Phase IIa study of tosposertib, a dual TGFβRI and VEGFR2 inhibitor, in combination with pembrolizumab in recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC).

2635 Background: Tosposertib (TU2218) is a highly potent dual inhibitor of the transforming growth factor-β type I receptor (TGFβRI/ALK5) and vascular endothelial growth factor receptor 2 (VEGFR2), designed to simultaneously target immunosuppressive tumor microenvironment signaling and angiogenesis. This open-label, multicenter, non-randomized phase IIa trial evaluated the efficacy and safety of tosposertib in combination with pembrolizumab in patients with R/M HNSCC (NCT05784688). Methods: Eligible patients included anti–PD-(L)1–naïve patients with PD-L1 combined positive score (CPS) ≥1. Tosposertib (97.5 mg twice daily; 2 weeks on/1 week off) was administered orally in combination with pembrolizumab (200 mg intravenously every 3 weeks). Results: As of December 31, 2025, 29 patients (median age, 61 years; 76% male) had been enrolled, with a median follow-up duration of 6.0 months (range, 8–401 days). Primary tumor sites included the oral cavity (n=11, 37.9%), oropharynx (n=6, 20.7%), larynx (n=3, 10.3%), and nasal/paranasal regions (n=3, 10.3%). HPV positivity was observed in 13.8% (4/29) of patients. Among 26 efficacy-evaluable patients, responses were assessed by treatment line. In the first-line setting, 9 of 12 patients achieved an objective response (ORR, 75.0%), including 1 confirmed complete response (CR) and 8 partial responses (PRs; 6 confirmed, 2 unconfirmed). Among the 14 patients who had received at least one prior systemic therapy, the ORR was 42.9%, with 1 confirmed CR and 5 confirmed PRs. A numerically higher ORR was observed in patients with PD-L1 CPS ≥20 compared with those with CPS 1–10 (66.7% vs 52.9%). The most frequent any-grade treatment-emergent adverse events (TEAEs), (≥20%) [and ≥ Gr3 TEAEs], were rash (48.3% [20.7%]), mucosal inflammation (34.5% [13.8%]), pruritus (27.6% [3.4%]), weight loss (27.6% [0%]), and elevations in aspartate aminotransferase (AST; 20.7% [3.4%]) or alanine aminotransferase (ALT; 20.7% [3.4%]). Discontinuations due to TEAEs occurred in three patients. No treatment-related deaths were reported. Conclusions: Tosposertib in combination with pembrolizumab demonstrated a manageable safety profile and encouraging antitumor activity in patients with R/M HNSCC, with particularly robust efficacy observed in the first-line setting and a favorable trend in PD-L1–high tumors. Clinical trial information: NCT05784688 . Best overall response by subgroups. Best Overall ALL(n=26) Prior lines of therapy Prior lines of therapy PD-L1status, n (%) PD-L1status, n (%) Response, n (%) None(n=12) ≥1(n=14) CPS 1-19(n=17) CPS ≥20(n=9) Complete Response 2 (7.7) 1 (8.3) 1 (7.1) 1 (5.9) 1 (11.1) Partial Response 13 (50.0) 8 (66.7) 5 (35.7) 8 (47.1) 5 (55.6) Stable Disease 5 (19.2) 2 (16.7) 3 (21.4) 3 (17.6) 2 (22.2) Progressive Disease 6 (23.1) 1 (8.3) 5 (35.7) 5 (29.4) 1 (11.1) Response Rate (%) 57.7 75.0 42.9 52.9 66.7