DOI: 10.1097/hep.0000000000001902 ISSN: 0270-9139
A pivotal Phase 2 study of derazantinib for previously-treated, locally advanced or metastatic cholangiocarcinoma with FGFR2 aberrations: FIDES-01
Mitesh J. Borad, Michele Droz dit Busset, Milind M. Javle, Walid L. Shaib, Nicola Personeni, Kabir Mody, Hani Babiker, Francesca Bergamo, William P. Harris, Nevena Damjanov, Teresa Macarulla, Giovanni Brandi, Gianluca Masi, Ghassan K. Abou-Alfa, Thorvardur R. Halfdanarson, Jennifer Knox, Vincent C. Tam, Mathieu Bernat, Marc Engelhardt, Silke Friedmann, Manuel Häckl, Phil McKernan, Mikael Saulay, Laura W. Goff, Antoine Hollebecque, Jorge Adeva, Thomas R. Jeffry Evans, John Bridgewater, Friedrich Foerster, Stephan DiSean Kendall, Gaël Roth, David Cunningham, Arndt Vogel, Monica Niger, Amit Mahipal, Vincenzo Mazzaferro
Background & Aims:
To evaluate safety and efficacy of FGFR1–3 kinase inhibitor derazantinib, in advanced intrahepatic cholangiocarcinoma (iCCA) harboring
FGFR2
fusions or rearrangements (
FGFR2
F
), mutations (
FGFR2
M
), or amplifications (
FGFR2
A
), previously treated with chemotherapy.
Approach & Results:
Open-label, non-controlled Phase 2 trial. Patients with advanced iCCA, ≥1 prior chemotherapy, and
FGFR2
F
(Substudy 1) or
FGFR2
M
/FGFR
A
(Substudy 2), received once-daily oral derazantinib 300 mg until disease progression, unacceptable toxicity, consent withdrawal or investigator decision to stop. Efficacy was assessed by central radiology review using RECIST v1.1. Primary endpoints were objective response rate (ORR; Substudy 1) and 3-month progression-free survival (PFS3; Substudy 2). Other endpoints were PFS, ORR (Substudy 2), disease control rate (DCR), duration of response (DOR), and overall survival (OS). In Substudy 1, ORR and DCR were 22.3% (23/103 partial responses) and 75.7%, respectively; median (95% CI) PFS was 8.1 (5.5,8.3) months, DOR was 6.5 (4.6,9.2) months, and OS was 17.2 (12.5,22.4) months. In Substudy 2, PFS3 was 63% (27/43), ORR was 9.3% (3 partial, 1 complete response), DCR was 69.8%, and OS was 11.9 (8.4,15.9) months. There were no Grade 4 or 5 drug-related events. FGFR inhibitor class-specific toxicities included drug-related hyperphosphataemia (38%, Grade 3: 3%) and dry eye (36%). Nail disorders (10%, any grade or causality), stomatitis (5%), retinal events (5%), and palmar-plantar erythrodysesthesia (1%) were infrequent.
Conclusions:
In previously chemotherapy treated, FGFR-inhibitor-naïve patients with iCCA harboring
FGFR2
fusions, mutations, or amplifications, derazantinib showed clinically meaningful efficacy with durable objective responses, and a manageable safety profile.