Regulatory Decision Summary for Pemazyre

The primary source of safety and efficacy support for the proposed indication was a single-arm Phase 2 FIGHT-202 trial in patients with specific fibroblast growth factor receptor 2 (FGFR2) rearrangements. The efficacy population consisted of 107 patients with previously treated locally advanced or metastatic cholangiocarcinoma, and who had an FGFR2 gene fusion or non-fusion rearrangement, as determined by a clinical trial assay. Qualifying in-frame fusions and other rearrangements were predicted to have a breakpoint within intron 17/exon 18 of the FGFR2 gene leaving the FGFR2 kinase domain intact. Patients received Pemazyre in 21-day cycles consisting of 13.5 milligrams (mg) once daily oral dosing for 14 days, followed by 7 days off therapy. Pemazyre was administered until disease progression or unacceptable toxicity.

The prognosis for cholangiocarcinoma is generally poor owing to the aggressive nature of the disease, the paucity of effective treatment options, and the late stage at which the disease is typically diagnosed. Historically, published literature noting results from various second line therapies demonstrating overall response rates of less than 10% for second line or later treatments in advanced cholangiocarcinoma, and an estimated survival of only 5-6 months in this setting. In this context, the reported ORR of 35.5% and duration of response (DoR) of 9.1 months demonstrate a clinically meaningful benefit. After a median duration of therapy of 6.0 months, and median duration of efficacy follow-up of 15.4 months, there was a clinically meaningful confirmed objective response rate (ORR), as assessed by the independent review committee (IRC), of 35.5% (95% confidence interval [CI]: [27%, 45%]) including 3 complete responses (CRs) and 35 partial responses (PRs). The study achieved the predetermined threshold for a positive outcome, which required the lower limit of the 95% CI for ORR to exceed 15%. The detected responses appeared durable, with a median duration of response (DoR) of 9.1 months (95% CI: 6.0 months, 14.5 months), as assessed by the IRC. Subgroup analyses, while not statistically significant, demonstrated consistent, favourable ORR data, with the 95% CI of each participant group within the subgroups overlapping the 95% CI for all participants with the qualifying FGFR2 fusion or rearrangement. Overall, these efficacy data from Study FIGHT-202 provide promising evidence of a clinically meaningful benefit of pemigatinib in the proposed indication; however, time-to-event endpoints from an ongoing randomized Phase 3 trial are required, to confirm the clinical benefit suggested by the reported efficacy from the FIGHT-202 trial.

The primary analysis of the safety of the proposed regimen of pemigatinib was based on all patients enrolled in the Phase 2 Study FIGHT-202, regardless of FGFR2 genetic alteration status (number of subjects (N) = 146). As all participants received the same pemigatinib dose regimen, and FGFR status should not impact the safety profile of pemigatinib, the overall population of the study was considered the most appropriate for the primary safety analysis. These safety data were supported by a consistent safety profile revealed in the integrated safety data from patients treated with pemigatinib monotherapy across the studies in the clinical development program (N = 466); however, only the data from the 146 patients from Study FIGHT-202 were included in the safety labelling in the final Pemazyre Product Monograph.

In the pivotal Study FIGHT-202, the most common adverse reactions were consistent with other FGFR2 inhibitors. Hyperphosphatemia was expected due to the pharmacodynamics effect of pemigatinib, and was the most commonly reported treatment-emergent adverse event (TEAE), in 60% of patients. Phosphate elevations were not associated with any clinical sequelae in the pivotal trial. Adverse events of hyperphosphatemia were primarily managed by dose interruption (3.6%), dose reduction (0.9%), and phosphate-lowering therapy (29%).

Serious adverse events (SAEs) occurred in 45% of patients. Dose interruptions and dose reductions due to adverse events occurred in 43% and 14% of patients, respectively; most commonly due to stomatitis, palmar-plantar erythrodysesthesia syndrome, arthralgia, and fatigue. Grade ≥3 adverse events were reported in 64% of patients. The most frequently reported Grade ≥3 AE was hypophosphatemia; frequently reported during the 1-week off-treatment phase of the recommended dosing regimen. None of the events were serious, or led to discontinuation or dose reduction. The Product Monograph (PM) for Pemazyre recommends discontinuation of phosphate-lowering therapy and diet adjustment during pemigatinib treatment breaks, or if serum phosphate level falls below the normal range, in order to manage hypophosphatemia.

Serous retinal detachment (SRD) events are known adverse events associated with FGFR2 inhibitors, and led to pemigatinib discontinuation in 0.4% of patients, dose interruption in 1.7% of patients, and dose reduction in 0.4% of patients. Routine monitoring including optical coherence tomography (OCT) to detect asymptomatic SRD was not performed in pemigatinib clinical studies; therefore, the incidence of asymptomatic SRD with Pemazyre is unknown. However, baseline ophthalmological exams and routine monitoring for eye disorders were important risk mitigation measures in the pivotal study, and are recommended in the PM. To manage the risk of SRD, the PM for Pemazyre contains references to educational material regarding the diagnosis and management of SRD, for physicians.

Overall, the benefit-risk-uncertainty profile of pemigatinib for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement is considered acceptable, with adverse events typically manageable throughout the use of pemigatinib dose reduction, temporary treatment discontinuation, and/or standard medical care. Given the seriousness of the disease, the authorization of this indication is under the Notice of Compliance with conditions (NOC/c) Guidance; these data must be confirmed in the ongoing randomized Phase 3 Study INCB54828-302.

The Qualifying Notice (dated 6 August 2021) stated that the final study report of Study INCB54828-302 is required as a post-authorization commitment, as well as post-market surveillance commitments in alignment with recommendations from the Marketed Health Products Directorate (MHPD).   

For more information on Health Canadas decision, please view the Summary Basis of Decision.