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Futibatinib for FGFR2-Rearranged Intrahepatic Cholangiocarcinoma
Lipika Goyal1, Funda Meric-Bernstam1, Antoine Hollebecque1
1From the Department of Medicine, Stanford University School of Medicine, and the Stanford Cancer Center, Palo Alto (L.G.), and the University of California, San Francisco, San Francisco (R.K.K.) - both in California; the Mass General Cancer Center, Harvard Medical School (L.G.), and Dana-Farber Cancer Institute (T.A.A.) - both in Boston; the University of Texas M.D. Anderson Cancer Center, Houston (F.M.-B.); the Drug Development Department, Gustave Roussy, Villejuif (A.H.), and Centre Léon Bérard, Lyon (P.A.C.) - both in France; the University of Manchester and the Christie NHS Foundation Trust, Manchester (J.W.V.), and University College London Cancer Institute, London (J.A.B.) - both in the United Kingdom; National Cancer Center Hospital, Tokyo (C.M.), Kanagawa Cancer Center, Yokohama (J.F.), Hokkaido University Hospital Cancer Center, Sapporo (Y.K.), and Tohoku University Graduate School of Medicine, Sendai (K.M.) - all in Japan; the Hospital of the University of Pennsylvania (T.B.K.) and Sidney Kimmel Cancer Center at Thomas Jefferson University Hospital (E.P.M.) - both in Philadelphia; Amsterdam University Medical Center, University of Amsterdam, Amsterdam (H.-J.K.); Asan Medical Center, University of Ulsan College of Medicine (H.-M.C.), and Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine (D.-Y.O.) - both in Seoul, South Korea; the National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan (L.-T.C.); Vall d'Hebron Hospital Campus and Vall d'Hebron Institute of Oncology, University of Vic-Central University of Catalonia, Baselga Oncologic Institute, Hospital Quiron, Barcelona (J.T.); Mayo Clinic, Rochester, MN (A.M.); Johannes Gutenberg-Mainz University Medical Center, Mainz, Germany (M.M.); Mayo Clinic, Phoenix, AZ (D.A.); Epstein Health, Woodcliff Lake, NJ (R.S.E.); Taiho Oncology, Princeton, NJ (A.-B.H., T.S., V.W., Y.H., M.L., K.A.B.); and Ilumina, San Diego, CA (Y.F.).
Background:
Alterations in fibroblast growth factor receptor 2 (FGFR2) have emerged as promising drug targets for intrahepatic cholangiocarcinoma, a rare cancer with a poor prognosis. Futibatinib, a next-generation, covalently binding FGFR1-4 inhibitor, has been shown to have both antitumor activity in patients with FGFR-altered tumors and strong preclinical activity against acquired resistance mutations associated with ATP-competitive FGFR inhibitors.
Methods:
In this multinational, open-label, single-group, phase 2 study, we enrolled patients with unresectable or metastatic FGFR2 fusion-positive or FGFR2 rearrangement-positive intrahepatic cholangiocarcinoma and disease progression after one or more previous lines of systemic therapy (excluding FGFR inhibitors). The patients received oral futibatinib at a dose of 20 mg once daily in a continuous regimen. The primary end point was objective response (partial or complete response), as assessed by independent central review. Secondary end points included the response duration, progression-free and overall survival, safety, and patient-reported outcomes.
Results:
Between April 16, 2018, and November 29, 2019, a total of 103 patients were enrolled and received futibatinib. A total of 43 of 103 patients (42%; 95% confidence interval, 32 to 52) had a response, and the median duration of response was 9.7 months. Responses were consistent across patient subgroups, including patients with heavily pretreated disease, older adults, and patients who had co-occurring TP53 mutations. At a median follow-up of 17.1 months, the median progression-free survival was 9.0 months and overall survival was 21.7 months. Common treatment-related grade 3 adverse events were hyperphosphatemia (in 30% of the patients), an increased aspartate aminotransferase level (in 7%), stomatitis (in 6%), and fatigue (in 6%). Treatment-related adverse events led to permanent discontinuation of futibatinib in 2% of the patients. No treatment-related deaths occurred. Quality of life was maintained throughout treatment.
Conclusions:
In previously treated patients with FGFR2 fusion or rearrangement-positive intrahepatic cholangiocarcinoma, the use of futibatinib, a covalent FGFR inhibitor, led to measurable clinical benefit. (Funded by Taiho Oncology and Taiho Pharmaceutical; FOENIX-CCA2 ClinicalTrials.gov number, NCT02052778.).
Insights
Futibatinib demonstrated significant antitumor activity in patients with advanced intrahepatic cholangiocarcinoma harboring FGFR2 alterations. This FGFR inhibitor showed clinical benefit, including objective responses and prolonged survival, with manageable safety in a phase 2 study.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Fibroblast growth factor receptor 2 (FGFR2) alterations are key targets in intrahepatic cholangiocarcinoma (ICC), a rare and aggressive cancer.
- Futibatinib, a next-generation covalent inhibitor of FGFR1-4, exhibits antitumor activity and overcomes resistance mechanisms.
Purpose of the Study:
- To evaluate the efficacy and safety of futibatinib in patients with previously treated, unresectable or metastatic FGFR2 fusion-positive or rearrangement-positive ICC.
- To assess objective response rate, duration of response, progression-free survival, overall survival, and safety profile.
Main Methods:
- A multinational, open-label, single-group, phase 2 study enrolled 103 patients with advanced ICC and documented FGFR2 alterations.
- Patients received oral futibatinib 20 mg once daily.
- Primary endpoint was objective response assessed by independent central review; secondary endpoints included survival and safety.
Main Results:
- An objective response rate of 42% was observed, with a median duration of response of 9.7 months.
- Median progression-free survival was 9.0 months, and median overall survival was 21.7 months.
- Common grade 3 adverse events included hyperphosphatemia (30%) and stomatitis (6%); treatment discontinuation occurred in 2% of patients.
Conclusions:
- Futibatinib demonstrated significant clinical benefit in previously treated patients with FGFR2-altered ICC.
- The drug showed a favorable efficacy and safety profile, maintaining quality of life.
- Futibatinib represents a promising therapeutic option for this patient population.
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