Pembrolizumab vs Standard of Care in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma


Key Points

  • Pembrolizumab was associated with a “clinically meaningful” improvement in overall survival vs the standard of care.
  • Median overall survival was 8.4 months vs 6.9 months.

In the phase III KEYNOTE-040 trial reported in The Lancet, Cohen et al found that pembrolizumab (Keytruda) was associated with a “clinically meaningful prolongation of overall survival” vs investigator’s choice of standard therapies in patients with previously treated recurrent or metastatic head and neck squamous cell carcinoma. The trial is meant to serve as the confirmatory trial for the accelerated approval of pembrolizumab in this setting.

In the open-label trial, 495 patients from 97 sites in 20 countries were randomly assigned between December 2014 and May 2016 to receive pembrolizumab at 200 mg every 3 weeks (n = 247) or investigator’s choice of standard therapy (n = 248) consisting of standard doses of methotrexate (n = 65), docetaxel (n = 110), or cetuximab (Erbitux; n = 73). Patients had to have disease that progressed during or after platinum-containing treatment for recurrent or metastatic disease, or disease that recurred or progressed within 3 to 6 months of previous multimodal therapy containing platinum for locally advanced disease. The primary endpoint was overall survival in the intention-to-treat population.

Overall Survival

Median duration of follow-up was 7.5 months in the pembrolizumab group and 7.1 months in the standard-of-care group. At the time of the protocol-specified final analysis (based on a data cutoff of May 15, 2017), death had occurred in 179 (72%) of 247 patients in the pembrolizumab group vs 198 (80%) of 248 patients in the standard-of-care group; survival status was unconfirmed for 3 patients in the pembrolizumab group and 9 in the standard-of-care group.

The hazard ratio (HR) for death for pembrolizumab vs standard of care was 0.82 (95% confidence interval [CI] = 0.67–1.01, one-sided P = .0316), which did not meet the prespecified efficacy boundary (one-sided α of .0175). After survival status of the 12 outstanding patients was confirmed (based on the same data cutoff), the number of deaths increased to 181 (73%) of 247 in the pembrolizumab group and 207 (83%) of 248 in the standard-of-care group, with a hazard ratio of 0.80 (95% CI = 0.65–0.98, nominal P = .0161).

Median overall survival was 8.4 months vs 6.9 months in the 2 groups, respectively. Survival at 12 months was 37.0% vs 26.5%. Hazard ratios for death were similar across most subgroups, with all 95% confidence intervals overlapping those of the overall population.

Analysis by programmed cell death ligand 1 (PD-L1) expression showed a benefit of pembrolizumab among the 198 patients treated with pembrolizumab and 191 patients treated with standard of care, with combined positive score ≥ 1 (HR = 0.74, nominal P = .0049) and among the 64 and 65 patients with tumor proportion score ≥ 50% (HR = 0.53, nominal P = .0014).

Adverse Events

Treatment-related grade ≥ 3 adverse events occurred in 13% of the pembrolizumab group vs 36% of the standard-of-care group. The most common treatment-related adverse event of any grade was hypothyroiditis (13%) in the pembrolizumab group and fatigue (18%) in the standard-of-care group.

Treatment-related immune-mediated adverse events of any grade occurred in 26% of the pembrolizumab group. Treatment-related death occurred in 4 patients in the pembrolizumab group (unspecified cause, large intestine perforation, malignant neoplasm progression, and Stevens-Johnson syndrome, respectively) and 2 in the standard-of-care group (malignant neoplasm progression and pneumonia).

The investigators concluded, “The clinically meaningful prolongation of overall survival and favorable safety profile of pembrolizumab in patients with recurrent or metastatic head and neck squamous cell carcinoma support the further evaluation of pembrolizumab as a monotherapy and as part of combination therapy in earlier stages of disease.”

Ezra E.W. Cohen, MD, of the Moores Cancer Center, University of California, San Diego, is the corresponding author for The Lancet article.

Disclosure: The study was funded by Merck Sharp & Dohme, a subsidiary of Merck & Co. The study authors’ full disclosures can be found at

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