Setanaxib Added to Pembrolizumab for Fibroblast-Rich, Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck: a Phase 2 Randomized Study

Abstract Purpose Efficacy of checkpoint inhibitors (e.g., pembrolizumab) in head and neck squamous cell carcinoma (HNSCC) is limited by cancer-associated fibroblasts (CAFs). This randomized, double-blind, placebo-controlled, phase 2 trial (NCT05323656) evaluated the efficacy and safety of the reactive oxygen species inhibitor setanaxib with pembrolizumab in patients with CAF-rich HNSCC. Patients and Methods Participants (≥18 years) with recurrent or metastatic HNSCC with CAF tumor levels ≥5% received setanaxib (800 mg orally bid) or placebo for ≤105 weeks, plus intravenous pembrolizumab (200 mg q3w). The primary outcome was best percentage change from baseline in tumor size. Secondary outcomes included progression-free survival (PFS), overall survival (OS), and changes in tumor levels of CAFs, CD8+ tumor-infiltrating lymphocytes (TILs), and FOXP3+ T-regulatory cells at week 9. Results Fifty-five participants (setanaxib, n = 27; placebo, n = 28) were treated. Least squares (LS) mean (SE) best percentage changes in tumor size from baseline values were –7.9% (9.3%) (setanaxib) and –12.9% (9.0%) (placebo) (LS mean difference [80% CI]: 5.1 [–11.9, 22.0]; P = 0.7008). PFS hazard ratio (HR) (80% CI) was 0.58 (0.38, 0.89), favoring setanaxib (P = 0.1023 [threshold <0.2]). OS HR (80% CI) was 0.45 (0.24, 0.85), also favoring setanaxib (P = 0.1057). Transcriptomic analyses identified a significant increase in CD8+ TILs with setanaxib (P = 0.037) but not placebo. There were 33 serious adverse events (16 setanaxib, 17 placebo), leading to four deaths (all placebo). Conclusions These improvements in PFS, OS, and CD8+ TILs can guide further setanaxib research in patients with solid tumors.