The significant role of pemetinib/pemetinib tablets in the treatment of cholangiocarcinoma

Cholangiocarcinoma (CCA), as the second most common primary liver cancer after hepatocellular carcinoma, has always been the focus of research in the medical community. With the in-depth understanding of the molecular mechanism of CCA, a variety of targeted drugs have emerged, including the FGFR inhibitor-pemigatinib. The approval of this drug undoubtedly opens a new chapter in the treatment of hepatobiliary malignant tumors.

Pemetinib, a drug that selectively inhibits FGFR1, FGFR2, and FGFR3, has shown excellent results in the treatment of previously treated metastatic CCA with FGFR2 gene fusions or translocations. Its efficacy was first demonstrated in the FIGHT-101 Phase 1, two-part trial. The first part of the trial investigated the maximum tolerated dose and pharmacological activity of pemetinib through elevated serum phosphate levels, while the second part focused on determining the optimal dose in solid tumors with FGFR amplification, translocation, or mutation.

The study results show that the maximum steady-state plasma drug concentration of pemetinib is proportional to the dose in the dose range of 1-20 mg, which further emphasizes the necessity of once-daily dosing. Of note, in the first part of the trial, no dose-limiting toxicities (DLTs) were reported, while in the second part, the recommended dose was determined to be 13.5 mg.

In theFIGHT-101 trial, a total of 128 cancer patients were enrolled, 16.4% of whom had CCA. Among these patients, partial response (PR) was observed in 9.4%, including 5 patients with CCA. The most common treatment-related emergent adverse event was hyperphosphatemia (75%), followed by stomatitis, alopecia, dysgeusia, and dry mouth.

FollowingThe FIGHT-202 phase 2 trial further explored the efficacy of pemetinib (13.5 mg daily, every three weeks) in a different pre-treated patient cohort. These cohorts included patients with CCA with FGFR2 fusions or rearrangements, patients with CCA with other FGF/FGFR abnormalities, and patients with CCA without FGF/FGFR abnormalities. The primary endpoint of the trial was the overall response rate (ORR). In the patient cohort with FGFR2 fusion/rearrangement, the ORR reached 35.5%, the median duration of response (DOR) was 7.5 months, and the median progression-free survival (PFS) and median overall survival (OS) were 6.9 months and 21.1 months, respectively. In contrast, in the patient cohort with other FGF/FGFR mutations, the median PFS and OS were shorter, 2.1 months and 6.7 months, respectively; while in the patient cohort without FGF/FGFR mutations, the median PFS and OS were even shorter, 1.7 months and 4.0 months, respectively.

Similar to the FIGHT-101 trial, the most common adverse event in the FIGHT-202 trial was hyperphosphatemia (55%), followed by alopecia, dysgeusia, diarrhea, fatigue, and dry mouth. Grade 3 or higher adverse events occurred in 64% of patients, with grade 3-4 hypophosphatemia being the most common (12%). In addition, China's CIBI375A201 phase trial also reported similar results, in which the ORR in patients with previously treated advanced CCA was 60% and the median DOR was 8.3 months. In a study involving 31 patients with CCA with FGFR2 fusions or rearrangements, the median PFS was 9.1%.

Overall, pemetinib has demonstrated significant efficacy and controllable safety in the treatment of cholangiocarcinoma, providing a new treatment option for these patients.