FDA Approves Perioperative Pembrolizumab in Head and Neck SCC

This approval marks the first perioperative treatment OKed for treatment of HNSCC.

The FDA approved perioperative treatment with pembrolizumab (Keytruda) in resectable locally advanced head and neck squamous cell carcinoma (HNSCC) with PD-L1-expressing tumors, according to the agency.

The immunotherapy is approved to be used first as a single agent, then combined with radiotherapy in the adjuvant setting with or without cisplatin following surgery, followed by pembrolizumab monotherapy.

This approval marks the first in HNSCC in 6 years and is the first perioperative treatment approved for locally advanced disease.

The approval is based on findings from the randomized, multicenter, open-label KEYNOTE-689 trial (NCT03765918), in which 714 patients with resectable locally advanced HNSCC were randomly assigned 1:1 to 2 treatment arms. Patients received either neoadjuvant therapy at a 3-week interval for 2 cycles followed by adjuvant pembrolizumab at a 3-week interval for 3 cycles along with radiotherapy with or without cisplatin, and then pembrolizumab at a 3-week interval for 12 cycles; or no neoadjuvant treatment before surgery, followed by adjuvant radiotherapy with or without cisplatin.

If patients in either arm had high-risk pathological features, such as positive margins less than 1 mm or extranodal extension, at the time of surgery, they were given cisplatin with adjuvant radiotherapy.

Event-free survival (EFS), defined as time from randomization to the first occurrence of disease progression precluding definitive surgery, local or distant disease progression or recurrence, or death due to any cause, was the primary end point of the KEYNOTE-689 trial. The pembrolizumab regimen reduced the risk of disease progression or death by 30%.

Patients with PD-L1 expression with a combined positive score (CPS) of at least 1 had an EFS of 59.7 months (95% CI, 37.9-not reached [NR]) and 29.6 months (95% CI, 19.5-41.9) in the pembrolizumab and control arms, respectively (hazard ratio [HR], 0.70; 95% CI, 0.55-0.89; P = .00140).

A secondary end point of the trial was overall survival (OS). OS data were not mature at the time of analysis. However, with 76% of pre-specified deaths occurring in the population of patients with CPS of at least 1, no trend toward detriment is present.

In the neoadjuvant setting, 1.4% of patients who received pembrolizumab were unable to receive surgery because of adverse events, vs 1.4% of patients in the control arm. Patients’ experiences were consistent with prior findings on pembrolizumab.

The FDA recommends a dosage of 200 mg every 3 weeks or 400 mg every 6 weeks and requires that it be administered prior to chemotherapy if given on the same day.

Reference

FDA approves neoadjuvant and adjuvant pembrolizumab for resectable locally advanced head and neck squamous cell carcinoma. FDA. News release. 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