Based on the efficacy and safety data, the KEYNOTE-048 investigators point out that pembrolizumab plus platinum and 5-fluorouracil is an appropriate first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) and pembrolizumab monotherapy is an appropriate first-line treatment for PD-L1-positive recurrent or metastatic HNSCC. The study findings are published on 31 October 2019 in The Lancet.
Prof. Barbara Burtness of the Department of Medicine and Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA on behalf of study team wrote that KEYNOTE-048 was a randomised, phase III study in patients with untreated locally incurable recurrent or metastatic HNSCC. The study was conducted at 200 sites in 37 countries.
The study participants were stratified by PD-L1 expression, p16 status, and performance status. They were randomly allocated (1:1:1) to pembrolizumab alone, pembrolizumab plus a platinum and 5-fluorouracil (pembrolizumab with chemotherapy group), or cetuximab plus a platinum and 5-fluorouracil (cetuximab with chemotherapy group). Investigators and study participants were aware of treatment assignment. Investigators, participants, and representatives of the sponsor were masked to the PD-L1 combined positive score (CPS) results; PD-L1 positivity was not required for study entry.
Chemotherapy is a rational combination partner for immune checkpoint inhibitors in HNSCC because it disrupts tumour architecture potentially reducing immune exclusion, results in antigen shedding, and induces rapid disease control.
The study aimed to determine whether pembrolizumab as monotherapy or in combination with chemotherapy improves survival compared with cetuximab plus chemotherapy in patients with previously untreated recurrent or metastatic HNSCC. The primary endpoints were overall survival (OS) and progression-free survival (PFS) in the intention-to-treat population.
There were 14 primary hypotheses: superiority of pembrolizumab alone and of pembrolizumab with chemotherapy versus cetuximab with chemotherapy for OS and PFS in the PD-L1 CPS of 20 or more, CPS of 1 or more, and total populations and non-inferiority of pembrolizumab alone and pembrolizumab with chemotherapy versus cetuximab with chemotherapy for OS in the total population. The definitive findings for each hypothesis were obtained when statistical testing was completed for that hypothesis; this occurred at the second interim analysis for 11 hypotheses and at final analysis for 3 hypotheses. Safety was assessed in all participants who received at least one dose of allocated treatment.
Between April 2015 and January 2017, 882 patients were allocated to receive pembrolizumab alone (n=301), pembrolizumab with chemotherapy (n=281), or cetuximab with chemotherapy (n=300). Among these patients, 754 (85%) had CPS of 1 or more and 381 (43%) had CPS of 20 or more.
At the second interim analysis, pembrolizumab alone improved OS versus cetuximab with chemotherapy in the CPS of 20 or more population, median 14.9 months versus 10.7 months (hazard ratio [HR] 0.61, p = 0.0007) and CPS of 1 or more population, 12.3 months versus 10.3 months (HR 0.78, p = 0.0086) and was non-inferior in the total population, 11.6 months versus 10.7 months (HR 0.85).
Pembrolizumab with chemotherapy improved OS versus cetuximab with chemotherapy in the total population, 13.0 months versus10.7 months (HR 0.77, p = 0.0034) at the second interim analysis and in the CPS of 20 or more population, 14.7 months versus 11.0 months (HR 0.60, p = 0.0004) and CPS of 1 or more population, 13.6 months versus 10.4 months (HR 0.65, p < 0.0001) at final analysis.
Neither pembrolizumab alone nor pembrolizumab with chemotherapy improved PFS at the second interim analysis.
At final analysis, grade 3 or worse all-cause adverse events occurred in 164 (55%) of 300 treated patients in the pembrolizumab alone group, 235 (85%) of 276 in the pembrolizumab with chemotherapy group, and 239 (83%) of 287 in the cetuximab with chemotherapy group. Adverse events led to death in 25 (8%) patients in the pembrolizumab alone group, 32 (12%) in the pembrolizumab with chemotherapy group, and 28 (10%) in the cetuximab with chemotherapy group.
The authors concluded that first-line therapy with pembrolizumab monotherapy significantly improved OS in the PD-L1 CPS of 20 or more and CPS of 1 or more populations, had non-inferior OS in the total population, was associated with a substantially longer duration of response in all populations, and had a favourable safety profile compared with cetuximab with chemotherapy as first-line therapy for recurrent or metastatic advanced HNSCC. First-line therapy with pembrolizumab in combination with platinum and 5-fluorouracil significantly improved OS in the PD-L1 CPS of 20 or more, CPS of 1 or more, and total populations, was associated with a longer duration of response, and had a comparable safety profile versus cetuximab with chemotherapy.
The KEYNOTE-048 study of pembrolizumab given alone or in combination with a chemotherapy regimen of platinum and 5-fluorouracil establishes anti-PD-1-based therapy as a first-line treatment option for patients with locally incurable recurrent or metastatic HNSCC.
The study was funded by Merck Sharp & Dohme, a subsidiary of Merck & Co.
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. The Lancet; Published online 31 October 2019.DOI: https://doi.org/10.1016/S0140-6736(19)32591-7