Tinengotinib in patients with advanced, metastatic cholangiocarcinoma: Overall survival results and biomarker correlative analysis from a phase 2 clinical trial.
Authors: Fountzilas Christos , Liao Chih-Yi , Pelster Meredith , Li Daneng , Deming Dustin A. , Sahai Vaibhav , Kankeu Fonkoua Lionel Aurelien , Cohn Allen Lee , Mantry Parvez , Richards Donald A. , Kingsley Ed , Wu Frank , Peng Peng , Hennessy Katie , Wang Hui , Shan Yujun , Sun Caixia , Fan Jean , Javle Milind M. , Mahipal Amit 
Published: January 2025

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Background:
Tinengotinib, a spectrum-selective multi-kinase inhibitor with unique binding properties to
FGFR
, potently inhibited
FGFR2
fusion/rearrangement and acquired resistant/gatekeeper mutations in pre-clinical models and exhibited antitumor activity in cholangiocarcinoma (CCA) patients (pts) in phase 1/2 trials. Here we present the overall survival (OS) data and biomarker correlative analysis from a phase 2 clinical trial of tinengotinib in CCA.
Methods:
Eligible pts with advanced/metastatic CCA who had received ≥ 1 prior systemic chemotherapy with ECOG PS 0-1 were treated with tinengotinib 10 mg QD across four Cohorts: A1:
FGFR2
fusion(s) with primary progression on previous
FGFR
inhibitor (
FGFR
i); A2:
FGFR2
fusion(s) with progression after prior response to
FGFR
i; B:
FGFR
alteration(s) without
FGFR2
fusion(s); C:
FGFR
wild-type. Efficacy was evaluated per RECIST v1.1 and safety was assessed by CTCAE v5.0. Genomic alterations in circulating tumor DNA (ctDNA) were assessed by Foundation Medicine NGS panel at baseline, C3D1 and EOT. Planned correlative analyses of response (PR+SD>6 months) and PFS in pt subgroups based on ctDNA mutational status were performed.
Results:
55 eligible pts were enrolled (18 in A1, 11 in A2, 13 in B, 13 in C) with median age 61.0 [range 24-81] years, ECOG PS 0 in 50.9% pts, 56.4% female, and 60.0% with ≥ 3 lines of prior therapy. Among 42 pts with
FGFR
alterations, 78.4% had ≥ 1 prior
FGFR
i, and 97.6% had prior chemotherapy. Median follow up time was 8.6 months (0.4-30.5). The median OS (months) was 17.1 (95%CI 7.5-19.5) in A1; not reached (95%CI 9.6, -) in A2; 18.0 (95%CI 9.6, -) in A1+A2; not reached (95%CI 8.0, -) in B; 6.5 (95%CI 4.8-16.4) in C. The OS rate in A, B and C was 100%, 91.7% and 75% at month 3; 83.7%, 83.3% and 66.7% at month 6, and 65.8%, 55.6% and 23.8% at month 12. Partial response was observed in 26% (10/39) of evaluable FGFR-altered pts (A1+A2+B). The safety profile was consistent with previous reports. The most common any-grade treatment-related AEs were hypertension (63.6%) and diarrhea (47.3%). Baseline ctDNA results were available in 46 pts, 35 in cohorts A+B and 11 in C. A positive correlation was shown in MED12 mutation vs response (P=0.03476). BCOR and ARID1A mutation were found to be negatively associated with PFS (P=0.01366 and P=0.0437). Acquired/secondary mutations at baseline were observed in cohort A, including V564F/I (3/24 and 5/24) and N549K/H (5/24 and 5/24); favorable anti-tumor activity was noted despite these resistant mutations, consistent with preclinical data.
Conclusions:
Tinengotinib has shown promising anti-tumor efficacy in CCA pts with FGFR fusion after prior
FGFR
i and in those with primary FGFR mutations. An ongoing randomized phase III study will investigate tinengotinib vs. chemotherapy in FGFR inhibitor refractory CCA (NCT05948475).
Clinical trial information: NCT04919642
.