Elsevier

The Lancet Oncology

Volume 21, Issue 5, May 2020, Pages 671-684
The Lancet Oncology

Articles
Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study

https://doi.org/10.1016/S1470-2045(20)30109-1Get rights and content

Summary

Background

Fibroblast growth factor receptor (FGFR) 2 gene alterations are involved in the pathogenesis of cholangiocarcinoma. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3. This study evaluated the safety and antitumour activity of pemigatinib in patients with previously treated, locally advanced or metastatic cholangiocarcinoma with and without FGFR2 fusions or rearrangements.

Methods

In this multicentre, open-label, single-arm, multicohort, phase 2 study (FIGHT-202), patients aged 18 years or older with disease progression following at least one previous treatment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 recruited from 146 academic or community-based sites in the USA, Europe, the Middle East, and Asia were assigned to one of three cohorts: patients with FGFR2 fusions or rearrangements, patients with other FGF/FGFR alterations, or patients with no FGF/FGFR alterations. All enrolled patients received a starting dose of 13·5 mg oral pemigatinib once daily (21-day cycle; 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, withdrawal of consent, or physician decision. The primary endpoint was the proportion of patients who achieved an objective response among those with FGFR2 fusions or rearrangements, assessed centrally in all patients who received at least one dose of pemigatinib. This study is registered with ClinicalTrials.gov, NCT02924376, and enrolment is completed.

Findings

Between Jan 17, 2017, and March 22, 2019, 146 patients were enrolled: 107 with FGFR2 fusions or rearrangements, 20 with other FGF/FGFR alterations, 18 with no FGF/FGFR alterations, and one with an undetermined FGF/FGFR alteration. The median follow-up was 17·8 months (IQR 11·6–21·3). 38 (35·5% [95% CI 26·5–45·4]) patients with FGFR2 fusions or rearrangements achieved an objective response (three complete responses and 35 partial responses). Overall, hyperphosphataemia was the most common all-grade adverse event irrespective of cause (88 [60%] of 146 patients). 93 (64%) patients had a grade 3 or worse adverse event (irrespective of cause); the most frequent were hypophosphataemia (18 [12%]), arthralgia (nine [6%]), stomatitis (eight [5%]), hyponatraemia (eight [5%]), abdominal pain (seven [5%]), and fatigue (seven [5%]). 65 (45%) patients had serious adverse events; the most frequent were abdominal pain (seven [5%]), pyrexia (seven [5%]), cholangitis (five [3%]), and pleural effusion (five [3%]). Overall, 71 (49%) patients died during the study, most frequently because of disease progression (61 [42%]); no deaths were deemed to be treatment related.

Interpretation

These data support the therapeutic potential of pemigatinib in previously treated patients with cholangiocarcinoma who have FGFR2 fusions or rearrangements.

Funding

Incyte Corporation.

Introduction

Cholangiocarcinomas are a group of heterogeneous tumours classified as intrahepatic or extrahepatic (perihilar and distal) based on the tumour location in the biliary tract.1 Comprehensive genomic profiling has identified several potentially actionable oncogenic alterations in patients with cholangiocarcinoma,2 including in genes encoding fibroblast growth factor receptor (FGFR). Somatic alterations in FGFR can lead to aberrant FGFR signalling, which can drive tumorigenesis by enhancing cellular proliferation, migration, survival, and invasion, as well as angiogenesis.3 FGFR2 fusions and rearrangements are found almost exclusively in intrahepatic cholangiocarcinoma, occurring in 10–16% of patients.4, 5, 6 Consequently, in addition to other targeted agents, FGFR inhibitors are garnering interest as potential therapeutics for cholangiocarcinoma.7

Surgery is currently the only curative treatment for cholangiocarcinoma; however, surgery is an option for only around 35% of patients8 and, of those who undergo potentially curative resection, approximately 35% subsequently relapse within 2 years.9 The standard-of-care first-line treatment for locally advanced or metastatic cholangiocarcinoma is gemcitabine plus cisplatin.10 There is no established standard-of-care after failure of first-line chemotherapy, and the efficacy of second-line chemotherapy regimens for advanced biliary cancer remains low.11, 12, 13

