Tinengotinib Demonstrates Activity Following FGFR Inhibitor Resistance in Cholangiocarcinoma

Clinical Summary:

• Design/Population: This multicenter, open-label trial evaluated tinengotinib in patients with previously treated advanced or metastatic cholangiocarcinoma stratified by FGFR alteration status and prior FGFR inhibitor response.
• Key Outcomes: Tinengotinib demonstrated objective responses in patients with FGFR2 fusions and acquired resistance to prior FGFR inhibitors, as well as in those with other FGFR alterations. The safety profile was manageable, with hypertension, palmar-plantar erythrodysesthesia syndrome, and stomatitis among the most common grade 3 treatment-related adverse events.
• Clinical Relevance: These findings support tinengotinib as a potential treatment option for patients with FGFR-altered cholangiocarcinoma following progression on prior FGFR inhibitor therapy and provide a rationale for ongoing phase 3 evaluation.

Results from a multicenter phase 2 trial demonstrated that tinengotinib showed encouraging antitumor activity in selected patients with advanced cholangiocarcinoma, particularly those with FGFR2 fusions who developed acquired resistance to prior FGFR inhibitor therapy.

“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,” stated Milind Javle, MD, MD Anderson Cancer Center, Houston, Texas, and coauthors.

In this multicenter, open-label trial, 55 patients with previously treated advanced or metastatic cholangiocarcinoma received 10 mg of once daily tinengotinib in 28-day treatment cycles until disease progression or unacceptable toxicity. Patients were assigned to one of four cohorts according to FGFR status: FGFR2 fusions with primary FGFR inhibitor resistance (cohort A1; n = 18), FGFR2 fusions with acquired FGFR inhibitor resistance (cohort A2; n = 11), other FGFR alterations (cohort B; n = 13), or FGFR wild-type disease (cohort C; n = 13). The primary end point was objective response rate (ORR). Safety was a key secondary end point.

After a median follow-up of 11.3 months, the ORR was 6.3% in cohort A1, 30% in cohort A2, 23.1% in cohort B, and 0% in cohort C, demonstrating the greatest activity among patients with acquired FGFR inhibitor resistance.

The most common grade 3 treatment-related adverse events were hypertension (31%), palmar-plantar erythrodysesthesia syndrome (13%), and stomatitis (11%). Grade 4 treatment-related adverse events occurred in 2 patients and included increased lipase and posterior reversible encephalopathy syndrome. No treatment-related deaths were reported.

“These findings suggest that tinengotinib might have activity in patients with cholangiocarcinoma with FGFR2 fusions that progressed following FGFR inhibitor therapy,” concluded Dr Javle et al. “The data from this phase 2 study supported the initiation of a phase 3 registration trial.” 

Source: 

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