AACR 2025: Neoadjuvant and adjuvant Pembrolizumab to Standard of Care Improves Outcomes in Newly Diagnosed Head and Neck Cancer

Results from a randomized, active-controlled, open-label phase 3 clinical trial presented at the annual meeting of the American Association for Cancer Research (AACR), held April 25-30, 2025 in Chicago, Illinois, demonstrate that pembrolizumab (Keytruda®; Merck & Co/MSD) given before and after surgery to supplement adjuvant therapy improved responses and survival in patients with previously untreated, locally advanced head and neck squamous cell carcinoma (HNSCC).*

“Typically, many patients with newly diagnosed HNSCC undergo surgery, followed by radiation with or without chemotherapy,” explained study presenter Ravindra Uppaluri, MD, Ph.D, the Brigham and Women’s Hospital Endowed Chair in Otolaryngology and director of head and neck surgical oncology at the Dana-Farber Brigham Cancer Center, and an associate professor of Otolaryngology/Head and Neck Surgery at Harvard Medical School.

“This paradigm has been in place for more than two decades, and unfortunately outcomes for many patients continue to be unsatisfactory,” he said.

Immunotherapy can provide benefit both when tumors are initially diagnosed and in the setting of minimal residual disease after initial treatment.

“Before surgery, when tumor burden and antigen load are high, immunotherapy can enhance immune responses and start to act on tumor killing,” Uppaluri continued.

After standard-of-care treatment, immunotherapy can address any leftover cancer cells that may still be present,” Uppaluri said.

“Working with Douglas Adkins, MD, of Washington University School of Medicine, we had previously shown in a phase 2 trial that perioperative pembrolizumab was safe and led to intriguing clinical responses in surgically treated head and neck cancer patients.”

In the phase 3 KEYNOTE-689 trial, Uppaluri and colleagues sought to test whether adding immunotherapy to the current standard-of-care approach could protect against recurrence. In the randomized, active-controlled, open-label study, the investigators enrolled 714 patients with stage 3-4 HNSCC (including in the larynx, hypopharynx, and oral cavity).

All participating patients underwent surgery and then received pathology-directed adjuvant therapy, and 363 of these patients were randomized to receive before and after surgery. The primary endpoint was event-free survival (recurrence or death) and the secondary endpoints were major pathologic response (mPR) rate, defined as 90% or more tumor reduction, and overall survival.

With half of patients having at least 38.3 months of follow-up, patients treated with pembrolizumab were at least 27% less likely to have experienced recurrence. Patients who received pembrolizumab were more likely to have an mPR compared to those who did not receive pembrolizumab, and both survival and mPR benefits were observed more frequently in patients whose tumors expressed PD-L1.

Tumors with high PD-L1 expression, defined by a combined positive score of 10 or more, were associated with a 13.7% increase in mPR rate prior to surgery, and were 34% less likely to recur.

Adverse events
Treatment-related adverse events grade 3 and higher occurred at similar rates in both arms of the study with four and one deaths in the pembrolizumab versus standard-of-care groups, respectively. Grade 3 or higher otentially immune-mediated adverse events occurred in 10% of participants in the pembrolizumab group, including one grade 5 event of pneumonitis.

“Hundreds of patients all over the world participated in this important trial and implementing their contribution to changing the current standard of care is a major goal,” Uppaluri said.

“This new information supports changing the current standard of care to now include neoadjuvant and adjuvant pembrolizumab. For the first time in more than 20 years, patients with this challenging disease have a new therapeutic approach,” he added.

Moving forward, Uppaluri wants to improve the implementation of this strategy.

“Now that we know this is a safe approach, we can start thinking about how we can potentially modify surgery and/or the adjuvant therapy to try to reduce the challenges patients face from the side effects of our treatments,” Uppaluri concluded.

Study limitation
A limitation of this study is the lack of analysis regarding the relative contribution of the neoadjuvant and adjuvant components to the positive result of the trial. While both phases of immunotherapy treatment could have impacted antitumor immune responses, the contribution of each phase to the observed clinical outcomes was not determined.

The study was funded by Merck & Co, Inc.

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Note: * Standard of Care (SOC) included surgery and postoperative radiotherapy [PORT] with or without concurrent chemotherapy.

Clinical trials
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 ID NCT03765918

Highlights of prescribing information
Pembrolizumab (Keytruda®; Merck & Co/MSD)[Prescribing Information]

Reference
[1] Uppaluri R, Haddad RI, Tao Y, Le Tourneau C, Lee NY, Westra W, Chernock R, Tahara M, Harrington K, Klochikhin AL, Braña I, Vasconcelos Alves G, Hughes BGM, Oliva M, Figueiredo Lima IP, Ueda T, Rutkowski T, Schroeder U, Mauz PS, Fuereder T, Laban S, Oridate N, Popovtzer A, Mach N, Korobko Y, Alpuim Costa D, Hooda-Nehra A, Rodriguez CP, Bryan Bell R, Manschot C, Benjamin K, Gumuscu B, Adkins  D. Neoadjuvant and adjuvant pembrolizumab plus standard of care (SOC) in resectable locally advanced head and neck squamous cell carcinoma (LA HNSCC): Phase 3 KEYNOTE-689 study. In: Proceedings of the 116th Annual Meeting of the American Association for Cancer Research; 2025 April 25-30; Chicago, IL.: AACR; 2025. Abstract nr CT001

Featured image: American Association for Cancer Research (AACR). Photo courtesy 2016 – 2025 © AACR/Todd Buchanan. Used with permission.

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