FDA Grants Priority Review to Perioperative Pembrolizumab in Resectable HNSCC

The FDA has accepted and granted priority review to a supplemental biologics license application (sBLA) seeking the approval of pembrolizumab (Keytruda) as neoadjuvant treatment, then continued as adjuvant therapy in combination with standard-of-care radiotherapy with or without cisplatin, and then as monotherapy as maintenance for patients with resectable, locally advanced head and neck squamous cell carcinoma (HNSCC).1

A target action date of July 23, 2025, has been set by the FDA for the application under the Prescription Drug User Fee Act.

Topline findings from a prespecified first interim analysis of the phase 3 KEYNOTE-689 trial (NCT03765918)provided the basis for the sBLA.1,2Among patients with resectable locally advanced HNSCC, the perioperative pembrolizumab regimen generated a statistically significant and clinically meaningful improvement in event-free survival (EFS), as well as a significant improvement in the secondary end point of major pathological response (mPR) rate, vs adjuvant radiotherapy with or without cisplatin alone.

Notably, a trend toward improved overall survival (OS) was observed with pembrolizumab; however, statistical significance was not reached in patients with a PD-L1 combined positive score (CPS) of 10 or greater at the time of the analysis.2 OS will also be evaluated at the next interim analysis. Pembrolizumab’s safety profile was consistent with that observed in prior studies, and no new safety signals were reported.

These findings, which will be presented at an upcoming medical meeting, established KEYNOTE-689 as the first phase 3 trial to demonstrate a significant benefit with PD-1 inhibition in an intention-to-treat population with earlier-stage HNSCC, according to Merck.1

"The standard of care for patients with resectable locally advanced HNSCC has remained the same for over 2 decades, representing a significant unmet need for new treatment options,” Marjorie Green, MD, senior vice president and head of Late-Stage Oncology, Global Clinical Development, Merck Research Laboratories, stated in a news release. “Based on the compelling results of the KEYNOTE-689 trial, we hope to reduce the risk of recurrence and disease progression in earlier stages of disease. We look forward to working with the FDA to potentially bring [pembrolizumab] to these patients as soon as possible.”

According to previously reported data from 2 phase 2 trials (NCT02296684; NCT02641093), neoadjuvant pembrolizumab also demonstrated signals of efficacy and pathological response at the time of surgery in patients with high-risk, resectable, locally advanced HNSCC.3

Pembrolizumab is currently approved as monotherapy and in several combinations for patients with metastatic or unresectable, recurrent HNSCC in several countries, including the United States, Europe, China, and Japan.1

KEYNOTE-689 Overview

KEYNOTE-689 was a randomized, active-controlled, open-label trial evaluating neoadjuvant pembrolizumab followed by adjuvant pembrolizumab plus radiotherapy, with or without cisplatin, and maintenance pembrolizumab alone in patients 18 years of age or older with newly diagnosed, resectable stage III or IVA locally advanced HNSCC.

Eligible patients were required to have histologically confirmed, resectable, nonmetastatic squamous cell carcinoma that was either a stage III, T4, N0-2, M0, human papillomavirus (HPV)–positive oropharyngeal primary tumor; stage III or IVA HPV-negative oropharyngeal cancer; or stage III or IVA larynx/hypopharynx/oral cavity primary tumors.4 An ECOG performance status of 0 or 1 was also required.

The study’s primary end point was EFS. Secondary end points included OS, mPR rate, pathological complete response rate, and safety, all of which were stratified by PD-L1 CPS status.1

Approximately 704 patients were enrolled onto the study and randomly assigned 1:1 to receive either pembrolizumab or standard therapy. In the investigational arm, patients received 200 mg of intravenous (IV) pembrolizumab every 3 weeks for 2 cycles as neoadjuvant therapy, followed by adjuvant pembrolizumab every 3 weeks for 15 cycles plus standard radiotherapy. High-risk patients also received 100 mg/m² of IV cisplatin every 3 weeks for 3 cycles. In the control arm, patients did not receive neoadjuvant therapy prior to surgery. Following surgery, patients received adjuvant radiotherapy with or without cisplatin according to whether they had high- or low-risk disease, respectively.

References

1. FDA grants priority review to Merck’s application for KEYTRUDA® (pembrolizumab) plus standard of care as perioperative treatment for resectable locally advanced head and neck squamous cell carcinoma. News release. Merck. February 25, 2025. Accessed February 25, 2025. https://www.merck.com/news/fda-grants-priority-review-to-mercks-application-for-keytruda-pembrolizumab-plus-standard-of-care-as-perioperative-treatment-for-resectable-locally-advanced-head-and-neck-squamous-cel/
2. Merck’s Keytruda (pembrolizumab) met primary endpoint of event-free survival (EFS) as perioperative treatment regimen in patients with resected, locally advanced head and neck squamous cell carcinoma. News release. Merck. October 8, 2024. Accessed February 25, 2025. https://www.merck.com/news/mercks-keytruda-pembrolizumab-met-primary-endpoint-of-event-free-survival-efs-as-perioperative-treatment-regimen-in-patients-with-resected-locally-advanced-head-and-neck-squamous-c/
3. Uppaluri R, Lee NY, Westra W, et al. KEYNOTE-689: Phase 3 study of adjuvant and neoadjuvant pembrolizumab combined with standard of care (SOC) in patients with resectable, locally advanced head and neck squamous cell carcinoma. J Clin Oncol. 2019;37(suppl 15):TPS6090. doi:10.1200/JCO.2019.37.15_suppl.TPS609
4. 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 February 25, 2025. https://clinicaltrials.gov/study/NCT03765918