Infigratinib (BGJ398) in previously treated patients with advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements: mature results from a multicentre, open-label, single-arm, phase 2 study
Treatment options are sparse for patients with advanced cholangiocarcinoma after progression on first-line gemcitabine-based therapy. FGFR2 fusions or rearrangements occur in 10–16% of patients with intrahepatic cholangiocarcinoma. Infigratinib is a selective, ATP-competitive inhibitor of fibroblast growth factor receptors. We aimed to evaluate the antitumour activity of infigratinib in patients with locally advanced or metastatic cholangiocarcinoma, FGFR2 alterations, and previous gemcitabine-based treatment.
Methods
This multicentre, open-label, single-arm, phase 2 study recruited patients from 18 academic centres and hospitals in the USA, Belgium, Spain, Germany, Singapore, Taiwan, and Thailand. Eligible participants were aged 18 years or older, had histologically or cytologically confirmed, locally advanced or metastatic cholangiocarcinoma and FGFR2 fusions or rearrangements, and were previously treated with at least one gemcitabine-containing regimen. Patients received 125 mg of oral infigratinib once daily for 21 days of 28-day cycles until disease progression, intolerance, withdrawal of consent, or death. Radiological tumour evaluation was done at baseline and every 8 weeks until disease progression via CT or MRI of the chest, abdomen, and pelvis. The primary endpoint was objective response rate, defined as the proportion of patients with a best overall response of a confirmed complete or partial response, as assessed by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors, version 1.1. The primary outcome and safety were analysed in the full analysis set, which comprised all patients who received at least one dose of infigratinib. This trial is registered with ClinicalTrials.gov, NCT02150967, and is ongoing.
Findings
Between June 23, 2014, and March 31, 2020, 122 patients were enrolled into our study, of whom 108 with FGFR2 fusions or rearrangements received at least one dose of infigratinib and comprised the full analysis set. After a median follow-up of 10·6 months (IQR 6·2–15·6), the BICR-assessed objective response rate was 23·1% (95% CI 15·6–32·2; 25 of 108 patients), with one confirmed complete response in a patient who only had non-target lesions identified at baseline and 24 partial responses. The most common treatment-emergent adverse events of any grade were hyperphosphataemia (n=83), stomatitis (n=59), fatigue (n=43), and alopecia (n=41). The most common ocular toxicity was dry eyes (n=37). Central serous retinopathy-like and retinal pigment epithelial detachment-like events occurred in 18 (17%) patients, of which ten (9%) were grade 1, seven (6%) were grade 2, and one (1%) was grade 3. There were no treatment-related deaths.
Interpretation
Infigratinib has promising clinical activity and a manageable adverse event profile in previously treated patients with locally advanced or metastatic cholangiocarcinoma harbouring FGFR2 gene fusions or rearrangements, and so represents a potential new therapeutic option in this setting.
Funding
QED Therapeutics and Novartis.
