Pembrolizumab Earns FDA Priority Review in Locally Advanced HNSCC

Support for the supplemental biologics license application is based on phase 3 KEYNOTE-689 trial data.

The FDA has granted priority review to a supplemental biologics license application (sBLA) for pembrolizumab (Keytruda) as a neoadjuvant monotherapy and an adjuvant combination treatment with standard-of-care radiotherapy with or without cisplatin in patients with locally advanced head and neck squamous cell carcinoma (HNSCC), according to a news release from the drug’s developer, Merck.¹

The FDA has set a Prescription Drug User Fee Act (PDUFA) date of June 23, 2025.

Support for the decision is based on results from the phase 3 KEYNOTE-689 trial (NCT03765918). In patients with resectable locally advanced HNSCC, pembrolizumab-based treatment demonstrated a statistically significant and clinically meaningful improvement in event-free survival (EFS) vs adjuvant radiotherapy alone, meeting the study’s primary end point.

The study’s key secondary end point was met as well, with the investigational agent showing a statistically significant improvement in major pathological response (mPR) vs adjuvant radiotherapy alone. Furthermore, no new safety signals were identified on trial, and the safety profile of pembrolizumab was consistent with that observed in previously reported studies.

"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 oncology, global clinical development at Merck Research Laboratories, said in the press release.¹ “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.”

Patients who were treatment-naïve with newly diagnosed, stage III or IVA resectable, locally advanced HNSCC in the phase 3 KEYNOTE-689 trial (n = 704) were randomly assigned 1:1 to receive either pembrolizumab plus radiotherapy or radiotherapy alone. Patients in the investigational arm received 200 mg of intravenous pembrolizumab every 3 weeks for 2 cycles in the neoadjuvant setting, followed by 200 mg of intravenous pembrolizumab every 3 weeks for 15 cycles plus radiotherapy and 100 mg/m² of intravenous cisplatin every 3 weeks for 3 cycles for patients at a high risk––patients at a low risk received 200 mg of intravenous pembrolizumab every 3 weeks for 15 cycles plus radiotherapy.

Those treated in the radiotherapy alone arm received no neoadjuvant therapy. Following surgery, patients at a high risk received the same radiotherapy/cisplatin regimen without pembrolizumab, and patients at a low risk received radiotherapy without cisplatin.

The primary end point of the trial was EFS, and key secondary end points included overall survival, mPR, pathological complete response (pCR), and safety.

Patients 18 years and older with histologically confirmed, newly diagnosed, resectable, non-metastatic, squamous cell carcinoma eligible for primary surgery were included on the study.² Additionally, patients eligible for enrollment had evaluable tumor burden assessed by CT scan or MRI based on RECIST v1.1 criteria, had provided newly obtained core or excisional biopsy of a lesion not previously irradiated, and had an ECOG performance status score of 0 or 1 within 10 days of random assignment.

Patients with stage T4B or N3 locally advanced HNSCC or those with distant metastases were excluded from trial enrollment. Additionally, patients previously treated with an anti-PD1, anti–PD-L1, anti–PD-L2, or agent directed to another co-inhibitory T-cell receptor, as well as those who had received prior radiotherapy or systemic anti-cancer therapy, were ineligible for trial enrollment.

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://tinyurl.com/yeypvde6
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 February 25, 2025. https://tinyurl.com/4fhazr8p