| 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.). © 2025 Massachusetts Medical Society. |
| Keywords: |
adult; controlled study; event free survival; aged; middle aged; clinical trial; fatigue; mortality; cisplatin; advanced cancer; diarrhea; adjuvant therapy; postoperative care; chemotherapy, adjuvant; neoadjuvant therapy; metabolism; progression free survival; multiple cycle treatment; neutrophil count; anemia; tumor volume; nausea; randomized controlled trial; vomiting; creatinine; pathology; radiation injury; monoclonal antibody; asthenia; pneumonia; pruritus; rash; alanine aminotransferase; aspartate aminotransferase; dysphagia; odynophagia; head and neck cancer; head and neck neoplasms; multicenter study; adjuvant chemotherapy; xerostomia; surgery; dermatitis; phase 3 clinical trial; leukocyte count; hyperthyroidism; hypothyroidism; drug therapy; adjuvant radiotherapy; good clinical practice; disease exacerbation; therapy; head and neck tumor; lymphocyte count; chemoradiotherapy; platelet count; mouth pain; dysgeusia; wart virus; human experiment; programmed death 1 ligand 1; pathological complete response; progression-free survival; head and neck squamous cell carcinoma; skin injury; decreased appetite; otolaryngology; thrush; hematology/oncology; antibodies, monoclonal, humanized; very elderly; intention to treat analysis; humans; human; male; female; article; pembrolizumab; squamous cell carcinoma of head and neck; cd274 protein, human; ecog performance status; immunological antineoplastic agent; antineoplastic agents, immunological; b7-h1 antigen; treatments in oncology; otolaryngology general
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