Tinengotinib Shows Activity in Previously Treated FGFR-Altered Cholangiocarcinoma

A NEW multicentre phase 2 trial has reported promising activity for tinengotinib, a next-generation FGFR inhibitor, in adults with advanced or metastatic cholangiocarcinoma who had already received systemic therapy. The findings could mark an important step for patients who develop resistance to existing FGFR-targeted treatments such as pemigatinib and futibatinib, a major clinical hurdle in this aggressive and often fatal cancer.

Overcoming Resistance in Cholangiocarcinoma with Tinengotinib

Conducted across 32 US centres, the open-label study enrolled 55 patients aged 18 years and older, all with prior chemotherapy exposure and good performance status (ECOG 0–1). Participants were divided into four cohorts based on their tumour FGFR status. Cohort A1 included patients with FGFR2 fusions exhibiting primary resistance to prior FGFR inhibitors, while cohort A2 comprised patients with FGFR2 fusions who had developed acquired resistance. Cohort B included patients with other FGFR alterations, and cohort C consisted of those with FGFR wild-type tumours.

Patients received tinengotinib 10 mg orally once daily in continuous 28-day cycles until progression, unacceptable toxicity, or withdrawal. The primary endpoint was objective response rate (ORR) based on RECIST 1.1 criteria among efficacy-evaluable patients.

After a median follow-up of 11.3 months, early anti-tumour activity was concentrated in molecularly selected groups. In cohort A2, representing patients with acquired FGFR inhibitor resistance, the ORR reached 30.0%, with three confirmed partial responses. Cohort B, comprising patients with non-FGFR2 alterations, showed a 23.1% response rate. By contrast, primary FGFR inhibitor resistance (cohort A1) yielded a modest 6.3% ORR, and no responses were observed in FGFR wild-type tumours (cohort C).

The safety profile was in keeping with FGFR pathway inhibition. Grade 3 treatment-related adverse events included hypertension (31%), palmar-plantar erythrodysesthesia (13%), and stomatitis (11%). Grade 4 events were rare (4%) and included increased lipase and one case of posterior reversible encephalopathy syndrome. No treatment-related deaths occurred.

Next Steps: Phase 3 Trials to Confirm Clinical Benefit

Taken together, the results suggest that tinengotinib may overcome acquired resistance to earlier-generation FGFR inhibitors, which is an area of urgent unmet need. The investigators note that signals of activity in non-FGFR2 altered tumours further broaden potential applicability. Based on these findings, a phase 3 registration trial has now been initiated to better define clinical benefit and confirm durability of response.

Reference

Javle M et al. Tinengotinib for adults with advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 trial. Lancet Gastroenterol Hepatol. 2025. doi:  10.1016/S2468-1253(25)00230-4