In 2016, the FDA approved PD-1 inhibition with either pembrolizumab or nivolumab for the second-line treatment of patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC), after progression on platinum-based chemotherapy. Now, data from KEYNOTE-048 demonstrate the efficacy of pembrolizumab in the frontline.

In this three-arm phase III trial, 882 patients received either standard-of-care (SoC) cetuximab plus chemotherapy (carboplatin or cisplatin and 5-fluorouracil), pembrolizumab alone or pembrolizumab plus chemotherapy. Patients were enrolled irrespective of tumour PD-L1 expression, but were stratified by PD-L1 combined positive score (CPS; ≥1% or ≥20%).

In the intention-to-treat population, pembrolizumab plus chemotherapy improved overall survival (OS) compared with SoC treatment (13.0 months versus 10.7 months; HR 0.77, 95% CI 0.63–0.93; P = 0.0034), and pembrolizumab monotherapy was non-inferior to the SoC regimen (median 11.6 months versus 10.7 months; HR 0.85, 95% CI 0.71–1.03). Pembrolizumab, with or without chemotherapy, improved OS in the CPS ≥1% and ≥20% subgroups, with hazard ratios of 0.60–0.78 and P values of <0.009; however, neither of these treatments improved progression-free survival. Interestingly, the median duration of response was ~23 months with pembrolizumab alone, regardless of CPS, compared with <7.1 months with this agent plus chemotherapy and ≤4.5 months with the SoC regimen. The impressive durability of responses in the monotherapy arm was offset by a considerably lower response rate (17% versus 36% in both chemotherapy arms).

These data supported two new FDA approvals of pembrolizumab for the frontline treatment of patients with recurrent and/or metastatic HNSCC, in combination with chemotherapy for all patients and as monotherapy for those with a CPS ≥1%. Notably, pembrolizumab monotherapy, the safest treatment (grade ≥3 adverse event rate 55% versus 83–85% with the chemotherapy combinations), might result in durable responses in ~20% of patients with PD-L1-positive HNSCC, although better biomarkers are needed to distinguish these patients from those who require additional chemotherapy.