日本批准的培米替尼用于不可切除性FGFR+胆道癌

In this multicenter, open-label, phase 2 trial, researchers set out to study the safety and antitumor activity of pemetinib in patients with previously treated locally advanced or metastatic cholangiocarcinoma with and without FGF/FGFR mutations.

To be included in the trial, patients must be 18 years or older, have a histological or cytological diagnosis of locally advanced or metastatic cholangiocarcinoma, have documented progressive disease after at least 1 systemic therapy, have radiographic measurable disease according to RECIST v1.1 criteria, and have an ECOG performance status of 0-2, among other criteria.

Patients were centrally pre-screened for FGF/FGFR status and assigned to 3 trial groups based on their centrally confirmed results: FGFR2 fusion or rearrangement group, other FGF/FGFR mutation group, and no FGF/FGFR mutation group.

All subjects received pemetinib orally, with a starting dose of 13.5 mg once daily. Subjects were treated until progression of radiation disease, intolerable toxicity, withdrawal of consent, or physician decision to discontinue treatment. Dosing can be interrupted for up to 14 days and toxicity can be eliminated.

The trial's primary endpoint is the proportion of patients with FGFR2 fusions or rearrangements who achieve an objective response at an independent center. The main secondary endpoints of the trial are: the proportion of patients achieving objective response in all patients with FGF/FGFR mutations and in patients without FGF/FGFR mutations, DOR, disease control rate, progression-free survival (PFS), overall survival (OS), safety and pharmacokinetics.

A total of 1,206 patients were prescreened for FGF/FGFR status using the FoundationOne test; of these, 1,120 patients did not have the mutation or declined to participate in the trial. The remaining 86 patients were eligible for inclusion. An additional 85 patients with FGF/FGFR mutations were also eligible. Of the 171 patients, 146 participated in the trial between January 17, 2017, and March 22, 2019. Among 146 patients, 107 had FGFR2 fusions or rearrangements, 20 had other FGF/FGFR mutations, and 18 had no FGF/FGFR mutations.

All subjects took at least 1 dose of pemetinib. Except for 1 patient with unknown FGF/FGFR status who was not included in the efficacy analysis, they were all included in the safety and efficacy population. The overall median follow-up time was 17.8 months, and the median follow-up times for the FGFR2 fusion or rearrangement group, other FGF/FGFR mutation group, and no FGF/FGFR mutation group were 15.4 months, 19.9 months, and 24.2 months, respectively. In these trial groups, the median treatment duration was 7.2 months, 1.4 months, and 1.3 months, respectively.

The median age of all subjects was 59 years, 92% had an ECOG performance status of 0 or 1, 86% had metastatic disease, and 39% had received 2 or more lines of systemic therapy. In addition, most subjects had received platinum-based chemotherapy before entering the trial. The most commonly accepted chemotherapy regimen was gemcitabine combined with cisplatin, with 47% of patients receiving this regimen. Notably, 98% of patients with FGFR2 fusions or rearrangements had intrahepatic cholangiocarcinoma.

Additional results showed that the median response time to first use of pemetinib was 2.7 months. Additionally, among 103 patients with FGFR2 fusions or rearrangements, 88% had a decrease in target lesion size when measured after baseline examination.

Among patients with FGFR2 fusions or rearrangements, the median PFS with pemetinib was 6.9 months (95% CI, 6.2-9.6). Among patients with additional FGF/FGFR2 mutations, the median PFS was 2.1 months (95% CI, 1.2-4.9), whereas among patients without FGF/FGFR mutations, the median PFS was 1.7 months (95% CI, 1.3-1.8). Among patients with FGF/FGFR2 mutations, the Kaplan-Meier estimate of PFS was 62% at 6 months and 29% at 12 months.

Furthermore, at the time of data outage, the OS data is still immature. At this point, 37% of patients in the FGF/FGFR2 group had died. Median OS was 21.1 months (95% CI, 14.8–not estimable). The median OS of patients with other FGF/FGFR mutations was 6.7 months (95% CI, 2.1-10.6), while the median OS of patients without mutations was 4.0 months (95% CI, 2.3-6.5).

References:

https://www.onclive.com/view/pemigatinib-approved-in-japan-for-unresectable-fgfr-biliary-tract-cancer