Barbara Burtness, MD

As reported in The Lancet by Barbara Burtness, MD, 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 (HNSCC), with pembrolizumab alone improving survival among programmed cell death ligand 1 (PD-L1)-positive patients.

Study Details

The open-label trial included 882 patients from 200 sites in 37 countries. They were randomly assigned 1:1:1 between April 2015 and January 2017 to receive pembrolizumab alone (n = 301), pembrolizumab with a platinum therapy (cisplatin or carboplatin) plus fluorouracil (n = 281), or cetuximab with a platinum therapy plus fluorouracil (n = 300). The primary endpoints of the trial were overall and progression-free survival in the intention-to-treat population, including analysis in patients with PD-L1 combined positive score (CPS) of ≥ 20 and ≥ 1.

Comparison of the two combination groups included only those patients in the cetuximab group who had been randomly assigned prior to closing of the pembrolizumab plus chemotherapy group (n = 278). Of patients receiving study chemotherapy, 57% of those receiving pembrolizumab and 56% to 57% of those receiving cetuximab received carboplatin. Among the 882 patients, CPS was ≥ 1 in 754 patients (85%) and ≥ 20 in 381 (43%).

Overall Survival

Median durations of follow-up were 11.5 months in the pembrolizumab monotherapy group, 13.0 months in the pembrolizumab plus chemotherapy group, and 10.7 months in the cetuximab plus chemotherapy group.

At second interim analysis, pembrolizumab alone improved overall survival vs cetuximab plus chemotherapy among patients with CPS ≥ 20 (median = 14.9 vs 10.7 months, hazard ratio [HR] = 0.61, P = .0007) and among patients with CPS ≥ 1 (median = 12.3 vs 10.3 months, HR = 0.78, P = .0086); it 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 also improved overall survival among patients with CPS ≥ 20 (median = 14.7 vs 11.0 months, HR = 0.60, P = .0004) and patients with CPS ≥1 (median = 13.6 vs 10.4 months, HR = 0.65, P < .0001) at final analysis.

Pembrolizumab plus chemotherapy improved overall survival vs cetuximab plus chemotherapy in the total study population as well (median = 13.0 vs 10.7 months, HR = 0.77, P = .0034) at second interim analysis.

Progression-Free Survival

At second interim analysis (final analysis of progression-free survival), compared with cetuximab plus chemotherapy, pembrolizumab alone did not improve progression-free survival in the CPS ≥ 20 population (median = 3.4 vs 5.0 months, HR = 0.99, P = .456) and no benefit was observed for pembrolizumab plus chemotherapy in the CPS ≥ 20 population (median = 5.8 vs 5.2 months, HR = 0.73, P =.016) or total population (median = 4.9 vs 5.1 months, HR = 0.92,  P = .170).

Responses

For pembrolizumab monotherapy vs cetuximab plus chemotherapy, objective response rates were 23% vs 36% in the CPS ≥ 20 population, 19% vs 35% in the CPS ≥ 1 population, and 17% vs 36% in the total population; 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, 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 monotherapy group (most common = anemia [5%]), 85% of the pembrolizumab plus chemotherapy group (most common = anemia [25%] and neutropenia [18%]), and 83% of the cetuximab plus chemotherapy group (most common = neutropenia [21%] and anemia [17%]). Potential immune-related adverse events of any grade occurred in 31%, 26%, and 24% of patients, respectively, and were grade ≥ 3 in 7%, 5%, and 10%. The most common were hypothyroidism (16% to 18%) in the two pembrolizumab groups and infusion reactions (9%) 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 treatment-related in 1%, 4%, and 3%.

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

Dr. Burtness, of the Department of Medicine and Yale Cancer Center, Yale University School of Medicine, is the corresponding author of The Lancet article.

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