Abstract 825: Correlation of clinical and biomarker data in FGFR inhibitor failed metastatic cholangiocarcinoma patients with tumor response to tinengotinib

Abstract Background: Cholangiocarcinoma (CCA) patients (pts) harboring FGFR fusions treated with FGFR inhibitors (FGFRi) have shown clinical benefit, but often have progression in 5- 7 months. Secondary polyclonal mutations in the FGFR2 kinase domain (KD) may be a mechanism for acquired resistance to FGFRi. Tinengotinib, a spectrum-selective multi-kinase inhibitor with unique binding properties to FGFR2, potently inhibited FGFR2 KD mutations in pre-clinical models and exhibited antitumor activity in CCA pts. Here we present two cases of CCA pts treated with tinengotinib in a phase Ib/II trial. Methods: Biomarker samples were collected at baseline and C3D1 timepoints as an exploratory endpoint for pts receiving tinengotinib therapy. Efficacy was evaluated by RECIST v1.1. Tissue and blood samples were analyzed by FoundationOne® CDx and FoundationOne® Liquid CDx test, respectively, for FGFR alterations. Results: Two CCA pts received oral tinengotinib 12mg once daily continuously for 28-day cycles and completed biomarker sampling at baseline and C3D1. Both pts were previously treated with chemotherapy and pemigatinib. Pt A is a 28yr female with CCA metastatic to liver and bone. Tinengotinib was initiated in August 2021. The pt achieved a partial response (PR) with tumor reductions of 29.2%, 36% and 41.6% at C3D1, C4D1 and C5D1, respectively. Pt A was treated for 210 days, discontinuing due to radiographic disease progression following a 17-day dose interruption for suspected grade 3 TSH increase. The progression-free survival (PFS) was 6.9 months. Baseline biomarker data showed presence of KD mutations including: E565G/A, N549H, K659M and I548T. At C3D1, E565G had reduced from 1.36% to 0.09%, and there was disappearance of all other FGFR2 KD mutations. Pt B is a 40yr female with CCA metastatic to liver, lung and lymph nodes. Tinengotinib was initiated in August 2021. The pt achieved a PR with tumor reductions of 23.4% and 48.6% at C3D1 and C5D1, respectively. Pt B was on treatment for 181 days and discontinued due to progression in non-target lesions at C6D1, following a 23-day dose interruption for unrelated grade 3 ALT increase. PFS was 5.9 months. Baseline biomarker data showed presence of KD mutations including: E565A/G/K, V564L/I/F, N549K/T Conclusions: An inverse correlation between the presence of KD mutations and the response to tinengotinib treatment was observed in these two FGFRi relapsed/refractory metastatic CCA pts. This suggests tinengotinib may overcome acquired resistance to FGFRi in CCA pts. An ongoing randomized phase III study is investigating tinengotinib vs. chemotherapy in FGFRi refractory/relapsed CCA (NCT05948475). Clinical trial information: NCT04742959 Citation Format: Sarina A. Piha-Paul, Sanjay Goel, Chih-Yi Liao, Nashat Gabrail, Farshid Dayyani, Syed Kazmi, Sayeh Lavasani, Katie Hennessy, Hui Wang, Caixia Sun, Peng Peng, Jean Fan, Milind Javle. Correlation of clinical and biomarker data in FGFR inhibitor failed metastatic cholangiocarcinoma patients with tumor response to tinengotinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 825.