Perioperative Pembrolizumab Combo Improves EFS in Locally Advanced HNSCC

There were no new safety signals, and the safety profile of pembrolizumab was comparable with prior reports of the agent. Investigators plan to present results from KEYNOTE-689 at a future medical meeting and submit their data to regulatory authorities.

Administering pembrolizumab (Keytruda) as perioperative therapy reached the primary end point of event-free survival (EFS) among patients with stage III or IVA resected locally advanced head and neck squamous cell carcinoma (LA-HNSCC), according to a press release on findings from the phase 3 KEYNOTE-689 trial (NCT03765918).¹

Based on an independent data monitoring committee’s pre-specified interim analysis, a treatment regimen consisting of neoadjuvant pembrolizumab before surgery, adjuvant pembrolizumab plus standard radiotherapy with or without cisplatin, and pembrolizumab maintenance elicited a statistically significant and clinically meaningful EFS improvement compared with adjuvant radiotherapy alone. Data also showed a statistically significant major pathological response (mPR) improvement in the pembrolizumab arm.

Pembrolizumab-based treatment also produced a trend toward improved overall survival (OS) vs treatment in the comparator arm, although these data did not reach statistical significance among patients with a PD-L1 combined positive score (CPS) of 10 or higher at the time of analysis. Additionally, OS outcomes among those with a CPS of 1 or higher and the intent-to-treat population were not formally tested due to statistical testing hierarchy. The trial’s next interim analysis will include an evaluation of OS.

There were no new safety signals, and the safety profile of pembrolizumab was comparable with prior reports of the agent. Investigators plan to present results from KEYNOTE-689 at a future medical meeting and submit their data to regulatory authorities.

“These results are substantial, as KEYNOTE-689 marks the first positive trial in 2 decades for patients with resected, [LA-HNSCC],” Marjorie Green, MD, senior vice president and head of oncology, global clinical development at Merck Research Laboratories, said in the press release.¹ “These statistically significant and clinically meaningful findings have the potential to be practice-changing and continue to highlight the promising role of [pembrolizumab] for certain patients with earlier stages of disease.”

In the active-controlled, open-label KEYNOTE-689 trial, 704 patients were randomly assigned 1:1 to receive either pembrolizumab at 200 mg intravenously every 3 weeks for 2 cycles in the neoadjuvant setting or did not receive neoadjuvant therapy before undergoing surgery. After completing surgery, patients then received adjuvant pembrolizumab at 200 mg intravenously every 3 weeks for 15 cycles plus standard-of-care radiotherapy with or without cisplatin at 100 mg/m² intravenously every 3 weeks for 3 cycles or radiotherapy alone with or without cisplatin.

The trial’s primary end point was EFS. Secondary end points included OS, mPR, pathological complete response, and safety. Investigators also assessed global health status or quality of life based on responses to the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire.²

Patients 18 years and older with histologically confirmed resectable, non-metastatic, squamous cell carcinoma that is stage III human papillomavirus (HPV)–positive oropharyngeal primary disease; stage III or IVA oropharyngeal HPV-negative disease; or stage III or IVA larynx, hypopharynx, or oral cavity primary disease were eligible for enrollment on the trial. Other requirements for study entry included having eligibility to undergo surgery based on investigator discretion and local practice, evaluable tumor burden per RECIST v1.1 criteria, provision of newly obtained core or excisional biopsy of a tumor lesion not previously irradiated, and an ECOG performance status of 0 or 1.

Those with cancer outside of the oropharynx, larynx, hypopharynx, or oral cavity such as nasopharyngeal, sinus, other para-nasal, or other unknown primary head and neck cancer were ineligible for enrollment on the trial. Patients were also unable to enroll if they had received a live vaccine within 30 days before randomization.

References

1. 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 October 8, 2024. https://tinyurl.com/5yjmk2v6
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 April 16, 2024. Accessed October 8, 2024. https://tinyurl.com/4fhazr8p