In an interim analysis of a phase III trial (KEYNOTE-689) reported in The New England Journal of Medicine, Uppaluri et al examined the survival benefit of adding perioperative pembrolizumab to standard care in patients with locally advanced head and neck squamous cell carcinoma.
Study Details
In the international open-label trial, 714 patients were randomly assigned between December 2018 and October 2023 to receive 2 cycles of neoadjuvant pembrolizumab and 15 cycles of adjuvant pembrolizumab at 200 mg every 3 weeks in addition to standard care (n = 363) or standard care alone (n = 351); standard care included surgery and adjuvant radiotherapy with or without concomitant cisplatin. The primary endpoint was event-free survival, sequentially assessed in patients with PD-L1 expression with a combined positive score (CPS) of 10 or more (CPS-10 population), PD-L1 with a CPS of 1 or more (CPS-1 population), and all patients.
Key Findings
Among 363 patients in the pembrolizumab group, 234 had a CPS of 10 or more and 347 had a CPS of 1 or more. Among 351 patients in the standard care group, 231 had a CPS of 10 or more and 335 had a CPS of 1 or more.
Surgery was completed in 88.4% of the pembrolizumab group after neoadjuvant treatment and 87.7% of the standard care group. Surgery was delayed in 38 patients receiving neoadjuvant pembrolizumab and 10 in the standard care group. The median time from the end of neoadjuvant therapy to surgery was 3.0 weeks in the pembrolizumab group, and the median time from randomization to surgery was 1.9 weeks in the standard care group.
At the first interim analysis, median follow-up was 38.3 months (range = 9.0–66.5 months). Event-free survival at 36 months was 59.8% in the pembrolizumab group vs 45.9% in the control group in the CPS-10 population (hazard ratio [HR] = 0.66, 95% confidence interval [CI] = 0.49–0.88, P = .004); 58.2% vs 44.9% in the CPS-1 population (HR = 0.70, 95% CI = 0.55–0.89, P = .003); and 57.6% vs 46.4% in the total population (HR = 0.73, 95% CI = 0.58–0.92, P = .008).
Grade ≥ 3 treatment-related adverse events occurred in 44.6% of the pembrolizumab group and 42.9% of the standard care group; the most common adverse events were stomatitis (11.6%), decreased lymphocytes (5.5%), and decreased neutrophils (5.3%) in the pembrolizumab group and stomatitis (13.3%), decreased neutrophils (11.7%), and decreased white blood cells (8.9%) in the standard care group. Treatment-related serious adverse events were reported in 19.1% vs 10.5%. Immune-mediated adverse events of grade 3 or higher were seen in 10.0% of the pembrolizumab group, including pneumonitis in six patients. There were four treatment-related deaths in the pembrolizumab group (from renal failure, COVID-19–related pneumonia, pneumonitis, and unknown cause) and one in the standard care group (from acute kidney injury).
Ravindra Uppaluri, MD, PhD
The investigators concluded: “The addition of neoadjuvant and adjuvant pembrolizumab to standard care significantly improved event-free survival among participants with locally advanced [head and neck squamous cell carcinoma]. Neoadjuvant pembrolizumab did not affect the likelihood of surgical completion. No new safety signals were identified.”
Ravindra Uppaluri, MD, PhD, of Brigham and Women’s Hospital, Boston, is the corresponding author of The New England Journal of Medicine article.
Disclosure: The study was funded by Merck Sharp and Dohme, a subsidiary of Merck. For full disclosures of all study authors, visit The New England Journal of Medicine.