Introduction
Cholangiocarcinoma is a rare and aggressive malignancy that typically presents at diagnosis as locally advanced or metastatic disease.1 The per-capita incidence of cholangiocarcinoma is highest in northeastern Thailand and lowest in Canada.2 In the USA, the incidence of intrahepatic cholangiocarcinoma increased between 2000 and 2015, with an annual percentage change of 5·06%,3 and an estimated 8000 new cases of cholangiocarcinoma are diagnosed annually.4 Patients with metastatic disease survive for an estimated median of 11·7 months (95% CI 9·5–14·3) from the time of diagnosis5 and the 5-year relative survival rate for patients with metastatic intrahepatic cholangiocarcinoma is 2%.4
First-line treatment options for patients with locally advanced or metastatic cholangiocarcinoma include gemcitabine plus cisplatin, which is the only regimen for which National Comprehensive Cancer Network level 1 evidence is available (based on the results of the ABC-02 study).5, 6 Second-line options include fluorouracil–folinic acid–oxaliplatin (FOLFOX),7 gemcitabine-based combinations, or fluorouracil-based combinations, although there is insufficient evidence to recommend specific regimens in this setting.8
Research in context
Evidence before this study
Treatment options for patients with cholangiocarcinoma after progression on first-line gemcitabine-based therapy are sparse and prognosis is poor. Identification of molecular drivers implicated in the development of specific cholangiocarcinoma subtypes is changing the standard of care in this disease. These drivers include genomic alterations in the fibroblast growth factor receptor (FGFR), particularly FGFR2 fusions or rearrangements, which have been shown to drive tumourigenesis in cholangiocarcinoma and other cancers. We searched PubMed for articles published in English between Jan 1, 2010, and Jan 6, 2021, using the search terms “advanced OR metastatic, cholangiocarcinoma OR biliary tract cancer”, “treatment”, and “FGFR OR fibroblast growth factor receptor”. We identified six reports describing clinical trials of FGFR inhibitors in patients with cholangiocarcinoma harbouring alterations in the genes coding for fibroblast growth factors and FGFRs, reflecting the relative novelty of this approach. Only two completed phase 2 studies, involving infigratinib and pemigatinib, have been reported to date.
Added value of this study
Our study is an ongoing, open-label, multicohort, phase 2 study evaluating the safety and activity of infigratinib in patients with locally advanced or metastatic cholangiocarcinoma that has progressed on one or more previous treatment lines. Accrual into cohort 1, which includes 108 patients with FGFR2 fusions or other rearrangements, is now complete. We observed objective, confirmed responses in 25 patients (objective response rate 23·1%, 95% CI 15·6–32·2), with responses in all subgroups studied, including in patients who had two or more previous treatment lines. The adverse event profile of infigratinib was consistent with previous reports and in line with reported class effects of these agents. Cohorts 2 and 3 are ongoing and will provide further insight into the activity of infigratinib in patients with other FGFR alterations and in those previously exposed to FGFR inhibitors other than infigratinib.
Implications of all the available evidence
Infigratinib, administered as a second-line or later-line treatment, showed meaningful clinical activity against chemotherapy-refractory cholangiocarcinoma with FGFR2 fusions or rearrangements. Adverse events were largely reversible and manageable, and consistent with previous observations in this patient population. The encouraging findings from this study have resulted in the initiation of a phase 3 study of infigratinib versus gemcitabine–cisplatin in the first-line setting (NCT03773302). Infigratinib represents a potential new therapeutic option for patients with cholangiocarcinoma and FGFR fusions or rearrangements.
Molecular drivers implicated in the development of specific cholangiocarcinoma subtypes have been identified,9, 10 including genomic alterations in the fibroblast growth factor receptor (FGFR) genes that result in constitutively active FGFR signalling. These FGFR alterations have been implicated in cholangiocarcinoma11 and urothelial cancer.12FGFR2 fusions or rearrangements (fusion events) have been identified in 10–16% of patients with intrahepatic cholangiocarcinoma.13, 14 Second-line or later-line chemotherapy has limited efficacy in FGFR-altered cholangiocarcinoma. Among 37 patients with advanced cholangiocarcinoma and FGFR2 fusions who were undergoing third-line treatment with an FGFR inhibitor, retrospective analysis of outcomes associated with the second-line regimen identified a median progression-free survival of 4·6 months (95% CI 2·7–7·2) and an objective response rate of 5·4%.15 Available literature does not show a clear advantage for second-line chemotherapy in patients with FGFR2 fusion-positive versus FGFR2 wild-type cholangiocarcinoma and this topic is an intense area of investigation because of the small, retrospective nature of existing studies.16
Phase 1 and 2 trials with FGFR inhibitors, including infigratinib, have shown single-agent complete and partial responses, per Response Evaluation Criteria in Solid Tumours (RECIST), in patients with cholangiocarcinoma harbouring FGFR2 fusions and the development of treatment resistance through mutations in FGFR2,17 further supporting FGFR2 fusions as a therapeutic target for molecularly selected patients with cholangiocarcinoma.17, 18 Currently, only two FGFR inhibitors have received accelerated approval by the US Food and Drug Administration (FDA) for the targeted treatment of advanced solid malignancies: erdafitinib for patients with locally advanced or metastatic urothelial carcinoma with susceptible FGFR3 or FGFR2 alterations and progression following at least one line of previous platinum-containing chemotherapy,19 and pemigatinib for patients with previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion.20 Futibatinib has also received breakthrough therapy designation by the FDA for the treatment of patients with previously treated, locally advanced or metastatic cholangiocarcinoma with FGFR2 fusions and other rearrangements.21 Given the heterogeneous nature of FGFR alterations and the emergence of resistance mechanisms, more agents able to effectively inhibit FGFR alterations are needed.
