS ≥ 20 population. The hazard ratio for progression-free survival was 1.29 (95% confidence interval [CI] = 1.09–1.53) for single-agent pembrolizumab. For pembrolizumab/chemotherapy, it was 0.76 (95% CI = 0.58–1.01) for CPS ≥ 20 and 0.84 (95% CI = 0.69–1.02) for CPS ≥ 1. The response rate was higher with chemotherapy, indicating that in the most symptomatic patients, there could be an advantage for including chemotherapy even with a CPS > 20.

Response rates for pembrolizumab plus chemotherapy were 42.9% vs 38.2% in the CPS ≥ 20 population and 36.4% vs 35.7% in the CPS ≥ 1 population. The median duration of response with the combination was around 7 months—almost double that for ­EXTREME. Interestingly, with the single agent, response rates were approximately half those achieved with chemotherapy (16.9% vs 36.0% in the total population), but the duration of response was much longer (median 22.6 vs 4.5 months).

All-cause grade 3 to 5 adverse event rates were 54.7% for pembrolizumab alone, 85.1% for pembrolizumab/chemotherapy, and 83.3% for cetuximab/chemotherapy. ■


DISCLOSURE: Dr. Rischin has received research funding from Amgen, Bristol-Myers Squibb, Genentech/Roche, GlaxoSmithKline, Merck, and Regeneron and travel expenses from Merck. Dr. Burtness has been a consultant or advisor for Aduro Biotech, Alligator Biosciences, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, CUE Biopharma, Genentech/Roche, GlaxoSmithKline, MedImmune, Merck, and Rakuten and has received travel expenses from Merck.


1. Rischin D, Harrington K, Greil R, et al: Protocol-specified final results of the KEYNOTE-048 trial of pembrolizumab as first-line therapy for recurrent/metastatic head and neck squamous cell carcinoma. 2019 ASCO Annual Meeting. Abstract 6000. Presented May 31, 2019.

2. Burtness B, Harrington KJ, Greil R, et al: KEYNOTE-048: Phase 3 study of first-line pembrolizumab for recurrent/metastatic head and neck squamous cell carcinoma. ESMO 2018 Congress. Abstract LBA8_PR. Presented October 22, 2018.

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