The Lynx Group

Pemazyre First FDA-Approved Therapy for Cholangiocarcinoma plus FGFR2 Fusion

June 2020, Vol 11, No 3

On April 17, 2020, the FDA approved pemigatinib (Pemazyre; Incyte), an oral kinase inhibitor, as the first treatment for adults (aged ≥18 years) with previously treated, locally advanced or metastatic cholangiocarcinoma that is associated with a fibroblast growth factor receptor 2 (FGFR2) gene fusion or other rearrangements, as detected by an FDA-approved test. This is the first targeted therapy approved for patients with advanced cholangiocarcinoma. Until now, the standard of therapy for this patient population has been chemotherapy combinations.

The FDA approved pemigatinib using its priority review process and granted the drug breakthrough therapy and orphan drug designations. Approximately 9% to 14% of patients with cholangiocarcinoma have FGFR2 gene fusions.

“With Pemazyre, we considered the observed efficacy results to be clinically meaningful and the overall risk to benefit assessment for patients with tumors harboring FGFR2 gene fusions and other rearrangements to be favorable, particularly when we considered that these patients have no other good options following first line treatment with chemotherapy,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence.

On the same day, the FDA also approved Foundation Medicine’s FoundationOne CDx as the companion diagnostic for pemigatinib. FoundationOne CDx is a next-generation sequencing test and the first and only FDA-approved companion diagnostic test for this indication. This test is currently approved as a companion diagnostic for 20 therapies for various cancer types.

Cholangiocarcinoma is a rare gastrointestinal cancer that forms in the bile ducts. Currently, cholangiocarcinoma represents 2.4% of all new cancers diagnosed in the United States. FGFR mutations play an important role in tumor-cell proliferation and survival, migration, and angiogenesis. Activating fusions, rearrangements, translocations, and gene amplifications in the FGFR biomarker are associated with various cancers.

Pemigatinib is a potent, selective, oral inhibitor of FGFR isoforms 1, 2, and 3; in preclinical studies, the drug has demonstrated selective pharmacologic activity against cancer cells with FGFR alterations.

The FDA’s approval of pemigatinib was based on the results of the FIGHT-202 clinical trial, a multicenter, open-label, single-arm study that enrolled 107 patients with locally advanced or metastatic cholangiocarcinoma and FGFR2 fusions or rearrangements who had received previous treatment. All enrolled patients received pemigatinib 13.5 mg once daily for 14 days followed by 7 days off in 21-day cycles, until disease progression or unacceptable adverse events. The primary end point was overall response rate; the secondary end point was duration of response.

In patients with FGFR1 fusions or rearrangements, the overall response rate was 36% (N = 38), including 2.8% of patients with a complete response and 33% of patients with a partial response. Among the 38 patients who had a response to therapy with pemigatinib, 24 patients had a response lasting ≥6 months and 7 patients had a response lasting ≥12 months; the median duration of response was 9.1 months. No data are yet available to show whether pemigatinib improves survival duration or symptoms of the disease.

The most common (≥20%) adverse reactions with pemigatinib were hyperphosphatemia and hypophosphatemia, alopecia, diarrhea, nail toxicity, fatigue, dysgeusia, nausea, constipation, stomatitis, dry eye and/or mouth, decreased appetite, vomiting, joint pain, abdominal pain, back pain, and dry skin.

The FDA approved pemigatinib under the accelerated approval protocol based on tumor response. Continued approval of the drug may be contingent on additional data from confirmatory clinical trials that further demonstrate the drug’s clinical benefit.

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