The Japanese Ministry of Health, Labour, and Welfare has approved pemigatinib for the treatment of patients with unresectable biliary tract cancer with a FGFR2 fusion gene, worsening following chemotherapy.
The Japanese Ministry of Health, Labour, and Welfare (MHLW) has approved pemigatinib (Pemazyre) for the treatment of patients with unresectable biliary tract cancer with a FGFR2 fusion gene, worsening following chemotherapy.1
The regulatory decision was based on data from the phase 2 FIGHT-202 trial (NCT02924376), in which pemigatinib elicited an objective response rate of 35.5% (95% CI, 26.5%-45.4%) in 107 patients with FGFR2 fusions or rearrangements. Of those who responded to treatment, 2.8% had a complete response, 32.7% had a partial response, and 46.7% experienced stable disease. The median duration of response (DOR) achieved with pemigatinib was 7.5 months (95% CI, 5.7-14.5).
“The MHLW approval of [pemigatinib] is an important milestone for the biliary tract cancer community and underscores our commitment to finding and delivering solutions for patients with significant unmet medical needs,” Lothar Finke, MD, PhD, general manager of Incyte Asia, stated in a press release. “Biliary tract cancer is a rare and serious condition, and we are proud that with the support of the MHLW we will be able to bring a new targeted treatment to more patients around the world.”
In the multicenter, open-label phase 2 trial, investigators set out to examine the safety and antitumor activity of pemigatinib in patients with previously treated, locally advanced or metastatic cholangiocarcinoma with or without FGF/FGFR alterations.2
To be eligible for enrollment, patients had to be at least 18 years of age, have a histological or cytological diagnosis of locally advanced or metastatic cholangiocarcinoma with documented progressive disease after at least 1 prior systemic therapy, have radiographically measurable disease per RECIST v1.1 criteria, and an ECOG performance status of 0 to 2, among other criteria.
Patients were prescreened centrally for FGF/FGFR status and based on their centrally confirmed results, they were assigned to 1 of 3 cohorts: those with FGFR2 fusions or rearrangements, those with other FGF/FGFR alterations, and those without FGF/FGFR alterations.
All participants were given oral pemigatinib at a starting dose of 13.5 mg once daily, irrespective of cohort assignment. Treatment was given until radiological disease progression, intolerable toxicity, withdrawn consent, or physician choice. Dosing with the agent could be interrupted for up to 14 days to allow for toxicities to resolve.
The primary end point of the trial was the proportion of patients with FGFR2 fusions or rearrangements who achieved an objective response per independent central review. Key secondary end points of the trial were the proportion of patients with an objective response in those with other FGF/FGFR alterations, in all patients with FGF/FGFR alterations, and in patients without FGF/FGFR alterations, as well as DOR, disease control rate, progression-free survival (PFS), overall survival (OS), safety, and pharmacokinetics.
A total of 1206 patients were prescreened for FGF/FGFR status using the FoundationOne test; of these patients, 1120 did not harbor these mutations or they declined to participate on the study. The remaining 86 patients were evaluated for eligibility. An additional 85 patients who had FGF/FGFR alterations were also assessed for eligibility. Of the 171 patients, 146 enrolled to the trial between January 17, 2017 and March 22, 2019. Of the 146 patients, 107 had FGFR2 fusions or rearrangements, 20 had other FGF/FGFR alterations, and 18 did not have FGF/FGFR alterations.
All participants were given at least 1 dose of pemigatinib and they were included in both the safety and efficacy populations with the exception of 1 patient who had undetermined FGF/FGFR status, who was not included in the efficacy analysis. The overall median follow-up was 17.8 months, with a median follow-up of 15.4 months, 19.9 months, and 24.2 months in those with FGFR2 fusions or rearrangements, in those with other FGF/FGFR alterations, and in those without FGF/FGFR alterations. In these cohorts, the median duration of treatment was 7.2 months, 1.4 months, and 1.3 months, respectively.
The median age of participants across all cohorts analyzed was 59 years, 92% had an ECOG performance status of 0 or 1, 86% had metastatic disease, and 39% had previously received 2 or more systemic treatments. Moreover, the majority of participants had previously received platinum-based chemotherapy immediately before entering the study. The most commonly received chemotherapy regimen was that of gemcitabine plus cisplatin, which was received by 47% of patients. Notably, among those with FGFR2 fusions or rearrangements, 98% had intrahepatic cholangiocarcinoma.
Additional results showed that the median time to first response with pemigatinib was 2.7 months. Moreover, 88% of 103 patients with FGFR2 fusions or rearrangements who had post-baseline measurements experienced reductions in their target lesion size.
The median PFS with pemigatinib was 6.9 months (95% CI, 6.2-9.6) in patients with FGFR2 fusions or rearrangements. In those with other FGF/FGFR2 alterations, the median PFS was 2.1 months (95% CI, 1.2-4.9), while it was 1.7 months (95% CI, 1.3-1.8) in those without FGF/FGFR alterations. The Kaplan-Meier estimates of PFS at 6 months in those with FGF/FGFR2 alterations was 62%; at 12 months, the estimated rate is 29%.
Additionally, the OS data were still not mature at the time of data cutoff. At this time, 37% of patients had died in the FGF/FGFR2 cohort. The median OS was 21.1 months (95% CI, 14.8–not estimable). The median OS in those with other FGF/FGFR alterations was 6.7 months (95% CI, 2.1-10.6), while it was 4.0 months (95% CI, 2.3-6.5) in those without the alterations.
Notably, objective responses observed in the FGF/FGFR2 cohort were noted across all demographic and disease subsets evaluated; the median PFS was also found to be similar across these subgroups.
Of the 146 patients enrolled to the trial, 79% discontinued treatment; this included 71% of those with FGFR2 fusions or rearrangements, 100% of those with other FGF/FGFR2 alterations, 100% of those without these alterations, and the patient who had undetermined FGF/FGFR2 status. Most patients discontinued due to disease progression (55%, 75%, and 67%, respectively).
The most common toxicity experienced with the agent was hyperphosphatemia, which was experienced by 58.2% of patients, irrespective of cause. Other toxicities reported with pemigatinib included alopecia, diarrhea, fatigue, dysgeusia, nausea, constipation, stomatitis, dry mouth, and decreased appetite. Most of these effects were grade 1 or 2 in severity.
However, 64% of patients experienced grade 3 or higher toxicities, the most common of which were hyperphosphatemia (12%), arthralgia (9%), stomatitis (5%), hyponatremia (5%), abdominal pain (5%), and fatigue (5%).
Previously, the MHLW granted pemigatinib an orphan drug designation for this indication. In April 2020, the FDA approved pemigatinib for the treatment of patients with previously treated, locally advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements based on data from FIGHT-202.