Pembrolizumab as neoadjuvant and adjuvant therapy in combination with standard of care in resectable, locally advanced head and neck squamous cell carcinoma: Phase 3 KEYNOTE-689

Abstract Introduction: In phase 2 studies (NCT02296684 and NCT02641093), neoadjuvant and adjuvant pembrolizumab demonstrated pathologic response and acceptable safety in high-risk, resectable locally advanced (LA) head and neck squamous cell carcinoma (HNSCC). KEYNOTE-689 (NCT03765918) is a randomized, open-label, phase 3 trial designed to evaluate neoadjuvant pembrolizumab and adjuvant pembrolizumab plus standard of care (SOC) in previously untreated LA HNSCC. Materials and Methods: Eligible patients have histologically confirmed, newly diagnosed, resectable, LA HNSCC (stage III oropharyngeal p16-positive disease [T4 (N0-N2), M0]; stage III/IVA oropharyngeal p16-negative; or stage III/IVA laryngeal or hypopharyngeal disease or disease of the oral cavity, independent of p16 status), evaluable disease, newly obtained core or excisional biopsy, and ECOG performance status of 0 or 1. Approximately 704 patients will be randomly assigned 1:1 to arm A: neoadjuvant pembrolizumab 200 mg every 3 weeks (2 cycles), surgical resection, then adjuvant pembrolizumab 200 mg every 3 weeks (15 cycles) plus SOC or arm B: surgical resection then adjuvant SOC. SOC is adjuvant radiotherapy, 60 Gy total, 30 fractions for low-risk disease; adjuvant chemoradiation, 3 cycles of cisplatin 100 mg/m2 every 3 weeks plus 66 Gy total, 33 fractions for high-risk disease; adjuvant radiation, 70 Gy total, 35 fractions for gross residual disease. Randomization will be stratified by primary tumor site (oropharynx/oral cavity vs larynx vs hypopharynx), tumor stage (III vs IVA), and PD-L1 status (TPS ≥50% vs TPS <50%). Postoperative imaging will occur 12 weeks after completion of SOC treatment, every 3 months until year 3, then every 6 months until year 5. Dual primary end points are major pathologic response and event-free survival per RECIST v1.1. Secondary end points are overall survival, pathologic complete response, health-related quality-of-life, and safety. End points except safety will be evaluated in patients whose tumors express PD-L1 CPS ≥1 and regardless of PD-L1 status. Results: Recruitment is ongoing at sites in Asia, Australia, Europe, North America, and South America. Conclusions: Results of KEYNOTE-689 will elucidate the role of pembrolizumab as neoadjuvant therapy and adjuvant therapy plus SOC in patients with LA HNSCC. Citation Format: Arkadiy Klochikhin, Robert I. Haddad, Amichay Meirovitz, Sufia Safina, Irene Brana, Christophe Le Tourneau, Ravindra Uppaluri, Nancy Y. Lee, Ezra E. W. Cohen, Rebecca Chernock, William Westra, Hong Liu, Burak Gumuscu, Kimberly Benjamin, Douglas Adkins. Pembrolizumab as neoadjuvant and adjuvant therapy in combination with standard of care in resectable, locally advanced head and neck squamous cell carcinoma: Phase 3 KEYNOTE-689 [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-002.