Tinengotinib for adults with advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 trial

Background: Cholangiocarcinoma is a rare, aggressive cancer often driven by FGFR2 fusions, which are targetable with inhibitors such as pemigatinib and futibatinib. However, resistance frequently develops due to acquired FGFR2 mutations. In this study, we aimed to evaluate the efficacy and safety of tinengotinib in previously treated patients with advanced cholangiocarcinoma. Methods: This open-label, multicentre, phase 2 trial was done at 32 medical centres in the USA. Eligible patients were aged 18 years or older with advanced or metastatic cholangiocarcinoma, who had previous systemic chemotherapy, and an Eastern Cooperative Oncology Group score of 0–1. Patients were assigned to one of four cohorts on the basis of FGFR status: cohort A1, FGFR2 fusions with primary FGFR inhibitor resistance; cohort A2, FGFR2 fusions with acquired FGFR inhibitor resistance; cohort B, other FGFR alterations; or cohort C, FGFR wild-type. Patints orally self-administered tinengotinib 10 mg daily in 28-day cycles in 28-day treatment cycles until documented disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was objective response rate as per investigator assessment, defined as the proportion of patients with confirmed tumour response (complete response or partial response) that was redocumented 4 weeks or after initial assessment based on RECIST (version 1.1), as assessed by the investigator. The primary endpoint was assessed in the in the efficacy evaluable population, which included all patients who received at least one dose of tinengotinib, had measurable disease at baseline, and had at least one post-baseline tumour assessment. Safety assessed in all patients who received at least one dose of tinengotinib. This trial is registered withClinicalTrials.gov,NCT04919642, and enrolment is complete. Findings: Between Nov 19, 2021, and March 5, 2024, 55 patients were enrolled and assigned to one of four cohorts (cohort A1 [n=18], cohort A2 [n=11], cohort B [n=13], and cohort C [n=13]); all received tinengotinib. Patients had a median age of 61 years (IQR 56–68); 31 (56%) patients were female. All patients had received at least one previous systemic therapy. Median follow-up was 11·3 months (IQR 6·5–17·3). Among 51 patients included in the efficacy evaluable set, the objective response rate was 6·3% (95% CI 0·2–30·2; one confirmed partial response) in cohort A1, 30·0% (6·7–65·3; three confirmed partial responses) in cohort A2, 23·1% (5·0–53·8; three confirmed partial responses) in cohort B, and 0% in cohort C. Grade 3 treatment-related adverse events included hypertension in 17 (31%) of 55 patients, palmar-plantar erythrodysesthesia syndrome in seven (13%) patients, and stomatitis in six (11%) patients. Grade 4 treatment-related adverse events occurred in two (4%) of 55 patients (increased lipase [n=1] and posterior reversible encephalopathy syndrome [n=1]); no grade 5 treatment-related adverse events were reported. Interpretation: These findings suggest that tinengotinib might have activity in patients with cholangiocarcinoma with FGFR2 fusions that progressed following FGFR inhibitor therapy. Anti-tumour activity was also observed in patients with other FGFR alterations. The data from this phase 2 study supported the initiation of a phase 3 registration trial. Funding: TransThera Sciences.