FDA Approves Perioperative Pembrolizumab for Resectable, Locally Advanced HNSCC

FDA

The FDA has approved pembrolizumab (Keytruda) as a single agent as neoadjuvant treatment, continued as adjuvant treatment in combination with radiotherapy with or without cisplatin after surgery, and then as a single agent, for adult patients with resectable, locally advanced head and neck squamous cell carcinoma whose tumors express PD-L1 with a combined positive score (CPS) of at least 1, as determined by an FDA-approved test.1

This regulatory decision was supported by results from the phase 3 KEYNOTE-689 trial (NCT03765918), which demonstrated a statistically significant and clinically meaningful improvement in event-free survival (EFS) with perioperative pembrolizumab compared with standard-of-care (SOC) adjuvant radiotherapy with or without cisplatin alone.

Findings supporting the approval showed that among patients with PD-L1 CPS of at least 1 (n = 682), patients treated with the pembrolizumab regimen experienced a median event-free survival (EFS) of 59.7 months (95% CI, 37.9-not reached) compared with 29.6 months (95% CI, 19.5-41.9) for those given the control regimen (HR, 0.70; 95% CI, 0.55-0.89; P = .0014).

KEYNOTE-689 Trial Overview

KEYNOTE-689 was a global, randomized, open-label trial evaluating the efficacy and safety of perioperative pembrolizumab vs SOC therapy in patients with newly diagnosed, resectable, locally advanced stage III or IVA HNSCC.2 Eligible patients had not received prior systemic treatment for their disease and were considered appropriate candidates for surgery and subsequent adjuvant radiotherapy or chemoradiotherapy.

Patients were randomly assigned to receive either perioperative pembrolizumab—comprising neoadjuvant pembrolizumab, adjuvant pembrolizumab plus radiotherapy with or without cisplatin, and maintenance pembrolizumab—or SOC adjuvant radiotherapy with or without cisplatin. Treatment continued per protocol until completion of planned perioperative therapy or until disease progression, unacceptable toxicity, or withdrawal of consent.

The primary end point of the trial was EFS. Key secondary end points included mPR rate, overall survival (OS), and safety.

Additional Efficacy Findings

A numerical trend toward improved OS was observed in patients with a PD-L1 CPS of at least 10; however, statistical significance was not achieved, and formal testing in the population of patients with a CPS of at least 1 and the full intention-to-treat population was not performed per the hierarchical testing strategy. OS data will be evaluated at a future analysis.

Safety Profile of Pembrolizumab in HNSCC

The safety profile of perioperative pembrolizumab was consistent with previous studies of the agent, with no new safety signals observed. Additional safety and efficacy findings will be presented at an upcoming medical conference.

References

1. FDA approves neoadjuvant and adjuvant pembrolizumab for resectable locally advanced head and neck squamous cell carcinoma. FDA. June 12, 2025. Accessed June 12, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neoadjuvant-and-adjuvant-pembrolizumab-resectable-locally-advanced-head-and-neck
2. Study of pembrolizumab given prior to surgery and in combination with radiotherapy given post-surgery for advanced head and neck squamous cell carcinoma (MK-3475-689). ClinicalTrials.gov. Updated February 7, 2025. Accessed April 21, 2025. https://clinicaltrials.gov/study/NCT03765918