Infigratinib (BGJ398) is an orally bioavailable, potent, selective ATP-competitive inhibitor of FGFRs.22, 23 Infigratinib selectively inhibits the kinase activity of FGFR-1, FGFR-2, and FGFR-3, with single-digit nanomolar inhibitory concentration values.23 Infigratinib has shown single-agent activity and a manageable safety profile against tumours with FGFR alterations in early clinical studies.24
We aimed to evaluate the antitumour activity of infigratinib in patients with locally advanced or metastatic cholangiocarcinoma, FGFR2 alterations, and previous gemcitabine-based treatment.25 Interim results, which included safety and activity data from 71 patients in cohort 1, have previously been reported.26 We now report a mature analysis after completing accrual in cohort 1.
Section snippets
Study design and participants
This multicentre, open-label, single-arm, phase 2 study was done in patients with unresectable, locally advanced or metastatic cholangiocarcinoma with FGFR alterations who had previously received gemcitabine, with or without cisplatin or carboplatin, in the advanced or metastatic setting. Patients were recruited from 18 academic centres and hospitals in the USA, Belgium, Spain, Germany, Singapore, Taiwan, and Thailand. The study design comprised three cohorts. Cohort 1, which has completed
Results
Between June 23, 2014, and March 31, 2020, (the data cutoff date for this analysis), 122 patients were enrolled into our study, of whom 108 with FGFR2 fusions or rearrangements were included in cohort 1, received at least one dose of infigratinib, and comprised the full analysis set (figure 1). FGFR2 fusion status was determined by local or institutional laboratory tests in 96 (89%) of 108 patients by use of next-generation sequencing (84 [78%] patients), fluorescence in situ hybridisation
Discussion
These mature results from our study show that infigratinib had meaningful clinical activity in patients with previously treated cholangiocarcinoma harbouring FGFR2 fusions or rearrangements, half of whom were being treated in the third or later line. The confirmed BICR-assessed objective response rate was 23·1% (95% CI 15·6–32·2) and the objective response rate in the second-line setting was 34·0% (21·2–48·8). The median time to response was 3·6 months, the median duration of response was 5·0
Data sharing
The deidentified individual participant data that underlie the results reported in this Article, the research protocol, data dictionaries, and additional supporting documents might be made available on written request from qualified researchers for scientifically valid research proposals submitted to the authors of this publication ([email protected]). Data requests shall be considered beginning 6 months and ending 2 years after publication of the study, provided that any investigational drug
This document is a summary of the French intergroup guidelines of the management of biliary tract cancers (BTC) (intrahepatic, perihilar and distal cholangiocarcinomas, and gallbladder carcinomas) published in September 2023, available on the website of the French Society of Gastroenterology (SNFGE) (www.tncd.org).
This collaborative work was conducted under the auspices of French medical and surgical societies involved in the management of BTC. Recommendations were graded in three categories (A, B and C) according to the level of scientific evidence until August 2023.
