Liao, Chih-Yi

566 Background: FGFR inhibitors (FGFRi) have an established role in treating FGFR2-altered (alt) cholangiocarcinoma (CCA). Tinengotinib, a novel FGFRi, has shown promising activity overcoming acquired resistance to prior FGFRi. We present biomarker analyses evaluating tinengotinib’s ability to overcome prior FGFRi resistance and to elucidate mechanism of resistance to tinengotinib. Methods: Eligible patients (pts) with advanced/metastatic CCA who had received ≥ 1 prior systemic chemotherapy were treated with tinengotinib 10 mg daily across 4 Cohorts: A1: FGFR2 fusion (fus) with primary progressive disease (PD) on prior FGFRi; A2: FGFR2 fus with PD after prior response to FGFRi; B: FGFR alt without FGFR2 fus; C: FGFR wild-type. Efficacy was assessed by RECIST v1.1. All pts underwent liquid biopsy for circulating tumor DNA (ctDNA) at baseline; additional timepoints include cycle 3 day 1 (C3D1), time of PD, and end of treatment (EOT). Samples were analyzed using FoundationOne Liquid panel. Results: 27 out of 55 enrolled pts had biomarker samples collected at baseline and C3D1. Among them, pts in A1 (n=10, 107 mutations (mut)), B (n=8, 90 mut) and C (n=5, 74 mut) showed a significant decrease in short variant allele frequencies (VAF) from baseline to C3D1 by a median relative VAF reduction of 100% (p<0.0001) for each of the three cohorts. Although a median relative VAF reduction of 33.3% was seen in A2 (n=4, 15 mut), this was not significant (p=0.6093) likely due to low baseline mutation burden. A ≥50% reduction in ctDNA was associated with improved progression free survival (p<0.0014). Additionally, 100% of median relative reductions in FGFR2 kinase domain (KD) mut were seen in A1 and B (p<0.0001, 95% CI 100-100% and p=0.0156, 95% CI 83.6-100%, respectively), with 92% and 57% clearance of initial FGFR2 KD mut by C3D1. In a subgroup of 10 pts with biomarker sampling at baseline and EOT, 3 pts in A1 with acquired resistance showed emergence of novel FGFR2 mut, loss of FGFR-sensitive mut and new mut in alternate pathways (e.g., AKT, EGFR, RAS/MAPK) while retaining the original FGFR2 fus. 1 pt from B developed resistance due to new FGFR2 rearrangements and FGFR2 mut. 4 FGFR wild-type pts from C developed resistance involving mut in TP53, KRAS, and other oncogenic drivers. Conclusions: These findings provide genomic evidence that tinengotinib may overcome resistance to prior FGFRi treatment in FGFR2 fus-positive CCA, as reflected by significantly reductions in ctDNA VAFs and frequent clearance of FGFR2 KD mutations. The emergence of resistance alterations including de novo FGFR2 mutations and bypass pathways activations indicates acquired resistance that may limit long-term benefit. These results support further investigation with expanded biomarker sampling to better characterize resistance evolution and guide therapy optimization in an ongoing Phase 3 trial. Clinical trial information: NCT04919642 .

TPS4196 Background: Advanced BTC patients have poor prognosis. Up to 40% of BTCs have KRAS mutations and are associated with worse overall survival (OS). With a median OS of 7.7 months in KRAS wild-type compared to 1.7 months in KRAS mutated disease, these alterations are independent poor prognostic factors in BTC. Gemcitabine and cisplatin (GC) with or without immunotherapy are often used as 1st-line therapies. However, there is a lack of data on best 2nd-line regimens. mFOLFOX6 (5-fluorouracil [5-FU], leucovorin [LV], oxaliplatin) or liposomal irinotecan+5-FU+LV are options when no biomarkers are found (e.g., MSI-H, BRAFV600E, FGFR-fusions, IDH1-mutation, HER2-overexpression). Prior studies do not demonstrate benefit with MEK inhibitors (MEKi), but none of the studies had biomarker selection. Pre-clinical studies in BTC cell lines suggest synergy between MEKi and 5-FU. Thymidylate synthase (TS )levels induced by 5-FU are downregulated by addition of binimetinib. Early clinical studies show safety and tolerance of this combination. In this study, we will evaluate if the combination of mFOLFOX6+binimetinib improves OS for patients with BTC and MAPK mutations compared to mFOLFOX6 alone in 2nd-line therapy. Methods: EAY191-A6 is a treatment study arm of the NCI ComboMATCH master registration trial EAY191. The A6 trial has a randomized phase II design, enrolling a maximum of 66 patients. Patients with any MAPK pathway mutations except those with available therapies will be eligible. Patient must first enroll to the EAY191 master trial. Local molecular results may be used for enrollment. Submission of tissue at baseline is mandatory. Eligible patients will be randomized 1:1 to mFOLFOX6 vs mFOLFOX6 + binimetinib (45 mg oral twice a day every 14 days). Stratification factors include location and stage of disease. Primary efficacy analysis will compare OS in the intent-to-treat population. If the observed hazard ratio (HR) of experimental arm vs standard of care is < 0.545 (corresponding to an observed increase in OS by 5 months or longer), experimental treatment will be considered superior. An interim futility analysis at 50% of expected events will be conducted. If the observed HR is ≥ 1, experimental treatment will not be considered superior, and accrual maybe suspended. Secondary endpoints include progression-free survival, objective response rate, duration of response, disease control rate and toxicity of treatments. Exploratory objectives include prognostic modeling, correlations of genomic alterations with response or resistance and use of machine learning for outcome prediction. This study is active and open to accrual. Clinical trial information: NCT05564403 .