The U.S. Food and Drug Administration approved pembrolizumab (Keytruda, Merck) for adult patients with resectable, locally advanced head and neck squamous cell carcinoma (HNSCC) whose tumors express PD-L1 with a Combined Positive Score (CPS) of 1 or higher, as determined by an FDA-approved test. This is the first FDA approval in HNSCC in six years and marks the first perioperative indication in this cancer type, supporting the use of pembrolizumab both before and after surgery.
The approval is based on results from the Phase 3 KEYNOTE-689 trial, a randomized, multicenter, open-label study involving 714 patients with Stage III to IVA resectable HNSCC. Patients were randomized to receive either neoadjuvant pembrolizumab (two cycles before surgery), followed by adjuvant pembrolizumab with radiotherapy (with or without cisplatin) and then monotherapy pembrolizumab for 12 additional cycles; or standard care without neoadjuvant therapy, followed by surgery and adjuvant radiotherapy with or without cisplatin. In both arms, patients received cisplatin with radiotherapy if high-risk pathological features such as positive surgical margins or extranodal extension were present.
The primary efficacy endpoint was event-free survival (EFS), defined as the time from randomization to disease progression precluding surgery, recurrence, or death from any cause. Among patients with PD-L1 CPS ≥1 tumors (n=682), median EFS was 59.7 months in the pembrolizumab arm compared to 29.6 months in the control arm. The hazard ratio was 0.70 (95% CI: 0.55 to 0.89), with a statistically significant p-value of 0.0014. Overall survival data were not yet mature, with 76% of prespecified events reached, but no adverse survival trends were noted.
The proportion of patients unable to proceed to surgery due to adverse reactions was 1.4% in both arms. The safety profile of pembrolizumab was consistent with previous findings, with known risks including immune-related adverse events, infusion-related reactions, and embryo-fetal toxicity.