INDUCE-3: A Randomized Phase II/III Study of First-line Feladilimab plus Pembrolizumab in Patients with Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma

Purpose: Feladilimab, an inducible T-cell co‑stimulatory receptor agonist, demonstrated clinical activity in combination with pembrolizumab in a Phase I head and neck squamous cell carcinoma (HNSCC) expansion cohort, prompting further evaluation in patients in this setting. Patients and methods: INDUCE-3 (NCT04128696) was a randomized, double-blind, Phase II/III study in first-line programmed death-ligand 1-positive recurrent and/or metastatic HNSCC patients. A 2-in-1 adaptive design was implemented, with an option to expand the Phase II study into a Phase III confirmatory study. Patients were randomized 1:1 to receive feladilimab plus pembrolizumab or placebo plus pembrolizumab; up to 35 cycles of treatment for approximately 2 years. Primary endpoints were overall survival (OS) and investigator-assessed progression-free survival (PFS). Results: The study enrolled 315 patients. Following review of unblinded interim data in 140 patients, an Independent Data Monitoring Committee recommended stopping patient accrual based on prespecified criteria. Existing patients discontinued feladilimab or placebo. Pembrolizumab treatment continued until prespecified stopping criteria were met. This study demonstrated no evidence of an effect in favor of feladilimab plus pembrolizumab, with an adjusted HR of 1.51 for OS and 1.40 for PFS (median OS: 44.1 weeks [95% confidence interval (CI): 35.9-NA]; median PFS: 10.1 weeks [95% CI: 9.1-15.0]) versus placebo plus pembrolizumab (median OS: not reached; median PFS: 16.0 weeks [95% CI: 14.3-26.1]). The incidence of treatment-related adverse events was higher in the placebo group. Conclusions: This analysis does not support the combination of feladilimab plus pembrolizumab due to lack of superiority over placebo plus pembrolizumab.