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Neoadjuvant and Adjuvant Pembrolizumab in Locally Advanced Head and Neck Cancer

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Title: Neoadjuvant and Adjuvant Pembrolizumab in Locally Advanced Head and Neck Cancer
Authors: Uppaluri, Ravindra, Haddad, Robert I, Tao, Yungan, Le Tourneau, Christophe, Lee, Nancy Y, Westra, William, Chernock, Rebecca, Tahara, Makoto, Harrington, Kevin J, Klochikhin, Arkadiy L, Braña, Irene, Vasconcelos Alves, Gustavo, Hughes, Brett G M, Oliva, Marc, Pinto Figueiredo Lima, Iane, Ueda, Tsutomu, Rutkowski, Tomasz, Schroeder, Ursula, Mauz, Paul-Stefan, Fuereder, Thorsten, Laban, Simon, Oridate, Nobuhiko, Popovtzer, Aron, Mach, Nicolas, Korobko, Yevhen, Costa, Diogo Alpuim, Hooda-Nehra, Anupama, Rodriguez, Cristina P, Bell, R Bryan, Manschot, Cole, Benjamin, Kimberly, Gumuscu, Burak, Adkins, Douglas, KEYNOTE-689 Investigators
Source: New England Journal of Medicine. 393:37-50
Publisher Information: Massachusetts Medical Society, 2025.
Publication Year: 2025
Subject Terms: Adult, Male, Antibodies, Monoclonal, Humanized / adverse effects, Antibodies, Monoclonal, Humanized / administration & dosage, Young Adult, Chemotherapy, Adjuvant / methods, B7-H1 Antigen / analysis, B7-H1 Antigen / antagonists & inhibitors, Humans, Neoadjuvant Therapy / adverse effects, Antineoplastic Agents, Immunological / administration & dosage, Antineoplastic Agents, Immunological / adverse effects, Aged, Aged, 80 and over, Head and Neck Neoplasms / mortality, Head and Neck Neoplasms / pathology, Squamous Cell Carcinoma of Head and Neck / pathology, Middle Aged, Head and Neck Neoplasms / drug therapy, Neoadjuvant Therapy / methods, Progression-Free Survival, Squamous Cell Carcinoma of Head and Neck / surgery, Intention to Treat Analysis, B7-H1 Antigen / metabolism, Treatment Outcome, Head and Neck Neoplasms / surgery, Squamous Cell Carcinoma of Head and Neck / drug therapy, Female, Chemotherapy, Adjuvant / adverse effects, Squamous Cell Carcinoma of Head and Neck / mortality
Description: 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.).
Document Type: Article
File Description: application/pdf
Language: English
ISSN: 1533-4406
0028-4793
DOI: 10.1056/nejmoa2415434
Rights: URL: http://www.nejmgroup.org/legal/terms-of-use.htm
Accession Number: edsair.doi.dedup.....b3a4aab120e3fd20a4e5cb6dbc7829df
Database: OpenAIRE
Description
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.).
ISSN:15334406
00284793
DOI:10.1056/nejmoa2415434