NCE 401

The inactivation of endothelial cells induced by VEGF stimulation was completely ameliorated by TU2218, an effect not observed with vactosertib, which inhibits only TGFβ signaling. As another strategy, combination of anti-CTLA4 therapy and TU2218 resulted in high complete regression (CR) rates in CT26 and WEHI-164 tumor models. In particular, immunological memory generated by the combination of anti-CTLA4 and TU2218 in the CT26 model prevented the development of tumors after additional tumor cell transplantation, suggesting that the TU2218-based combination has therapeutic potential in immunotherapy.

The starting dose of TU2218 in combination with pembrolizumab was 105mg/day, with subsequent incremental doses of 150mg/day and 195mg/day. Conclusions TU2218, a first-in-class oral dual inhibitor against TGFβRI and VEGFR2, was well-tolerated in the monotherapy and will be subsequently investigated for the combination therapy with PD-L1.

This is a first-in-human study to investigate the safety and tolerability of TU2218 mono- and combination therapy with pembrolizumab. To date, clinical studies of TU2218 are ongoing. Conclusions TU2218, a first-in-class oral dual inhibitor against TGFβRI and VEGFR2, was well-tolerated in the monotherapy.

P1b/2a, N=142, Recruiting, TiumBio Co., Ltd. | Trial completion date: May 2024 --> Dec 2028 | Trial primary completion date: Dec 2023 --> Dec 2026

The restored level of ICAM-1 and VCAM-1 at 1 μM TU2218 was equivalent to the activity of combined treatment of 1 μM Vactosertib (ALK5 inhibitor) and 25 μg/ml Ramucirumab (VEGFR2 inhibitor). We conclude that TU2218 leads not only to the enhancement of T cell-traffic toward TME, but also to the conversion of immune balance favorable to anti-PD1 therapy. The Phase 1b trial of TU2218 combined with pembrolizumab is underway for advanced solid cancers (NCT05204862).