FDA Approves Pembrolizumab for Treatable Advanced Head and Neck Cancer

On June 12, 2025, the Food and Drug Administration (FDA) granted approval to pembrolizumab, marketed as Keytruda by Merck, for use in adults with resectable locally advanced head and neck squamous cell carcinoma (HNSCC). This approval is specifically for patients whose tumors express PD-L1 with a Combined Positive Score (CPS) of 1 or greater, as determined through an FDA-approved test. Pembrolizumab is authorized to be used as a neoadjuvant treatment on its own and continued as an adjuvant therapy in combination with radiotherapy, with or without cisplatin, following surgery. Subsequently, it is used as a single agent thereafter. This marks the first FDA approval for HNSCC in six years and represents the first-ever perioperative approval for locally advanced HNSCC.

The drug's efficacy was examined through the KEYNOTE-689 study (NCT02358031), a randomized, multicenter, open-label trial involving 714 patients diagnosed with resectable locally advanced HNSCC, classified as Stage III-IVA according to the AJCC 8th edition. Patients were assigned randomly in a 1:1 ratio to receive one of two treatment regimens: the first group received neoadjuvant pembrolizumab every three weeks for two cycles, followed by adjuvant pembrolizumab every three weeks for three cycles alongside radiotherapy, with or without cisplatin. After this, pembrolizumab was administered as a single agent every three weeks for 12 cycles. The second group did not receive neoadjuvant treatment before surgery but underwent adjuvant radiotherapy with or without cisplatin afterward. In both treatment groups, patients with high-risk pathological features, such as positive margins of less than 1 mm or extranodal extension observed during surgery, received cisplatin along with adjuvant radiotherapy.

The primary efficacy endpoint was event-free survival (EFS), assessed by blinded independent central review. EFS was defined as the duration from randomization to the first occurrence of any of the following events: disease progression that prevented definitive surgery, local or distant disease progression or recurrence, or death from any cause. Additional efficacy outcomes included overall survival (OS). For patients with tumors expressing PD-L1 CPS ≥1 (n=682), the median EFS was 59.7 months in the pembrolizumab group compared to 29.6 months in the control group, with a hazard ratio of 0.70, indicating a significant improvement in the pembrolizumab arm. At the time of the analysis, OS results were still maturing, with 76% of pre-specified deaths in the CPS ≥1 group, but no negative trend was observed.

Regarding safety, 1.4% of patients receiving neoadjuvant pembrolizumab were unable to undergo surgery due to adverse effects, a rate comparable to the control group. Pembrolizumab's prescribing information highlights warnings about immune-mediated adverse reactions, infusion-related reactions, and possible embryo-fetal toxicity. The adverse reactions observed were aligned with previous experiences with pembrolizumab.

The recommended dosage for pembrolizumab is 200 mg every three weeks or 400 mg every six weeks, and it should be administered before chemotherapy if given on the same day. This review was part of Project Orbis, an initiative from the FDA Oncology Center of Excellence, which allows for the simultaneous submission and evaluation of oncology drugs among international partners. For this review, the FDA collaborated with agencies in Australia, Brazil, Canada, and Switzerland. The application was also granted priority review status, designed to expedite the evaluation process for treatments addressing serious conditions.