Tinengotinib (TT-00420) in advanced/metastatic FGFR2-altered cholangiocarcinoma following prior chemotherapy and FGFR inhibitor treatment: Results from a phase II study (FIRST-08).

4133 Background: Subsequent treatment options for advanced cholangiocarcinoma (CCA) after failure of chemotherapy and FGFR inhibitors (FGFRi) are limited. Tinengotinib (TT-00420), a novel FGFRi, potently inhibited FGFR2 fusion/rearrangement and acquired resistant/FGFR2 kinase domain mutations. The FIRST-08 study is an open-label, multicenter Phase II study in Chinese patients (pts) with advanced/metastatic CCA (NCT06057571). Methods: Eligible pts with advanced/metastatic CCA harboring FGFR2 fusion or arrangement, who had failed prior chemotherapy and one FGFRi, received tinengotinib 10 mg orally once daily in 21-day cycles. The primary endpoint was objective response rate (ORR) per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints included progression free survival (PFS), disease control rate (DCR), duration of response (DoR), overall survival (OS), safety, PK and quality of life (QOL) per EORTC QLQ-C30. Results: As of June 27, 2025, 50 pts were enrolled (median age 56.5 years; 52.0% male; ECOG of 1: 44.0%). Median follow-up was 8.5 months. Forty percent had ≥ 3 prior systemic regimens, 66.0% had prior immunotherapy, and 42.0% had received other targeted therapies beyond FGFRi. The ORR by BICR was 28.0% (95%CI, 17.5~41.7) with 14 confirmed partial responses, and median DoR was 7.9 (5.6~ -) months. The disease control rate (DCR) was 82.0%. The median PFS was 5.7 (4.3~8.3) months. The median OS had not reached, with the 18 months survival rate 66.9% (47.3~80.6). Common Gr3/4 TRAEs (≥15%) included hypertension (42.0%), palmar-plantar erythrodysesthesia syndrome (16.0%), No Gr 5 TRAE was observed. 41 out of 50 pts had biomarker ctDNA samples collected at baseline, 82.9% pts had FGFR2 fusion and 48.8% had FGFR2 mutation (SNV). 28 pts had biomarker ctDNA samples collected at both baseline and C3D1. A significant decrease in maximum variant allele frequencies (MaxVAF) from baseline to C3D1 by a median relative VAF reduction of 83.7% (p<0.0001), indicating strong molecular response to tinengotinib. Conclusions: Tinengotinib demonstrated durable clinical anti-tumor activity and a manageable safety profile in heavily pretreated CCA pts with FGFR2 fusion/rearrangement following prior chemotherapy and FGFRi therapy. Clinical trial information: NCT06057571 . Efficacy outcomes by BICR and investigator. BICR Investigator ORR, % (95%CI) 28.0 (17.5~41.7) 20.0 (11.2~33.0) DCR, % (95%CI) 82.0 (69.2~90.2) 78.0 (64.8~87.3) mPFS, months (95%CI) 5.7 (4.3~8.3) 6.9 (4.3~8.5) mDoR, months (95%CI) 7.9 (5.6~ -) 6.6 (2.4~ -)