Phase 3 Study of Tinengotinib Versus Physician’s Choice in Patients With FGFR-Altered, Chemotherapy- and FGFR Inhibitor-R/R CCA: Study Design of FIRST-308

Fibroblast growth factor receptor (FGFR) alterations are observed in approximately 10% to 15% of adult individuals diagnosed with advanced intrahepatic cholangiocarcinoma (CCA).¹

Following systemic chemotherapy, the initial FGFR inhibitors (FGFRi) pemigatinib and futibatinib have been approved for treating advanced CCA with FGFR2 fusions or rearrangements.^2,3

Secondary polyclonal mutations frequently affect the FGFR kinase domain, a prominent mechanism of acquired resistance where disease progression may still occur within 6 to 9 months of treatment.⁴

Tinengotinib, a novel multikinase inhibitor with high potency against a variety of FGFR2 kinase domain mutations, has shown promising clinical benefit in patients with FGFR-altered metastatic CCA who were heavily pretreated with chemotherapy and FGFRi(s) in 2 active phase 1/2 clinical trials (NCT04742959 and NCT04919642). This study design was presented at ASCO GI.

FIRST-308 (NCT0594875) is an open-label, phase 2, randomized, global, multicenter study that will evaluate the efficacy and safety of oral tinengotinib versus physician’s choice in patients with FGFR-altered, chemotherapy- and FGFRi-refractory/

relapsed (R/R) CCA. Approximately 200 patients will be enrolled in the United States, Europe, and Asia.

Key eligibility criteria include aged ≥18 years, Eastern Cooperative Oncology Group performance status of 0 or 1, documentation of FGFR2 fusion/rearrangement gene status, prior treatment with at least 1 line of chemotherapy, and exactly 1 prior FDA-approved FGFRi for unresectable or metastatic disease.

This study consists of parts A and B; part A selects a dose for part B. Eligible patients will be randomized in a 2:2:1 ratio to receive tinengotinib 8 mg daily, tinengotinib 10 mg daily, or physician’s choice (leucovorin, fluorouracil, and oxaliplatin [FOLFOX] or folinic acid, fluorouracil, and irinotecan [FOLFIRI]) in part A, or 2:1 in part B to receive the recommended part B dose or physician’s choice.

Patients will be stratified at randomization by geographic region (North America, Europe, and Other), prior lines of chemotherapy (1 or ≥2), and physician’s choice, which consisted of FOLFOX or FOLFIRI.

Patients will continue to receive study treatment until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or termination of study by the sponsor, whichever occurs first. Part A's primary endpoint is safety/tolerability; the secondary endpoints include objective response rate (ORR), duration of response (DOR), and pharmacokinetic analysis.

Part B’s primary endpoint is progression-free survival; the secondary endpoints include median overall survival (OS), ORR, DOR, safety, quality of life, and population pharmacokinetics.

Tumor assessments will be conducted at baseline/screening and every 8 weeks ±7 days or as clinically indicated. Tumor response will be assessed according to RECIST (version 1.1) and confirmed by a blinded independent central imaging review. Safety will be assessed with CTCAE (version 5.0 or the most current version).

Blood will be collected to measure plasma concentrations of tinengotinib, and plasma and tumor biopsy samples will be tested for biomarkers to evaluate their association with the observed clinical responses to tinengotinib. This study is currently open for enrollment.⁵

References

1. Valery M, Vasseur D, Fachinetti F, et al. Targetable molecular alterations in the treatment of biliary tract cancers: an overview of the available treatments. Cancers (Basel). 2023;15(18):4446.
2. Patel TH, Marcus L, Horiba MN, et al. FDA approval summary: pemigatinib for previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with FGFR2 fusion or other rearrangement. Clin Cancer Res. 2023;29(5):838-842.
3. Gandhy SU, Casak SJ, Mushti SL, et al. FDA approval summary: futibatinib for unresectable advanced or metastatic, chemotherapy refractory intrahepatic cholangiocarcinoma with FGFR2 fusions or other rearrangements. Clin Cancer Res. 2023;29(20):

4027-4031.

4. Goyal L, Saha SK, Liu LY, et al. Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive cholangiocarcinoma. Cancer Discov. 2017;7(3):252-263.
5. Javle M, Rimassa L, Goyal L, et al. First-308: phase III study of tinengotinib versus physician’s choice in patients with FGFR-altered, chemotherapy- and FGFR inhibitor–refractory/relapsed cholangiocarcinoma. San Francisco, CA, & online: presented at ASCO Gastrointestinal Cancers Symposium; January 18-20, 2024: poster P4.