Adnkronos Rome, April 30 (Adnkronos Salute) – In patients with head and neck cancer, immunotherapy with pembrolizumab, before and after surgery in addition to standard care, reduces the risk of recurrence or death by 27% compared to the standard care of radiotherapy alone (with or without chemotherapy) following surgery. This is demonstrated by the results of the phase 3 Keynote-689 study, presented for the first time in a plenary session at the 2025 Aacr (American Association for Cancer Research) Congress and selected for the official program of the scientific society's press conference.
The study evaluated pembrolizumab, Msd’s anti-PD-1 therapy, as a perioperative treatment regimen for patients with resected, locally advanced head and neck squamous cell carcinoma (La-Hnscc) of stage III or IV-A. Results from the first interim analysis of the study showed that pembrolizumab significantly improved survival free of EFS events (recurrence or death).
"In 2024, approximately 6 new cases of head and neck cancer were estimated in Italy," explains Lisa Licitra, head of Medical Oncology 3 Head and Neck Cancer at the Fondazione Irccs Istituto nazionale tumori di Milano. "They can affect different sites, including the oral cavity, pharynx, and larynx. The main risk factors are smoking, alcohol, and papillomavirus infection. Immunotherapy is already the standard of care in metastatic disease. In light of the data from the Keynote-689 study, immunotherapy can change clinical practice even in earlier stages that are candidates for surgery. In fact, it is the first positive study in over twenty years in patients with locally advanced squamous cell carcinoma of the head and neck."
These results "are significant and represent a turning point for these patients and for clinicians," the specialist emphasizes. "We are faced with a new therapeutic regimen that can offer the possibility of reducing the risk of recurrence and progression of the disease. The addition of immunotherapy with pembrolizumab to standard-of-care surgery and adjuvant radio(chemo)therapy has led to a significant reduction in the risk of events compared to the standard of care. In addition, thanks to the effect of preoperative therapy with pembolizumab, a reduction in the number of cases destined to receive postoperative treatment based on chemoradiotherapy has been observed. This de-escalation effect of postoperative treatment," Licitra explains, "is important because we know it has an impact on toxicities and, therefore, a favorable impact on the quality of life of patients."
In detail – as stated in a note – at the median follow-up of 38,3 months (range 9,0-66,5), treatment with pembrolizumab before surgery (neoadjuvant), then in combination with standard of care radiotherapy – Soc (with or without cisplatin) after surgery followed by pembrolizumab alone (adjuvant), reduced the risk of events (EFS) by 34% (Hr=0,66 [95% CI, 0,49-0,88]; p=.0022) in the Combined positive score (CPS) ≥10 population, by 30% (Hr=0,70 [95% CI, 0,55-0,89; p=.0014) in the population with CPS ≥1 and by 27% (Hr=0,73 [95% CI 0,58-0,92]; p=.0041) in the intent-to-treat (ITT) population, compared to adjuvant radiotherapy alone (with or without cisplatin) in the ITT population. In the Cps ≥10 population, the median EFS was 59,7 months in the pembrolizumab plus Soc group, standard of care, (95% CI, 41,1-not reached) versus 26,9 months (95% CI, 18,3-51,5) in the Soc group. In the Cps ≥1 population, the median EFS was 59,7 months (95% CI, 37,9-not reached) in the pembrolizumab plus Soc group versus 29,6 months (95% CI, 19,5-41,9) in the Soc group. In the ITT population, the median EFS was 51,8 months (95% CI, 37,5-not reached) in the pembrolizumab plus Soc group versus 30,4 months (95% CI, 21,8-50,1) in the Soc group. Soc. The safety profile of pembrolizumab was consistent with that observed in previous studies; no new safety signals were identified.
The study also showed a statistically significant improvement in major pathologic response rate, a key secondary endpoint, in patients with Cps ≥10, Cps ≥1, and the ITT population, compared to adjuvant radiotherapy alone. A trend toward improved overall survival (OS), another secondary endpoint, was observed in the Cps ≥10 population (HR=0,72 [95% CI 0,52-0,98]) at the time of the interim analysis for the pembrolizumab plus standard of care regimen compared to standard of care alone. The OS results did not reach statistical significance at the time of the interim analysis. Due to the hierarchy of statistical tests, no formal testing was performed in the Cps ≥1 and ITT populations. OS will be assessed in the next interim analysis.
“As the twelfth positive study of pembrolizumab in early-stage cancer,” said Marjorie Green, M.D., SVP and Head of Oncology, Global Clinical Development, MSD Research Laboratories, “the Keynote-689 results demonstrate our commitment to addressing an unmet clinical need. These exciting results demonstrate the potential of this regimen to change the landscape of care for certain patients facing this challenging disease. We are working with the FDA and global regulators to bring this new option to patients as soon as possible.” An additional biologics application for pembrolizumab based on data from the Keynote-689 study is currently under priority review by the Food and Drug Administration, with a Prescription Drug User Fee Act effective date, or targeted action, of June 23, 2025. Pembrolizumab is currently approved as monotherapy and in combination regimens for selected patients with unresectable metastatic or locally advanced HNSCC in the United States, Europe, China, Japan, and other countries.