FDA Approves Perioperative Pembrolizumab in Resectable HNSCC

This article originally appeared on TargetedOncology^TM.

The FDA has granted approval to pembrolizumab (Keytruda; Merck) for the treatment of adult patients with resectable, locally advanced HNSCC whose tumors express PD-L1 with a CPS of ≥1, as determined by an FDA-approved test.¹ The approval covers use of pembrolizumab as a single agent in the neoadjuvant setting, followed by adjuvant treatment with pembrolizumab in combination with radiotherapy with or without cisplatin after surgery, and then continued as a single agent.

This decision is based on compelling evidence from the phase 3 KEYNOTE-689 trial, a global, randomized, open-label study that compared perioperative pembrolizumab to standard-of-care (SOC) adjuvant radiotherapy with or without cisplatin in 714 patients with newly diagnosed, resectable, locally advanced stage III or IVA HNSCC.² Patients eligible for the trial had not received prior systemic therapy and were deemed suitable candidates for surgery and subsequent adjuvant radiotherapy or chemoradiotherapy.

The KEYNOTE-689 trial demonstrated a statistically significant and clinically meaningful improvement in event-free survival (EFS), the trial’s primary end point, in the perioperative pembrolizumab arm compared with the SOC arm. For patients whose tumors express PD-L1 CPS ≥1 (n = 682), the median EFS was 59.7 months (95% CI, 37.9 to not reached [NR]) for those given pembrolizumab vs 29.6 months (95% CI, 19.5-41.9) for those in the control arm (HR, 0.70; 95% CI, 0.55-0.89]; P = .00140). ³

Further, a statistically significant improvement in major pathological response (mPR), a key secondary end point, was also observed in patients receiving pembrolizumab. The safety profile of pembrolizumab in this setting was consistent with previously reported studies, and no new safety signals were identified.

The approval covers use of pembrolizumab as a single agent in the neoadjuvant setting, followed by adjuvant treatment with pembrolizumab in combination with radiotherapy with or without cisplatin after surgery, and then continued as a single agent. | Image credit: wladimir1804-stock.adobe.com

“The current standard of care was established over 20 years ago, which, despite multimodality treatment, resulted in suboptimal outcomes. The KEYNOTE-689 results represent a dramatic improvement over the current standard of care. I think it is an exciting time for patients and all providers who take care of patients with head and neck cancer,” Ravindra Uppaluri, MD, PhD, told Targeted Oncology^TM, in an interview.

In the KEYNOTE-689 trial, patients were randomized to receive either perioperative pembrolizumab or SOC. The pembrolizumab regimen consisted of neoadjuvant pembrolizumab, followed by adjuvant pembrolizumab plus radiotherapy with or without cisplatin, and then maintenance pembrolizumab as a single agent. Treatment continued until completion of planned therapy, disease progression, unacceptable toxicity, or withdrawal of consent.

While a numerical trend toward improved overall survival (OS) was observed in patients with a PD-L1 CPS of ≥ 10, this did not reach statistical significance in the KEYNOTE-689 trial. Formal OS testing in the broader CPS ≥ 1 population and the full intention-to-treat population was not performed at this time, adhering to the study's pre-defined hierarchical testing strategy. While the OS results were not yet mature at this interim analysis (with 76% of pre-specified OS events having occurred in the CPS ≥ 1 population), there was no observed trend toward a detriment in OS. Further evaluation of OS data is planned for a future analysis.

The established safety profile of pembrolizumab was reinforced in this study, with no new safety concerns arising from the perioperative use in HNSCC. Specifically, the most common adverse events (≥ 20%) with pembrolizumab were stomatitis (48%), radiation skin injury (40%), weight loss (36%), fatigue (33%), dysphagia (29%), constipation (27%), hypothyroidism (26%), nausea (24%), rash (22%), dry mouth (22%), diarrhea (22%), and musculoskeletal pain (22%).

Among those given neoadjuvant pembrolizumab, 1.4% were unable to receive surgery due to adverse reactions vs 1.4% on the control arm. Additionally, the median duration of exposure to pembrolizumab in the neoadjuvant phase was 3.1 weeks (range, 1 day to 4.9 weeks), and the median duration of exposure to pembrolizumab in the adjuvant phase was 42 weeks (range, 1 day to 82 weeks).

Additional findings on safety and efficacy are expected to be presented at an upcoming medical conference.

The recommended dose of pembrolizumab has been set for 200 mg every 3 weeks or 400 mg every 6 weeks. In the press release from the FDA, they state that pembrolizumab should be administered prior to chemotherapy when given on the same day.¹

This approval marks a significant advancement in the treatment landscape for resectable, locally advanced HNSCC patients expressing PD-L1, offering a new perioperative treatment option with demonstrated benefits in event-free survival and pathological response.

“Moving forward, the KEYNOTE 689 new standard of care will clearly be beneficial for patients and really requires care team integration and discussion upfront in getting these therapeutics to patients and getting them to surgery,” added Uppaluri, chief of head and neck surgery at the Dana-Farber Brigham Cancer Center and chief of the otolaryngology group at the Brigham and Women's Hospital, in the interview.

References

1. FDA approves neoadjuvant and adjuvant pembrolizumab for resectable locally advanced head and neck squamous cell carcinoma. FDA. June 12, 2025. Accessed June 13, 2025. https://tinyurl.com/47aztrcp

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 June 13, 2025. https://clinicaltrials.gov/study/NCT03765918

3. FDA approves Keytruda (pembrolizumab) for PD-L1+ resectable locally advanced head & neck squamous cell carcinoma as neoadjuvant treatment, continued as adjuvant treatment combined with radiotherapy with or without cisplatin then as a single agent. News release. Merck. June 13, 2025. Accessed June 13, 2025. https://tinyurl.com/yc8fydme