Tosposertib (TGFβRI/VEGFR2 inhibitor) + pembrolizumab drives 75% ORR in 1L R/M HNSCC

Tosposertib (TU2218) is an oral dual TGFβRI/ALK5 and VEGFR2 inhibitor designed to counter TGF-β–mediated immune exclusion and angiogenesis, here combined with pembrolizumab (anti–PD-1) in an open-label, multicenter, non-randomized Phase IIa trial in PD-(L)1–naïve R/M HNSCC with PD-L1 CPS ≥1 (NCT05784688). As of December 31, 2025, 29 patients enrolled and 26 were efficacy-evaluable: ORR was 57.7% overall, including 2 CRs (7.7%); ORR was 75.0% in 1L (9/12; 1 CR) and 42.9% after ≥1 prior systemic therapy (6/14; 1 CR), with higher ORR in CPS ≥20 vs CPS 1–10 (66.7% vs 52.9%). Grade ≥3 TEAEs included rash (20.7%), mucosal inflammation (13.8%), and AST/ALT elevations (each 3.4%); 3 patients discontinued due to TEAEs and there were no treatment-related deaths—efficacy benchmarks in this setting for pembrolizumab-based 1L therapy are typically far lower for pembro monotherapy (ORR ~15–25% depending on CPS), while pembro + platinum/5-FU historically lands around ~35–40% ORR (KEYNOTE-048), so a 75% ORR signal (even at n=12) is well above what we’d expect with SOC.