Clinical trials of pemetinib/pemetinib

In April 2020, the first such targeted therapy, pemigatinib, was approved for the treatment of patients with unresectable advanced or metastatic cholangiocarcinoma who have previously received fibroblast growth factor receptor 2 (FGFR 2) fusion or rearrangement therapy. Currently, surgery is the only curative treatment for rare biliary tract cancer, but only about 35% of patients can choose surgery. Among patients who choose surgical resection, about 35% of patients will relapse within 2 years. For patients with unresectable biliary tract cancer, the standard of care is gemcitabine plus cisplatin, according to findings from the phase 3 advanced biliary tract cancer study ABC-02.

Pemetinib is a small molecule inhibitor of FGFR1/2/3. In preclinical studies, it has been shown to be active against cancer cells with altered FGFR. Overall, FGFR1/2/3 fusions and amplifications are observed in 11% to 13% of patients with intrahepatic cholangiocarcinoma. These changes have not been found in extrahepatic disease. The FDA granted accelerated approval of pemetinib based on the results of FIGHT-202. FIGHT-202 is a multicenter, open-label, single-arm phase 2 study evaluating patients with locally advanced unresectable or metastatic cholangiocarcinoma who have received at least 1 prior line of therapy. The agency also approved FoundationOne CDx as a companion diagnostic to pemetinib.

InFIGHT-202, pemetinib monotherapy resulted in an overall response rate of 36% (95% CI, 27%-45%), including a 2.8% complete response rate and a 33% partial response rate. The median duration of response was 9.1 months (95% CI, 6.0-14.5); 63% of patients achieved a response of 6 months or longer, and 18% maintained a response of 12 months or longer. Of note, all responses were observed in patients with FGFR2 fusions or rearrangements; none were evident among study participants with other FGF/FGFR gene alterations or no FGF/FGFR gene alterations. Median OS was 21.1 months (95% CI, 14.8 to not estimable).

InFIGHT-202 safety population, serious adverse reactions (AEs) were observed in 45% of patients, of which 4.1% experienced fatal AEs, including dysplasia, bile duct obstruction, cholangitis, sepsis, and pleural effusion. Nine percent of patients discontinued treatment due to adverse events, including intestinal obstruction and acute kidney injury. 14% of patients required dose reduction due to adverse events. The safety profile of pemetinib is "manageable." Most AEs were grade 1 or 2 in severity, with the most common of these events including hyperphosphatemia (55%), alopecia (46%), dysgeusia (38%), diarrhea (34%), and fatigue (31%).