ABSTRACT
Introduction
The fibroblast growth factor receptor (FGFR) pathway is essential in cell proliferation, differentiation, migration, and survival. Cancers such as intrahepatic cholangiocarcinoma (IHCA) have demonstrated alterations of FGFR allowing unregulated growth. Infigratinib (BGJ398) is a potent ATP-competitive inhibitor of all four FGFR receptors as demonstrated by the consistently high prevalence of hyperphosphatemia, indicating disruption of FGFR-related phosphate homeostasis.
Areas covered
In this article, the authors discuss preclinical studies and the biological characterization of BGJ398 that inspired its investigation for cancer treatment. They summarize results from phase I and II studies and comment on ongoing phase III clinical trials primarily focusing on its role in treating IHCA.
Expert opinion
Infigratinib exhibits high potency FGFR1-3 inhibition in preclinical studies. Clinically, agents targeting FGFR including infigratinib show promising anti-tumor activity in targeted trials. Pemigatinib, an FGFR inhibitor, has recently been approved by the FDA for use in refractory IHCA. We believe infigratinib represents a promising agent in the treatment of refractory IHCA with FGFR2 fusions and is uniquely positioned to be a potential option in chemonaive patient populations. An ongoing phase III trial (PROOF-301) compares the efficacy and safety of infigratinib versus standard gemcitabine and cisplatin in untreated patients with IHCA and FGFR2 fusions.
Article Highlights
Fibroblastic growth factor receptor (FGFR) alterations including mutations, amplifications, and fusions have been demonstrated in a wide variety of cancers, including intrahepatic cholangiocarcinoma (IHCA) where there is often a need for salvage therapy.
The reversible noncompetitive inhibitor Infigratinib (BGJ398) is a highly selective for FGFR1-3 with a tolerable safety profile and promising preliminary activity based on a phase II clinical trial in patients with refractory IHCA and FGFR2 fusions.
A phase III clinical trial (PROOF-301) is ongoing to evaluate the efficacy of infigratinib compared to the current standard of gemcitabine and cisplatin for IHCA with FGFR2 fusions.
FGFR inhibition with Infigratinib has been used to enhance the apoptotic effect of chemotherapy agents, and infigratinib’s role in combination therapy must be addressed due to demonstrated resistance to FGFR inhibition with chronic BGJ398 exposure.
Other FGFR inhibitors have been evaluated in the treatment of IHCA, and pemigatinib is the first FGFR inhibitor approved by the FDA as salvage therapy for unresectable advanced IHCA and FGFR2 fusions demonstrating a role for this class of therapeutic in the treatment of IHCA.
This box summarizes key points contained in the article.
Overview of the Market
The available therapies for unresectable intrahepatic cholangiocarcinoma (IHCA) are limited. Beyond the standard first-line therapy of gemcitabine and cisplatin, the patient is often left without standard options. FGFR alterations including mutations, amplifications, and fusions have been demonstrated in a wide variety of cancers, including intrahepatic cholangiocarcinoma (IHCA) where there is often a need for salvage therapy. The recent FDA approval of the FGFR inhibitor pemigatinib suggests clinical relevance of targeting FGFR2 fusions in IHCA. Another FGFR inhibitor infigratinib has shown promise in early phase trials and is under investigation in a phase III randomized trial versus standard gemcitabine and cisplatin for IHCA with FGFR2 fusions. Additional FGFR inhibitors are being evaluated in intrahepatic cholangiocarcinoma with FGFR2 fusions including derazantinib, fubatinib, and erdafitinib.
Declaration of interest
Dr. Tanios Bekaii-Saab’s institution consults with Ipsen, Array Biopharma, Pfizer, Seattle Genetics, Bayer, Genentech, Incyte, Merck and has research funding from the above sources in addition to Agios, Arys, Boston Biomedical, Amgen, Celgene, Lilly, Clovis, Novartis, Mirati, Merus, Abgenomics, and BMS. He is a consultant for AbbVie, Boehringer Ingelheim, Janssen, Eisai, Daichii Sankyo, Natera, TreosBio, Celularity, Exact Science, Sobi, Beigene, Xilis, Astra Zeneca, Foundation Medicine and is on the scientific advisory board for Imugene, Immuneering, and Sun Biopharma. He is on the IDMC/DSMB for Astra Zeneca, Exelixis, Lilly, PanCan, 1Globe and has two patents, WO/2018/183,488 and WO/2019/055687. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.
Reviewers Disclosure
Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.