Fibroblast growth factor receptor (FGFR) inhibitors have become an important treatment option for patients with cholangiocarcinoma (CCA) harboring FGFR2 alterations. However, resistance to prior FGFR-targeted therapies remains a challenge. Tinengotinib, a novel FGFR inhibitor, has shown promising activity in overcoming resistance to prior FGFR-targeted therapies. This study, presented at ASCO GI 2026, focused on biomarker analyses from a phase 2 study (NCT04919642) to evaluate the ability of tinengotinib to address resistance to previous FGFR inhibitors and to further define mechanisms of resistance to tinengotinib itself.
Eligible patients with advanced or metastatic CCA with at least 1 prior systemic chemotherapy received tinengotinib 10 mg daily. Patients were stratified into 4 cohorts: A1 (FGFR2 fusion-positive with primary progressive disease on prior FGFR inhibitors), A2 (FGFR2 fusion-positive with progression after prior response to FGFR inhibitors), B (FGFR-altered without FGFR2 fusion), and C (FGFR wild-type). Efficacy was assessed using RECIST v1.1. Liquid biopsies for circulating tumor DNA (ctDNA) were collected at baseline, cycle 3 day 1 (C3D1), time of disease progression, and end of treatment (EOT). The FoundationOne Liquid panel was used to analyze samples.
Of the 29 patients enrolled in the trial overall, 27 had biomarker samples collected at baseline and C3D1. Patients in cohorts A1 (n=10; 107 mutations), B (n=8; 90 mutations), and C (n=5; 74 mutations) showed significant reductions in short variant allele frequencies (VAFs) from baseline to C3D1, with a median relative VAF reduction of 100% (P<.0001) in each cohort. In cohort A2 (n=4; 15 mutations), a median relative VAF reduction of 33.3% was observed but was not significant (P=.6093), perhaps due to low baseline mutation burden. A ≥50% reduction in ctDNA was associated with improved progression-free survival (P=.0014).
Median relative reductions of 100% in FGFR2 kinase domain (KD) mutations were observed in cohorts A1 and B (P<.0001, 95% CI, –100 to –100%; P=.0156, 95% CI, –100% to –83.6, respectively), with 92% and 57% clearance of FGFR2 initial KD mutations by C3D1.
In a subgroup of 10 patients sampled at baseline and EOT, resistance mechanisms were identified. Three patients in cohort A1 developed novel FGFR2 mutations, loss of FGFR-sensitive mutations, and new mutations in alternate pathways (e.g., AKT, EGFR, RAS/MAPK), while retaining the original FGFR2 fusion. Furthermore, 1 patient in cohort B developed resistance due to new FGFR2 rearrangements and mutations, and 4 patients in cohort C developed resistance involving TP53, KRAS, and other oncogenic drivers.
These findings provide genomic evidence that tinengotinib may overcome resistance to FGFR inhibitor resistance in FGFR2 fusion-positive CCA, with significant reductions in ctDNA VAFs and clearance of FGFR2 KD mutations. Emerging resistance alterations suggest that acquired resistance may limit long-term benefit and underscore the need for additional biomarker analyses in the ongoing phase 3 trial.
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