The FDA has granted a priority review to a new drug application for pemigatinib as a treatment for patients with previously treated, locally advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements.
Peter Langmuir, MD, group vice president, Targeted Therapies, Incyte
Peter Langmuir, MD
The FDA has granted a priority review to a new drug application (NDA) for pemigatinib as a treatment for patients with previously treated, locally advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements.1
The designation is based on interim findings from the multicohort, single-arm, phase II FIGHT-202 study, which showed that, at a median follow-up of 15 months, single-agent pemigatinib led to a 36% objective response rate (ORR) and a median duration of response of 7.5 months in a cohort of patients with FGFR2 fusions or rearrangements.2 The selective inhibitor of FGFR1, 2, and 3 was also associated with a manageable adverse event (AE) profile.
Under the Prescription Drug User Fee Act, the FDA will make a decision on the NDA by May 30, 2020.
“There is a significant need for new therapies for patients with cholangiocarcinoma, who have limited treatment options beyond first-line chemotherapy and often face a poor prognosis,” Peter Langmuir, MD, Group Vice President of Targeted Therapeutics at Incyte, the developer of pemigatinib, stated in a press release.
“We are very pleased that the FDA has accepted our NDA for Priority Review which we believe represents an important step toward providing the first treatment option for patients with previously treated, locally advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements. We intend to work closely with the FDA to bring this innovative targeted therapy to patients suffering from this devastating disease as soon as possible,” added Langmuir.
Patients with cholangiocarcinoma are often diagnosed at a late or advanced stage when the prognosis is poor, Incyte stated in the press release.
While first-line treatment for patients with locally advanced or metastatic cholangiocarcinoma is the chemotherapy combination of gemcitabine and cisplatin, second-line therapies have shown limited efficacy.
The FIGHT-202 trial was conducted in the United States, Europe, Middle East, and Asia. Patients who were eligible for enrollment had locally advanced or metastatic cholangiocarcinoma despite ≥1 line of prior therapy, had their FGF/FGFR status centrally confirmed, and adequate renal function was required.
Patients were stratified into 3 cohorts: those with FGFR2 fusions/rearrangements (cohort A; n = 107), those with other FGF/FGFR genetic alterations (cohort B; n = 20), and no FGF/FGFR alterations (cohort C; n = 18). Patients in each of the 3 cohorts were treated with oral pemigatinib (13.5 mg) using a 2-weeks-on/1-week-off schedule.
The study was not designed to make statistical comparisons between the 3 cohorts. The primary endpoint was the confirmed ORR in cohort A by independent central review.
Median age of the entire 146 patients who were enrolled enrolled was 59 years; however, 77% of patients in cohort A were <65 years, compared with 50% in cohort B, and 39% of patients in cohort C. Overall, 58% of patients were women (61% in cohort A), and 61% of patients were enrolled in North America, 24% in Western Europe, and 15% of patients were enrolled in other geographical areas.
Among the 107 patients in cohort A, 92 fusions and 15 rearrangements identified. A total of 56 unique fusion partners were identified, the most common of which was BICC1, which occurred in 29%. Forty-two partners were unique to a single patient, and no fusion partner was identified in 5% of patients.
Results showed that, in cohort A, the 36% ORR consisted of 3 (2.8%) complete responses, 35 (32.7%) partial responses, and 50 (46.7%) patients with stable disease, for a disease control rate of 82%. The ORR was consistent across subgroups, including when stratified by the number of prior lines of therapy and by FGFR2 rearrangement partner.
Additionally, the higher ORR translated into a longer median progression-free survival (PFS) in cohort A. Median PFS was 6.9 months in cohort A compared with 2.1 months in cohort B and 1.7 months in cohort C.
Overall survival (OS) data were not yet mature at the time of the March 22, 2019, data cutoff. However, but with a median duration of follow-up of 15.4 months and a median duration of treatment of 7.2 months, the median OS was 21.1 months in the cohort with FGFR2 fusions/rearrangements. Median OS was only 6.7 months in the cohort with other FGF/FGFR alterations after a median follow-up of 19.9 months, and only 4.0 months in the cohort without an FGF/FGFR alteration after a median follow-up of 24.2 months.
Regarding safety, AEs were found to be manageable and consistent with the mechanism of action of pemigatinib. The most common AE was hyperphosphatemia (60%), but no grade ≥3 cases were encountered. Hyperphosphatemia was managed with a low phosphate diet, phosphate binders, diuretics, and a reduction or interruption in the pemigatinib dose. Three patients required dose reductions/interruptions due to hyperphosphatemia.
Any-grade hypophosphatemia occurred in 23% of patients and was the most common grade ≥3 AE, with a rate of 12%. No case of hypophosphatemia was clinically significant and none led to treatment discontinuation or dose reduction. Serous retinal detachment occurred in 4% of patients and usually resolved spontaneously or after dose interruption.
Nine percent of patients discontinued due to AEs; the most frequent causes were intestinal obstruction and acute kidney injury (2 each). Treatment was discontinued due to progressive disease in all patients in cohorts B and C, and in 57 patients in cohort A. Dose reduction due to AEs was required in 14%, with the most common reasons being stomatitis (n = 11), palmar-plantar erythrodysesthesia syndrome (n = 5), arthralgia (n = 5), asthenia (n = 2), and onychomadesis (n = 2). Approximately 42% of patients required dose interruptions due to AEs.
Based on the data from FIGHT-202, a phase III study of pemigatinib compared with gemcitabine plus cisplatin in the first-line setting in patients with cholangiocarcinoma and FGFR2 fusions/rearrangements is ongoing (NCT03656536).