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KEYNOTE‑689: perioperative pembrolizumab redefines curative-intent treatment in resectable LA‑HNSCC

The Phase III KEYNOTE‑689 trial (NCT03765918) presented compelling results at ASCO 2025 and AACR 2025, confirming that adding pembrolizumab to standard perioperative therapy significantly improves event-free survival (EFS) in resectable, locally advanced head and neck squamous cell carcinoma (LA‑HNSCC). This statistical and clinically meaningful benefit marks the first major advance in more than two decades for this patient population. 1–3

KEYNOTE‑689 enrolled 714 patients with stage III or IVA LA‑HNSCC, randomly assigning them 1:1 to receive neoadjuvant pembrolizumab followed by surgery, standardized postoperative radiotherapy with or without cisplatin, and adjuvant pembrolizumab; or to standard-of-care (SOC) alone. 2 In prespecified biomarker analyses, the trial demonstrated substantial EFS improvement in both intent-to-treat and PD-L1-enriched subgroups. Median EFS for the overall population increased from 30.4 months in the control arm to 51.8 months with pembrolizumab (HR 0.73; P=0.0041). 1,4 Among patients with PD-L1 combined positive score (CPS) ≥10, median EFS reached 59.7 months versus 26.9 months in the SOC arm (HR 0.66; P=0.0022); benefits were observed even in those with CPS ≥1 (HR 0.70; P=0.0014).1,2

Perioperative pembrolizumab also significantly increased rates of major pathologic response, with more patients achieving <10% viable tumor at resection compared to SOC. 1,4 Importantly, the addition of pembrolizumab did not impede surgical feasibility; rates of completed surgery and timely postoperative therapy were similar across both arms. 2,5

The safety profile was consistent with known pembrolizumab toxicities. Rates of treatment-related adverse events and grade 3 or higher events were comparable between arms; immune-mediated toxicities such as hypothyroidism occurred more frequently with pembrolizumab but were manageable. 6 No new safety signals emerged in this perioperative context. 7

The FDA granted accelerated approval for perioperative pembrolizumab in PD-L1–expressing LA‑HNSCC on June 12, 2025, marking its first perioperative indication in head and neck cancer. Regulatory review was supported by these robust EFS improvements and favorable surgical and safety findings. 8 Overall survival (OS) data from KEYNOTE‑689 remain immature and remain under active follow-up, but early trends hint at potential benefit. 5 Future analyses will explore long-term OS, recurrence patterns, and biomarker influences on response. 2

In summary, KEYNOTE‑689 establishes a new benchmark in the curative-management of resectable LA‑HNSCC, delivering unprecedented EFS gains, an acceptable safety profile, and unchanged surgical outcomes. Perioperative pembrolizumab is poised to redefine multidisciplinary care and treatment algorithms. Upcoming OS data and translational findings will refine patient selection and further guide clinical implementation.

References:

  1. Addition of perioperative pembrolizumab to standard of care in newly diagnosed locally advanced head and neck cancer. Ascopost.com. 2025. Available from: https://ascopost.com/issues/may-10-2025/addition-of-perioperative-pembrolizumab-to-standard-of-care-in-newly-diagnosed-locally-advanced-head-and-neck-cancer/
  2. Adkins D, Haddad RI, Tao Y, et al. Neoadjuvant and adjuvant pembrolizumab plus standard of care (SOC) in resectable locally advanced head and neck squamous cell carcinoma (LA HNSCC): Exploratory efficacy analyses of the phase 3 KEYNOTE-689 study. Journal of Clinical Oncology. 2025 Jun;43(16_suppl):6012–2
  3. Uppaluri R. KEYNOTE‑689 leads to FDA approval of perioperative pembrolizumab in HNSCC. Targeted Oncology. Jun 14, 2025.
  4. Immunotherapy before and after surgery improves outcomes in head and neck cancer | Dana-Farber Cancer Institute [Internet]. Dana-farber.org. 2025.Available from: https://www.dana-farber.org/newsroom/news-releases/2025/immunotherapy-before-and-after-surgery-improves-outcomes-in-head-and-neck-cancer   
  5. Gerlach A. Neoadjuvant Pembrolizumab May Redefine Standard of Care in Locally Advanced Head and Neck Cancer. Pharmacy Times. 2025. Available from: https://www.pharmacytimes.com/view/neoadjuvant-pembrolizumab-may-redefine-standard-of-care-in-locally-advanced-head-and-neck-cancer
  6. Serani S. Perioperative Pembrolizumab Betters Survival in Stage III/IV Head and Neck Cancer. Targeted Oncology. 2024. Available from: https://www.targetedonc.com/view/perioperative-pembrolizumab-betters-survival-in-stage-iii-iv-head-and-neck-cancer
  7. Merck press release. KEYNOTE‑689 is first Phase 3 anti‑PD‑1 therapy to significantly improve EFS in perioperative setting.
  8. P53 Inc. Amol Akhade: Insights on KEYNOTE-689 immunotherapy breakthrough in non-metastatic HNSCC at AACR 2025 – OncoDaily. Oncodaily – Oncology News, Insights, Stories. 2025. Available from: https://oncodaily.com/insight/keynote-689-283046