BTC diagnosis and staging is mainly based on enhanced computed tomography, magnetic resonance imaging and (endoscopic) ultrasound-guided biopsy. Treatment strategy depends on BTC subtype and disease stage. Surgery followed by adjuvant capecitabine is recommended for localised disease. No neoadjuvant treatment is validated to date. Cisplatin-gemcitabine chemotherapy combined to the anti-PD-L1 inhibitor durvalumab is the first-line standard of care for advanced disease. Early systematic tumour molecular profiling is recommended to screen for actionable alterations (IDH1 mutations, FGFR2 rearrangements, HER2 amplification, BRAFV600E mutation, MSI/dMMR status, etc.) and guide subsequent lines of treatment. In the absence of actionable alterations, FOLFOX chemotherapy is the only second-line standard-of-care. No third-line chemotherapy standard is validated to date.
These guidelines are intended to provide a personalised therapeutic strategy for daily clinical practice. Each individual BTC case should be discussed by a multidisciplinary team.
Achondroplasia is the most common form of dwarfism in humans, caused by a common pathogenic variant in the gene encoding fibroblast growth factor receptor 3, FGFR3, which impairs the process of endochondral ossification of the growing skeleton. In this Review, we outline the clinical and genetic hallmarks of achondroplasia and related FGFR3 conditions, the natural history and impact of achondroplasia over a patient's lifespan, and diagnosis and management options. We then focus on the new and emerging drug therapies that target the underlying pathogenesis of this condition. These new options are changing the natural growth patterns of achondroplasia, with the prospect of better long-term health outcomes for patients.
2024, International Journal of Radiation Oncology Biology Physics
Combinatorial therapies consisting of radiation therapy (RT) with systemic therapies, particularly chemotherapy and targeted therapies, have moved the needle to augment disease control across nearly all disease sites for locally advanced disease. Evaluating these important combinations to incorporate more potent therapies with RT will aid our understanding of toxicity and efficacy for patients. This article discusses multiple disease sites and includes a compilation of contributions from expert Red Journal editors from each disease site. Leveraging improved systemic control with novel agents, we must continue efforts to study novel treatment combinations with RT.
Aberrant signaling via fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR4) has been identified as a driver of tumorigenesis and the development of many solid tumors, making FGFR4 is a promising target for anticancer therapy. Herein, we designed and synthesized a series of bis-acrylamide covalent FGFR4 inhibitors and evaluated their inhibitory activity against FGFRs, FGFR4 mutants, and their antitumor activity. CXF-007, verified by mass spectrometry and crystal structures to form covalent bonds with Cys552 of FGFR4 and Cys488 of FGFR1, exhibited stronger selectivity and potent inhibitory activity for FGFR4 and FGFR4 cysteine mutants. Moreover, CXF-007 exhibited significant antitumor activity in hepatocellular carcinoma cell lines and breast cancer cell lines through sustained inhibition of the FGFR4 signaling pathway. In summary, our study highlights a novel covalent FGFR4 inhibitor, CXF-007, which has the potential to overcome drug-induced FGFR4 mutations and might provide a new strategy for future anticancer drug discovery.
Novel tissue-agnostic therapeutics targeting driver mutations in tumor cells have been recently approved by FDA, driven by basket trials that have demonstrated their efficacy and safety across diverse tumor histology. However, the relative rarity of primary brain tumors (PBTs) has limited their representation in early trials of tissue-agnostic medications. Thus, consensus continues to evolve regarding utility of tissue-agnostic medications in routine practice for PBTs, a diverse group of neoplasms characterized by limited treatment options and unfavorable prognoses. We describe current and potential impact of tissue-agnostic approvals on management of PBTs. We discuss data from clinical trials for PBTs regarding tissue-agnostic targets, including BRAFV600E, neurotrophic tyrosine receptor kinase (NTRK) fusions, microsatellite instability-high (MSI-High), mismatch repair deficiency (dMMR), and high tumor mutational burden (TMB-H), in context of challenges in managing PBTs. Described are additional tissue-agnostic targets that hold promise for benefiting patients with PBTs, including RET fusion, fibroblast growth factor receptor (FGFR), ERBB2/HER2, and KRASG12C, and TP53Y220C.
