Neoadjuvant and Adjuvant Pembrolizumab in Locally Advanced Head and Neck Cancer

Uppaluri, Ravindra M.D., Ph.D.
Haddad, Robert I. M.D.
Tao, Yungan M.D., Ph.D.
Le Tourneau, Christophe M.D., Ph.D.
Lee, Nancy Y. M.D.
Westra, William M.D.
Chernock, Rebecca M.D.
Tahara, Makoto M.D., Ph.D.
Harrington, Kevin J. M.B., B.S., Ph.D.
Klochikhin, Arkadiy L. M.D.
Braña, Irene M.D., Ph.D.
Alves, Gustavo Vasconcelos M.D.
Hughes, Brett G. M. M.D.
Oliva, Marc M.D., Ph.D.
Figueiredo Lima, Iane Pinto M.D.
Ueda, Tsutomu M.D., Ph.D.
Rutkowski, Tomasz M.D., Ph.D.
Schroeder, Ursula M.D.
Mauz, Paul-Stefan M.D.
Fuereder, Thorsten M.D.
Laban, Simon M.D.
Oridate, Nobuhiko M.D., Ph.D.
Popovtzer, Aron M.D.
Mach, Nicolas M.D.
Korobko, Yevhen M.D., Ph.D.
Costa, Diogo Alpuim M.D.
Hooda-Nehra, Anupama M.D.
Rodriguez, Cristina P. M.D.
Bell, Bryan R. M.D.
Manschot, Cole Ph.D.
Benjamin, Kimberly M.D.
Gumuscu, Burak M.D., Ph.D.
Adkins, Douglas M.D.

¹Brigham and Women's Hospital, Harvard Medical School, Boston
²Dana-Farber Cancer Institute, Boston
³Institut Gustave Roussy, Villejuif, France
⁴Institut Curie, Paris
⁵Memorial Sloan Kettering Cancer Center, New York
⁶Icahn School of Medicine at Mount Sinai Hospital, New York
⁷Washington University School of Medicine, St. Louis
⁸National Cancer Center Hospital East, Kashiwa, Japan
⁹Institute of Cancer Research, Royal Marsden Hospital, London
¹⁰State Budgetary Institution of Healthcare, Yaroslavl Oncological Hospital, Yaroslavl, Russia
¹¹Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona
¹²Centro Integrado de Pesquisa em Oncologia, Hospital Nossa Senhora de Conceição, Porto Alegre, Brazil
¹³Royal Brisbane and Women's Hospital, University of Queensland, Brisbane, Australia
¹⁴Institut Català d'Oncologia L'Hospitalet, Institut d'Investigació Biomèdica de Bellvitge, Barcelona
¹⁵Centro Regional Integrado de Oncologia, Fortaleza, Brazil
¹⁶Hiroshima University Hospital, Hiroshima, Japan
¹⁷Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, Gliwice, Poland
¹⁸Department of Otorhinolaryngology, University of Lübeck, Lübeck, Germany
¹⁹Department of Otolaryngology, Head and Neck Surgery, University Hospital Tübingen, Tübingen, Germany
²⁰Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna
²¹Department of Otorhinolaryngology and Head and Neck Surgery, Ulm University Medical Center and Comprehensive Cancer Center Ulm, Ulm, Germany
²²Yokohama City University School of Medicine, Yokohama, Japan
²³Hadassah Medical Center, Jerusalem
²⁴Geneva University Hospital, University of Geneva, Geneva
²⁵National Cancer Institute, Kyiv, Ukraine
²⁶Hospital CUF Descobertas, Lisbon, Portugal
²⁷Rutgers Cancer Institute, Newark, NJ
²⁸Division of Hematology-Oncology, Department of Medicine, Rutgers New Jersey Medical School, Newark
²⁹Fred Hutchinson Cancer Center, University of Washington, Seattle
³⁰Providence Cancer Institute, Earle A. Chiles Research Institute, Portland, OR
³¹Merck, Rahway, NJ
³²Robert Ebert and Greg Stubblefield Head and Neck Tumor Center at Washington University School of Medicine, Alvin J. Siteman Cancer Center, and Barnes-Jewish Hospital, St. Louis

Dr. Uppaluri can be contacted at [email protected] or at Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115.

^*A complete list of the principal investigators in the KEYNOTE-689 trial is provided in the Supplementary Appendix, available at NEJM.org.

Supported by Merck Sharp and Dohme, a subsidiary of Merck (Rahway, NJ).

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This article was published on June 18, 2025, at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

New England Journal of Medicine 393(1):p 37-50, July 3, 2025. | DOI: 10.1056/NEJMoa2415434

Abstract

Background

The benefit of the addition of perioperative pembrolizumab to standard care with surgery and adjuvant therapy for patients with locally advanced head and neck squamous-cell carcinoma (HNSCC) is unclear.

Methods

In this phase 3, open-label trial, we randomly assigned participants with locally advanced HNSCC in a 1:1 ratio to receive 2 cycles of neoadjuvant pembrolizumab and 15 cycles of adjuvant pembrolizumab (both at a dose of 200 mg every 3 weeks) in addition to standard care (pembrolizumab group) or standard care alone (control group). Standard care was surgery and adjuvant radiotherapy with or without concomitant cisplatin. The primary end point was event-free survival, sequentially assessed in participants whose tumors expressed programmed death ligand 1 (PD-L1) with a combined positive score (CPS) of 10 or more (CPS-10 population), participants whose tumors expressed PD-L1 with a CPS of 1 or more (CPS-1 population), and all the participants. A higher CPS indicates a higher proportion of cells that express PD-L1.

Results

A total of 363 participants (234 with a CPS of ≥10 and 347 with a CPS of ≥1) were assigned to the pembrolizumab group and 351 (231 with a CPS of ≥10 and 335 with a CPS of ≥1) to the control group. Surgery was completed in approximately 88% of the participants in each group. At the first interim analysis, the median follow-up was 38.3 months. Event-free survival at 36 months was 59.8% in the pembrolizumab group and 45.9% in the control group (hazard ratio for progression, recurrence, or death, 0.66; 95% confidence interval [CI], 0.49 to 0.88; two-sided P=0.004) in the CPS-10 population; 58.2% and 44.9%, respectively (hazard ratio, 0.70; 95% CI, 0.55 to 0.89; two-sided P=0.003), in the CPS-1 population; and 57.6% and 46.4%, respectively (hazard ratio, 0.73; 95% CI, 0.58 to 0.92; two-sided P=0.008), in the total population. Grade 3 or higher treatment-related adverse events occurred in 44.6% of the participants in the pembrolizumab group and in 42.9% of those in the control group, including death in 1.1% and 0.3%, respectively. Potentially immune-mediated adverse events of grade 3 or higher occurred in 10.0% of the participants in the pembrolizumab group.

Conclusions

The addition of neoadjuvant and adjuvant pembrolizumab to standard care significantly improved event-free survival among participants with locally advanced HNSCC. Neoadjuvant pembrolizumab did not affect the likelihood of surgical completion. No new safety signals were identified. (Funded by Merck Sharp and Dohme, a subsidiary of Merck [Rahway, NJ]; KEYNOTE-689 ClinicalTrials.gov number, NCT03765918.)

Pembrolizumab in Head and Neck Cancer

In a phase 3 trial, the addition of neoadjuvant and adjuvant pembrolizumab to standard care improved event-free survival among participants with locally advanced head and neck cancer without affecting surgical outcomes.