Research in context

Evidence before this study

The incidence of intrahepatic cholangiocarcinoma has steadily increased worldwide over the past several decades, as have annual age-adjusted mortality rates. The standard-of-care first-line treatment for locally advanced or metastatic cholangiocarcinoma is gemcitabine plus cisplatin. However, treatment options are limited in the second-line setting. Several potentially actionable oncogenic alterations have been identified in patients with cholangiocarcinoma, including alterations in the fibroblast growth factor receptor (FGFR) gene. We searched PubMed and the American Society of Clinical Oncology and European Society for Medical Oncology abstract databases for manuscripts and abstracts published from database inception to Nov 14, 2019, without language restrictions. The search terms used were (“cholangiocarcinoma” OR “biliary tract cancer”) AND (“fibroblast growth factor receptor” OR “FGFR”). We identified 67 publications supporting a role for FGFR inhibitors in the treatment of intrahepatic cholangiocarcinoma, and for clinical trials in molecularly selected patient populations. Preclinical studies show that pemigatinib is a selective, potent, oral competitive inhibitor of FGFR1, FGFR2, and FGFR3. There are currently no published clinical studies of pemigatinib in this patient population.

Added value of this study

The FIbroblast Growth factor receptor inhibitor in oncology and Hematology Trial (FIGHT-202) is an international, open-label phase 2 trial evaluating the safety and antitumour activity of pemigatinib in 146 previously treated patients with locally advanced or metastatic cholangiocarcinoma. Among 107 patients with FGFR2 fusions or rearrangements, 38 (36%) achieved an objective response. This encouraging antitumour activity was observed across demographic and disease subgroups, including in heavily pretreated patients. The most common all-cause adverse event was hyperphosphataemia. Notable aspects of this study include incorporation of FGFR2 fusion partner-agnostic next-generation sequencing (ability to detect both known and novel FGFR2 fusions), and an independent central review of clinical responses. Moreover, the international design facilitated the enrolment of a large number of patients with cholangiocarcinoma with FGF/FGFR alterations (mostly FGFR2 rearrangements), despite this being a relatively rare cancer and a rare genomic alteration. This achievement provides impetus for future clinical trials in cholangiocarcinoma and in other rare cancers, for which achieving sufficient patient enrolment numbers can be challenging. Taken together, the data from this study add to a growing body of evidence supporting a role for FGFR inhibitors and other targeted agents for the treatment of cholangiocarcinoma by demonstrating that pemigatinib possesses antitumour activity and is associated with a manageable safety profile in patients with FGFR2 fusions or rearrangements.

Implications of all the available evidence

Based on the encouraging findings from this study, an international, phase 3, randomised, active-controlled trial is currently recruiting patients to compare pemigatinib with gemcitabine plus cisplatin chemotherapy as first-line therapy for unresectable or metastatic cholangiocarcinoma with FGFR2 rearrangements (FIGHT-302; ClinicalTrials.gov, NCT03656536). Pemigatinib could add to the range of treatments available to patients with cholangiocarcinoma and FGFR2 fusions or rearrangements, for whom current systemic therapies are not sufficiently effective.

Pemigatinib is a selective, potent, oral competitive inhibitor of FGFR1, FGFR2, and FGFR3.14 We report the final results from the multicentre, open-label phase 2 FIbroblast Growth factor receptor inhibitor in oncology and Hematology Trial (FIGHT-202), evaluating the safety and antitumour activity of pemigatinib in previously treated patients with locally advanced or metastatic cholangiocarcinoma, with or without FGF/FGFR alterations.

Section snippets

Study design and participants

This open-label, single-arm phase 2 trial was done at 146 academic or community-based sites in the USA, Europe, the Middle East, and Asia (appendix pp 2–4).

Patients were identified during routine clinical practice. Eligible patients were aged 18 years or older, had a histological or cytological diagnosis of locally advanced or metastatic cholangiocarcinoma with documented disease progression following at least one previous systemic cancer therapy (previous treatment with selective FGFR

Results

1206 patients were centrally prescreened for FGF/FGFR status using FoundationOne. 1120 patients did not harbor FGF/FGFR alterations or declined participation; the remaining 86 were assessed for eligibility (figure 1). An additional 85 patients already had an FGF/FGFR report from FoundationOne or from a local CLIA-certified test, all of whom were assessed for eligibility. Among these 171 patients, 146 were enrolled (25 patients who were centrally prescreened for FGF/FGFR status did not meet

Discussion

In this multicentre, open-label, phase 2 study in patients with cholangiocarcinoma who had progressed after at least one previous systemic therapy, 35·5% of patients with FGFR2 fusions or rearrangements treated with pemigatinib achieved an objective response, and responses were durable. No patients with other FGF/FGFR alterations or no FGF/FGFR alterations achieved a response, and overall survival and progression-free survival remained poor in these cohorts. The encouraging antitumour activity

Data sharing

Access to participant-level data for this study is not available at this time.

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