Background TU2218 is a highly potent, oral dual inhibitor against TGFβ type I receptor (TGFβRI/ALK5) and VEGFR2. VEGF and TGF-β pathways play important roles in the function of TME, especially in immune tolerance inextricably related with poor outcomes of anti-PD-(L)1 therapy. This is a first-in-human study to investigate the safety and tolerability of TU2218 mono- and combination therapy with pembrolizumab.
Methods This non-randomized, multinational, open-label study has been evaluating the safety, tolerability, PK, PD and preliminary efficacy of TU2218 mono- and combination therapy with pembrolizumab in advanced solid tumors. The eligible patients were aged ≥ 18 years, ECOG (0 or 1), and had measurable tumors per RECIST 1.1. TU2218 monotherapy was planned at 6 dose levels (30, 60, 105, 150, 195, 270 mg/day) with 2 weeks on and 1 week off in 3-week cycles according to the BOIN method. The starting dose of TU2218 given with pembrolizumab was determined after yielding TRAEs of at least Grade 2 in severity during monotherapy using the traditional 3+3 design.
Results Seventeen patients with advanced solid tumors received 5 different dose levels of monotherapy. Major demographics, treatment-related adverse events (TRAEs) and PK parameters are summarized in table 1.
No TRAEs of Grade 3 or higher were reported while all Grade 2 TRAEs were tolerable in TU2218 monotherapy. Systemic exposure to TU2218 increased over-proportionally with the dose-escalation. TU2218 showed reduction in PD marker of TGFβ, CTGF and PAI-1 after 7 days administration (figure 1) and correlation between TU2218 exposure (AUC) and PD markers of TGFβ and CTGF (P<0.05). 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.
Trial Registration This trial registered in clinicaltrials.gov. (NCT05204862)
Ethics Approval This study protocol, informed consent and all applicable information had been reviewed and approved by the IRB/ECs of the participating study indtitutions. (Salus IRB: Protocol Number TUC1PI-01, NXSAT21.72; Seoul National Univeraity Hospital Institutional Review Board Protocol Number TUC1PI-01, H-2203–016-1304; Institutional Review Board Asan Medical Center Protocol Number TUC1PI-01, 2022–0395)
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