First-in-human phase I/II study of a highly selective FGFR2 inhibitor 3HP-2827 in patients with advanced solid tumors harboring <i>FGFR2</i> alterations.

3114 Background: Molecular profiling of cholangiocarcinoma (CCA) is highly recommended to guide access to targeted therapies such as FGFR2 inhibitors. 3HP-2827 is a highly selective and potent FGFR2 inhibitor targeting FGFR2 alterations. Here we report the findings of 3HP-2827 in advanced solid tumors harboring FGFR2 alterations. Methods: This is a phase I/II study to evaluate the safety, tolerability, PK, and preliminary efficacy of 3HP-2827 in pts with advanced solid tumors harboring FGFR2 alterations. Pts failed to standard therapy with/without prior pan-FGFR inhibitor (FGFRi) are eligible for enrollment. Bayesian Optimal Interval (BOIN) and back filling design were employed in the dose-escalation stage of phase I, followed with the expansion stage. Treatment-related adverse events (TRAEs), PK, and anti-tumor activity (RECIST v1.1) were assessed. Results: As of Jan 8, 2026, a total of 52 pts (46 with CCA, 6 with others) were enrolled from 12 centers, received 3HP-2827 at doses of 60-180 mg once daily (QD), including 42 with FGFR2 fusion/rearrangement (f/r), 6 with FGFR2 mutation. 19 pts (36.5%) had prior FGFRi. No dose-limiting toxicities (DLTs) were observed at the dose levels of 60 mg, 120 mg, 180 mg QD. 3HP-2827 had favorable PK with doses≥120 mg QD providing FGFR2 occupancy＞90%. The most common TRAEs were FGFR2 on-target toxicities including dry mouth (69.2%, G3 1.9%), nail toxicity (67.3%, G3 3.8%), stomatitis (50%, G3 3.8%), dry eyes (26.9%, G3 1.9%), PPE (19.2%, G3 3.8%). 12 pts (23.1%) experienced at least one G3/G4 TRAE and no G5 TRAEs occurred. 7 pts (13.5%) experienced at least one serious adverse event, 4 (7.7%) of them were considered related to 3HP-2827. No discontinued treatment or death due to TRAEs. Anti-tumor activities were observed from 60 mg QD. Among 15 CCA pts (FGFR2 f/r, FGFRi-naive) who had at least one post-treatment tumor assessment, objective response rate (ORR) was 80% (95% CI: 51.9, 95.7), and disease control rate (DCR) was 100% (95% CI: 78.2, 100). The ORR and DCR in 15 CCA pts (FGFR2 f/r, FGFRi-refractory) was 26.7% (95% CI: 7.8, 55.1) and 86.7% (95% CI: 59.5, 98.3). The ORR and DCR in 4 advanced solid tumor pts (FGFR2 mutation, FGFRi-naive) was 75% (95% CI: 19.4, 99.4) and 100% (95% CI: 39.8, 100). Conclusions: 3HP-2827 was found to be safe and tolerable, with encouraging anti-tumor activity observed in pts with FGFR2 alterations. Further clinical efficacy will be explored in the expansion stage and phase II stage. Clinical trial information: NCT06378593 .