1014P - Phase Ib trial results of safety, pharmacokinetics and pharmacodynamics of TU2218, TGFβ-RI and VEGF-R2 dual inhibitor in combination with pembrolizumab in patients with advanced solid tumors

Background

TU2218 is a low molecular weight kinase inhibitor against TGF-β1 (ALK5) and VEGF R2. VEGF and TGF-β pathways play an important role in TME, contributing immune evasion. TU2218 has shown synergistically antitumor effects in combination with PD-1and PD-L1.

Methods

This open-label, multinational, multicenter phase 1 trial assessed safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of TU2218 alone and in combination with pembrolizumab to establish RP2DC in advanced solid tumors. Eligible patients were aged ≥ 18 years, had an ECOG performance status of 0 or 1, and measurable lesions per RECIST 1.1. Phase 1a involved sequential escalation of monotherapy to six doses of TU2218 ranging from 30 to 270 mg/day. In Phase 1b, 3 to 6 patients received three doses of TU2218 105 to 195 mg/day on a 2 weeks-on/1 week-off given with pembrolizumab 200 mg Q3W using 3+3 design.

Results

In Phase 1a, TU2218 monotherapy dosed up to 270mg/day (n=22), no Grade 3 or higher treatment related AE was reported, while all Grade 2 TRAEs were tolerable. TU2218 demonstrated reductions of PD markers and correlation between TU2218 exposures and particularly TGF-β1 (-16.5%) and CTGF (-45.4%) in groups of TU2218 C_max≥1.0 μM. In Phase 1b, 3 to 6 Patients received TU2218 at three dose levels of 105 to 195mg/day given with pembrolizumab 200mg Q3W. Most frequently observed TRAEs was pruritus (25%) and one patient experienced Grade 3 TRAE with maculo-papular rash (8.3%). The MTD was not identified during dose escalation evaluation period. Systemic exposure to TU2218 increased in dose dependent manner. The reductions of PD markers were observed in CTGF (-59.7%) and TGF-β1(-46.3%) at TU2218 dose of 195mg/day (n=4). The best ORR of overall dose levels demonstrated PR at 17%, SD at 50% and PD at 25%. All dose levels of TU2218 up to 195mg/day given with pembrolizumab were safe and tolerable.

Conclusions

TU2218, a first-in-class dual inhibitor against TGFβ-RI and VEGF-R2 was safe and well-tolerated in combination with pembrolizumab. The Recommended Phase 2 Dose of the Combination (RP2DC) was established for subsequent trials in specific cancer types.

Clinical trial identification

Phase 1a (TUC1PI-01): NCT05204862; Phase 1b (TUC1PI-02): NCT05784688.

Editorial acknowledgement

Legal entity responsible for the study

TiumBio Co., Ltd.

Funding

TiumBio Co., Ltd.; Merck Sharp & Dohme Llc, a subsidiary of Merck & Co., Inc.

Disclosure

All authors have declared no conflicts of interest.