As reported in The Lancet by Barbara Burtness, MD, of the Department of Medicine, Yale University School of Medicine, and colleagues, the phase III KEYNOTE-048 trial has shown improved overall survival with first-line pembrolizumab plus chemotherapy vs cetuximab plus chemotherapy among patients with recurrent or metastatic squamous cell carcinoma of the head and neck, with pembrolizumab alone also improving survival among programmed cell death ligand 1 (PD-L1)-positive patients.¹

Barbara Burtness, MD

Study findings support the June 2019 U.S. Food and Drug Administration approval of pembrolizumab in combination with platinum and fluorouracil (5-FU) in the first-line treatment of metastatic or unresectable recurrent head and neck squamous cell carcinoma and of pembrolizumab monotherapy in the first-line treatment of those patients with PD-L1 expression indicated by a Combined Positive Score (CPS) of at least 1.

Study Methodology

In the open-label trial, 882 patients from 200 sites in 37 countries were randomly assigned 1:1:1 between April 2015 and January 2017 to receive pembrolizumab alone (n = 301), pembrolizumab with a platinum plus 5-FU (n = 281), or cetuximab with a platinum plus 5-FU (n = 300). Pembrolizumab was given at 200 mg every 3 weeks until disease progression, intolerable toxicity, physician/participant decision, or 35 cycles, whichever occurred first. Cetuximab was given at a 400-mg/m² loading dose followed by 250 mg/m² per week until disease progression, intolerable toxicity, or physician/participant decision. Chemotherapy consisted of carboplatin AUC = 5 mg/m² or cisplatin at 100 mg/m² every 3 weeks plus 5-FU at 1,000 mg/m²/d for 4 consecutive days every 3 weeks for six cycles.

The primary endpoints were overall survival and progression-free survival in the intention-to-treat population, including prespecified analysis of outcomes in patients with CPS ≥ 20 and ≥ 1. Comparison of the combination groups included just those patients in the cetuximab group (n = 278) randomly assigned during accrual of the pembrolizumab-plus-chemotherapy group, which was briefly halted early during the conduct of the study for safety review. Of patients receiving study chemotherapy, 57% received carboplatin. Among the 882 patients, the CPS was at least 1 in 754 patients (85%) and at least 20 in 381 patients (43%).

Survival and Response Rates

The median durations of follow-up were 11.5 months with pembrolizumab alone, 13.0 months with pembrolizumab plus chemotherapy, and 10.7 months with cetuximab plus chemotherapy.

At second interim analysis, pembrolizumab alone improved overall survival vs cetuximab plus chemotherapy among 133 vs 122 patients with a CPS of at least 20 (median = 14.9 vs 10.7 months, hazard ratio [HR] = 0.61, P = .0007) and among 257 vs 255 patients with a CPS of at least 1 (median = 12.3 vs 10.3 months, HR = 0.78, P = .0086) and was noninferior in the total population (median = 11.6 vs 10.7 months, HR = 0.85, 95% confidence interval [CI] = 0.71–1.03).

Pembrolizumab plus chemotherapy improved overall survival vs cetuximab plus chemotherapy in the total population (median = 13.0 vs 10.7 months, HR = 0.77, P = .0034) at the second interim analysis and among the 126 vs 110 patients with a CPS of at least 20 (median = 14.7 vs 11.0 months, HR = 0.60, P = .0004) and the 242 vs 235 patients with a CPS of at least 1 (median = 13.6 vs 10.4 months, HR = 0.65, P < .0001) at final analysis.

At the second interim analysis (final analysis of progression-free survival), compared with cetuximab plus chemotherapy, pembrolizumab alone did not improve progression-free survival in the population with a CPS of at least 20 (median = 3.4 vs 5.0 months, HR = 0.99, P = .456), and no benefit was observed with pembrolizumab plus chemotherapy in the population with a CPS of at least 20 (median = 5.8 vs 5.2 months, HR = 0.73, P =.016) or the total population (median = 4.9 vs 5.1 months, HR = 0.92, P = .170). Since superiority was not shown for these comparisons, no formal statistical testing was performed for pembrolizumab alone vs cetuximab plus chemotherapy in the population with a CPS of at least 1 (median = 3.2 vs 5.0 months, HR = 1.16, 95% CI = 0.96–1.39) or the total population (median = 2.3 vs 5.2 months, HR = 1.34, 95% CI = 1.13–1.59) or for pembrolizumab plus chemotherapy vs cetuximab plus chemotherapy in the population with a CPS of at least 1 (median = 5.0 vs 5.0 months, HR = 0.82, 95% CI = 0.67–1.00).

At least one subsequent anticancer therapy was received by 49% of the pembrolizumab-alone group, 41% of the pembrolizumab-plus-chemotherapy group, and 53% of the cetuximab-plus-chemotherapy group, including 6%, 6%, and 25% who received programmed cell death protein 1 or PD-L1 inhibitor treatment.

At final analysis, for pembrolizumab alone vs cetuximab plus chemotherapy, the objective response rates were 23% vs 36% in the population with a CPS of at least 20, 19% vs 35% in the population with a CPS of at least 1, and 17% vs 36% in the total population; the median response durations were 22.6 vs 4.2 months, 23.4 vs 4.5 months, and 22.6 vs 4.5 months, respectively. For the pembrolizumab-plus-chemotherapy vs cetuximab-plus-chemotherapy groups, the objective response rates in the respective populations were 43% vs 38%, 36% vs 36%, and 36% vs 36%, with respective median response durations of 7.1 vs 4.2, 6.7 vs 4.3, and 6.7 vs 4.3 months.

Adverse Events

Grade ≥ 3 adverse events occurred in 55% of the pembrolizumab-alone group (most common was anemia), 85% of the pembrolizumab-plus-chemotherapy group (most common were anemia and neutropenia), and 83% of the cetuximab-plus-chemotherapy group (most common were neutropenia and anemia). Potential immune-related adverse events of any grade occurred in 31%, 26%, and 24% of patients and were grade ≥ 3 in 7%, 5%, and 10%. The most common immune-related adverse events were hypothyroidism in the two pembrolizumab groups and infusion reactions in the cetuximab group.

Adverse events led to discontinuation of any treatment in 12%, 33%, and 28% of patients. Adverse events led to death in 8%, 12%, and 10% of patients, with death considered related to treatment in 1%, 4%, and 3%.

The investigators concluded: “Based on the observed efficacy and safety, pembrolizumab plus platinum and fluorouracil is an appropriate first-line treatment for recurrent or metastatic [head/neck squamous cell carcinoma] and pembrolizumab monotherapy is an appropriate first-line treatment for PD-L1–positive recurrent or metastatic [head/neck squamous cell carcinoma].” 

DISCLOSURE: The study was funded by Merck Sharp & Dohme. For full disclosures of the study authors, visit thelancet.com.

REFERENCE

1. Burtness B, Harrington KJ, Greil R, et al: Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): A randomised, open-label, phase 3 study. Lancet 394:1915-1928, 2019.