Abstract CT285: KEYNOTE-689: A phase 3 study of neoadjuvant and adjuvant pembrolizumab plus standard of care (SOC) in locally advanced (LA) head and neck squamous cell carcinoma (HNSCC)

Abstract Background: In phase 2 studies (NCT02296684 and NCT02641093), neoadjuvant and adjuvant pembrolizumab demonstrated a pathological response (PR) and acceptable safety in patients with high-risk, resectable, LA HNSCC. KEYNOTE-689 (NCT03765918) is a randomized, open-label, phase 3 trial that will evaluate efficacy and safety of neoadjuvant pembrolizumab and adjuvant pembrolizumab in combination with SOC in patients with previously untreated LA HNSCC. Methods: Key eligibility criteria include histologically confirmed, newly diagnosed, resectable, nonmetastatic SCC (stage III oropharyngeal p16-positive disease [T4 (N0-N2), M0]; stage III/IVA oropharyngeal p16 negative; or stage III/IVA larynx or hypopharynx or oral cavity, independent of p16 status), evaluable tumor burden (measurable and/or nonmeasurable tumor lesions), newly obtained core or excisional biopsy, and ECOG performance status 0 or 1. Patients will be randomly assigned 1:1 to arms A and B. Randomization will be stratified by primary tumor site (oropharynx/oral cavity vs larynx vs hypopharynx), tumor stage (III vs IVA), and PD-L1 status defined by tumor proportion score 50% (TPS ≥50% vs TPS <50%). In arm A, patients will receive 200 mg Q3W neoadjuvant pembrolizumab for 2 cycles, followed by surgical resection, then 200 mg Q3W adjuvant pembrolizumab for 15 cycles in combination with SOC. In arm B, patients will undergo surgical resection followed by adjuvant SOC without pembrolizumab. SOC is radiotherapy alone (patients at low risk) or radiotherapy plus concurrent 100 mg/m2 Q3W cisplatin for 3 cycles (patients at high risk). Radiotherapy is standard fractionation at 2 Gy/fraction for 30, 33, or 35 fractions (60 Gy, 66 Gy, or 70 Gy) for patients at low risk or high risk or with gross residual disease, respectively. Treatment will continue until disease progression that is radiographically documented and verified by blinded independent central review, unacceptable toxicity, or investigator or patient decision to withdraw. Co-primary end points are major PR (≤10% invasive SCC within resected primary tumor and sampled regional lymph nodes per blinded central pathology) and event-free survival per RECIST 1.1 to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Secondary end points include overall survival, pathological complete response, health-related quality of life, and safety. All end points except safety will be evaluated in patients whose tumors express PD-L1 combined positive score ≥1 and in all patients regardless of tumor PD-L1 status. The first radiologic imaging in arm A will occur after 2 cycles of pembrolizumab and before surgery. Postoperative imaging will occur in both arms 12 weeks after SOC, then every 3 months until year 3 and every 6 months thereafter. Recruitment is ongoing; planned enrollment is ~704 patients. Citation Format: Nancy Y. Lee, Ravindra Uppaluri, William Westra, Ezra E. Cohen, Robert I. Haddad, Stephane Temam, Christophe Le Tourneau, Rebecca Chernock, Sufia Safina, Arkadiy Klochikhin, Amichay Meirovitz, Irene Brana, Joy Yang Ge, Ramona F. Swaby, Cecilia Pinheiro, Douglas Adkins. KEYNOTE-689: A phase 3 study of neoadjuvant and adjuvant pembrolizumab plus standard of care (SOC) in locally advanced (LA) head and neck squamous cell carcinoma (HNSCC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT285.