Cholangiocarcinoma remains a challenging malignancy with limited treatment options and poor long-term outcomes. First-line treatment typically consists of chemotherapy and immunotherapy combinations; however, the emergence of molecularly targeted therapies has transformed treatment opportunities for select patient subgroups. FGFR2 rearrangements represent one of the most clinically actionable genetic alterations in cholangiocarcinoma. Pemigatinib, a selective FGFR1-3 inhibitor, previously became the first approved targeted therapy for previously treated FGFR2-rearranged cholangiocarcinoma based on the Phase II FIGHT-202 study.

The Phase III FIGHT-302 trial evaluated whether pemigatinib could improve outcomes when used in the first-line setting compared with standard gemcitabine plus cisplatin chemotherapy. Despite screening more than 4,000 patients to identify eligible individuals with FGFR2 rearrangements, the study successfully demonstrated clinically meaningful efficacy benefits with targeted therapy.

KOL Insights-

“FIGHT-302 marks a milestone as the first Phase III study of a targeted therapy in untreated metastatic cholangiocarcinoma, demonstrating the power of precision medicine in FGFR2-rearranged disease.”– Expert Opinion

“Although FIGHT-302 was stopped early, it remains the largest randomized first-line study evaluating an FGFR inhibitor in FGFR2-rearranged cholangiocarcinoma. Given the established benefits of FGFR-targeted therapies in later treatment settings, these findings provide valuable insights into the role of FGFR inhibition earlier in the treatment paradigm and help refine future therapeutic strategies.”– Expert Opinion

Conclusion-

Cholangiocarcinoma accounts for around 10%-25% of primary hepatic cancers and 3% of gastrointestinal tumors. In the United States, cholangiocarcinoma incidence is increasing. Fibroblast growth factor receptor 2 (FGFR2) fusions and rearrangements have been detected in 1%-13% of patients with intrahepatic cholangiocarcinoma.

Pemigatinib is a selective, potent, oral inhibitor of FGFR1-3 and demonstrated efficacy in patients with previously treated, metastatic cholangiocarcinoma with FGFR2 alterations. The Phase III FIGHT-302 trial demonstrated that pemigatinib provides superior antitumor activity compared with standard gemcitabine plus cisplatin chemotherapy in patients with previously untreated FGFR2-rearranged metastatic cholangiocarcinoma. The study met its primary endpoint, achieving a significant progression-free survival benefit while also substantially improving objective response rates and duration of response.