Phase 1 trial of TU2218, TGFβ-RI and VEGF-R2 dual inhibitor in monotherapy and combination with pembrolizumab in patients with advanced solid tumors.

2613 Background: Pembrolizumab interrupts PD-1/-L1 interaction and is efficacious in many cancers. However, resistance may emerge in some of the patients treated. VEGF and TGF-β pathways play an important role in the development and function of the tumor-microenvironment (TME), contributing to be the immunosuppressive. TU2218 is a highly potent, orally available dual inhibitor against TGFβ type I receptor (ALK5) and VEGFR2. This was a first-in-human study to investigate the safety and tolerability of TU2218 monotherapy and combination therapy with pembrolizumab. Methods: This non-randomized, open-label, multinational, multicenter study evaluated the safety, tolerability, PK, and preliminary efficacy of TU2218 alone and combination with pembrolizumab to determine the Recommended Phase 2 Dose of the Combination (RP2DC) in advanced solid tumors. Eligible patients were ≥ 18 years of age, ECOG performance status of 0 or 1 and had measurable lesion per RECIST 1.1. Part A of monotherapy was sequentially escalated to 6 dose levels of TU2218 ranging from 30 to 270 mg/day on a 2 weeks-on/1 week-off regimen using a BOIN design. In part B, patients received TU2218 doses of 105, 150 and 195 mg/day on a 2 weeks-on/1 week-off cycle in combination with pembrolizumab 200mg once every 3 weeks. Dose escalation followed a 3+3 design with a DLT evaluation period. Results: In the TU2218 monotherapy dosed BID (n=22), no Grade 3 or higher treatment related AE was reported, while all Grade 2 TRAEs were tolerable. Systemic exposure to TU2218 increased in a dose dependent manner. Following seven days of administration, TU2218 demonstrated reductions in PD markers and a correlation was observed between TU2218 exposure and the decrease of PD markers, particularly TGF-β1 (-16.5%) and CTGF (-45.4%) blood levels in groups of TU2218 Cmax ≥ 1.0 μM. Patients (n=12) received TU2218 at doses levels of 105 to 195mg/day in combination with pembrolizumab 200mg once every 3 weeks. The most frequently observed TRAE was pruritus (25%, n=3) and one patient experienced Grade 3 TRAE with maculo-papular rash (8.3%, n=1). No DLT was observed during the dose escalation and the MTD was not identified. The best ORR in the combination cohort demonstrated PR at 8.3% (n=1), SD 50% (n=6) and PD at 33% (n=4). The dose level at 195mg/day of TU2218 in combination with pembrolizumab was safe and tolerable. Conclusions: TU2218, a first-in-class oral dual inhibitor against TGFβRI and VEGFR2 was well-tolerated in the monotherapy and in the combination therapy with pembrolizumab. The RP2DC was established for subsequent trials in specific cancer types. Clinical trial information: Phase 1a: NCT05204862 / Phase 1b: NCT05784688 .