Pemigatinib improves OS in FGFR2-altered cholangiocarcinoma

Pemigatinibshows strong survival benefit in patients with advanced cholangiocarcinoma who have previously receivedFGFR2 fusion or rearrangement therapy. In the single-arm phase 2 FIGHT-202 trial (NCT02924376), over a median follow-up period of 42.9 months, pemetinib was associated with a median overall survival (OS) of 17.5 months in patients with cholangiocarcinoma and FGFR2 mutations (95% CI, 14.4-22.9), whereas patients without these genetic alterations had shorter OS and progression-free survival (PFS).

Pemetinibis an oral selective inhibitor of FGFR1, FGFR2 and FGFR3 that has been studied in patients with cholangiocarcinoma, an epithelial tumor of the bile ducts. Key results from the trial led to the FDA's approval of pemetinib for patients with unresectable, locally advanced or metastatic cholangiocarcinoma who have previously received treatment with FGFR2 fusions or other rearrangements. Patients were included in FIGHT-202 if they had documented FGF/FGFR status and progression after at least 1 prior treatment for cholangiocarcinoma. There are 3 different groups. Cohort A included 108 patients with FGFR2 fusions or rearrangements; cohort B included 20 patients with other FGF/FGFR gene alterations; and cohort C consisted of 17 patients without FGF/FGFR gene alterations. Patients were required to have adequate hepatic and renal function and an ECOG performance status of 2 or better.

The primary endpoint isObjective response rate (ORR) by independent center review in Arm A. Secondary endpoints include objective response rate in Arms A and B; ORR in Arms B and C, duration of response (DOR), disease control rate (DCR), PFS, OS and safety for all cohorts. Patients took 13.5 mg of pemetinib orally daily for 2 weeks, followed by no treatment for 1 week, and repeated until progression, death, or unacceptable toxicity. Baseline characteristics of patients in the trial revealed some differences between cohorts. Compared with the other cohorts, Cohort A included a greater proportion of women (61%) and younger patients (median age, 55.5 years [range, 26-77]), and had the longest time since first diagnosis of cholangiocarcinoma (median, 1.3 years [range, 0.2-11.1]).

In addition, 99% of patients in cohort A had intrahepatic cholangiocarcinoma, compared with 65% and 59% in cohorts B and C, respectively. A lower percentage (82%) of patients in cohort A had metastatic disease compared with 100% in cohort B and 100% in cohort C94%. Of the total population, 39% had received 2 or more previous treatments. At a median follow-up of 42.9 months (range, 19.9-52.2), the ORR in Cohort A was 37% (95% CI, 28%-47%). At a median follow-up of 47.5 months (range, 43.7-51.1), the ORR was 0% (95% CI, 0%-17%) for cohort B, 0% for cohort c (95% CI, 0%-20%), and the DCR was 82% for cohort A, 40% for cohort B, and 18% for cohort c, which included 3 complete responses.

Among the 104 evaluable patients in CohortA, the median optimal percent change from baseline in the sum of target lesion diameters was -28.4% (range -100%-55%). The median hazard ratio for cohort A was 9.1 months (95% CI, 6.0-14.5). At the time of final analysis, the median PFS for this cohort was 7.0 months (95% CI, 6.1-10.5). For cohort B, median PFS was 2.1 months (95% CI, 1.2-4.9). For cohort C, median PFS was 1.5 months (95% CI, 1.4-1.8). Compared with the median OS of 17.5 months observed in cohort A, the median OS in cohort B was 6.7 months (95% CI, 2.1-10.6) and in cohort C was 4.0 months (95% CI, 2.0-4.6).

Safety was consistent with the primary analysis, with no new safety signals reported. Across all patients, the most common treatment-emergent adverse event (TEAE) of any grade was hyperphosphatemia, occurring in 59% of patients, but none of these conditions was grade 3 or higher. Grade 3 or higher TEAEs were reported in 69% of patients. The most common grade 3 or above TEAE was hypophosphatemia, occurring in 14.3% of patients. Other common low-grade TEAEs included alopecia (50%), diarrhea (48%), fatigue (44%), and nausea (41%). The treatment discontinuation rate due to TEAEs was 10.2%.

Overall, these results support the use of pemetinib in previously treated people with FGFR2 alterations and highlight the role of biomarker testing in identifying these patients with cholangiocarcinoma.