Infigratinib Shows Promising Early Activity in FGFR2-Altered Cholangiocarcinoma


The FGFR inhibitor infigratinib demonstrated promising clinical activity and a manageable safety profile in previously treated patients with locally advanced or metastatic cholangiocarcinoma whose tumors harbor FGFR2 gene fusions or rearrangement.

The FGFR inhibitor infigratinib (Truseltiq) demonstrated promising clinical activity and a manageable safety profile in previously treated patients with locally advanced or metastatic cholangiocarcinoma whose tumors harbor FGFR2 gene fusions or rearrangements. Investigators in a phase 2 trial (NCT02150967) believe these data published in The Lancet Gastroenterology and Hepatology could represent a new tool to treat this disease.1

Results showed that at a median follow up of 10.6 months (range, 6.2-15.6), the blinded independent central review (BICR) assessed objective response rate (ORR) with infigratinib was 23.1% (95% CI 15.6%-32.2%). These findings included 1 complete response (CR; 1%) and 24 partial responses (PRs; 22%).

“Infigratinib, administered as a second-line or later-line treatment, represents a potential new therapeutic option for patients with cholangiocarcinoma and FGFR2 fusions or rearrangements,” study authors wrote.

For patients with locally advanced or metastatic cholangiocarcinoma, the standard-of-care first-line treatment is gemcitabine plus cisplatin chemotherapy. Second-line treatment options include FOLFOX and gemcitabine- or fluorouracil-based combinations, although evidence is lacking for specific recommendations in this setting. Moreover, investigators have identified molecular drivers implicated in the development of specific cholangiocarcinoma subtypes, such as FGFR alterations, and second-line chemotherapy regimens have shown limited efficacy in patients with these alterations.

Previous phase 1 and 2 trials examining FGFR inhibitors have shown single-agent CRs and PRs in patients with FGFR2-altered cholangiocarcinoma, as well as the development of treatment resistance through mutations in FGFR2. This further supports utilizing FGFR2 fusions as a therapeutic target for molecularly selected patients.

The FDA has issued accelerated approvals for the FGFR inhibitors erdafitinib (Balversa) and pemigatinib (Pemazyre) have received by the FDA for this patient population. The agency granted a breakthrough therapy designation to a third FGFR inhibitor, futibatinib, in April 2021. However, investigators want to develop more agents to address the heterogeneity of FGFR alterations and the emergence of resistance mechanisms.

Infigratinib is a potent, selective ATP-competitive inhibitor of FGFR, with single-digit nanomolar inhibitory concentration values. Additionally, the agent has shown single-agent activity and a manageable safety profile against tumors with FGFR alterations in early clinical studies. As such, investigators sought to evaluate the antitumor activity of infigratinib in patients with locally advanced or metastatic cholangiocarcinoma, whose tumors harbor FGFR2 alterations, and who had received previous gemcitabine-based chemotherapy.

Investigators are conducting the 3-arm, phase 2, open-label, multicenter trial at 18 academic centers and hospitals in the United States, Belgium, Spain, Germany, Singapore, Taiwan, and Thailand. Cohort 1 is comprised of patients with FGFR2 fusions or rearrangements who have not received previous selective FGFR inhibitors. Cohort 2 will comprise patients with FGFR1 mutations and fusions or rearrangements, FGFR3 mutations and fusions or rearrangements, or FGFR2 mutations, who have not previously received an FGFR inhibitor. Finally, Cohort 3 will recruit patients with FGFR2 fusions or rearrangements who had received previous treatment with an FGFR inhibitor other than infigratinib.

Adults with histologically or cytologically confirmed cholangiocarcinoma with FGFR2 fusions or rearrangements are eligible for Cohort 1. Eligible patients were also required to have received at least 1 previous gemcitabine-based regimen for advanced or metastatic disease, as well as documented progression following that previous regimen or discontinuation from the previous regimen because of toxicity, an ECOG performance status of 1 or less, and measurable disease.

Those with cancer of the gallbladder or ampulla of Vater were not eligible. Additionally, patients who had been previously or are currently being treated with a mitogen-activated protein kinase kinase inhibitor, infigratinib, or another selective FGFR inhibitor, and those with neurological symptoms related to an underlying disease that required increasing doses of corticosteroids, current evidence of corneal or retinal disorders, or a history or current evidence of extensive tissue calcification, were not able to enroll.

Patients were assigned to 125 mg once-daily oral infigratinib for 21 consecutive days in 28-day cycles until disease progression, intolerance, withdrawal of consent, or death. Patients were allowed dose modifications and/or treatment interruptions of up to 14 days for the management of adverse effects (AEs).

The primary end point of the study was BICR-assessed ORR. Secondary endpoints included investigator-assessed ORR, BICR-assessed and investigator-assessed best overall response, BICR-assessed and investigator-assessed disease control rate (DCR), time to response (TTR), BICR-assessed and investigator-assessed progression-free survival (PFS), overall survival (OS), safety, and tolerability.

Among the 108 patients enrolled on Cohort 1 of the study, the median age was 53 years old (range, 44-64), and a majority were female (62%), White (72%), and located in North America (71%). Fifty-seven percent of patients had an ECOG performance status of 1, and 99% had stage IV disease. Additionally, 69% of patients had extrahepatic metastasis in the lungs, 57% in the lymph nodes, 26% in the bone, 15% in the peritoneum or ascites, and 33% in other locations. Furthermore, 63% had 2 or more metastatic sites, and 46% had received 1 or more lines of prior treatment.

The median TTR was 3.6 months (range, 1.8-3.8) and the median duration of response (DOR) was 5.0 months (range, 3.7-9.3). DCR was 84.3% (95% CI, 76.0%-90.6%). The investigator-assessed ORR was 30.6% (95% CI, 22.1%-40.2%) and the median investigator-assessed DOR was

6.0 months (range, 4.9-9.2). The discordance rate of BICR-assessed vs investigator-assessed confirmed responses was 20.4%.

At the time of data cutoff, the median PFS was 7.3 months (95% CI, 5.6-7.6) and the median OS was 12.2 months (95% CI, 10.7-14.9). Furthermore, the median duration of treatment with infigratinib was 5.5 months (range, 3.5-8.7).

In terms of safety, the most common treatment-emergent AEs (TEAEs) of any grade were hyperphosphatemia (77%), stomatitis (55%), fatigue (40%), alopecia (38%), and dry eye (34%). Grade 3 TEAEs occurred in 56% of patients, the most common of which were stomatitis (15%), hyponatremia (13%), and hypophosphatemia (12%). The median time to first onset of hyperphosphatemia was 8 days (range, 8-15), and no patients discontinued treatment because of hyperphosphatemia.

Overall, 60% of patients experienced AEs leading to dose reduction and 64% had AEs requiring dose interruption.

“Results from cohorts 2 and 3 of this study will provide further clarification regarding the role of infigratinib in patients with cholangiocarcinoma and FGFR1 and FGFR3 fusions and rearrangements, FGFR1, FGFR2, and FGFR3 mutations, and in patients previously treated with FGFR inhibitors other than infigratinib,” study authors concluded.


  1. Javle M, Roychowdhury S, Kelley RK, et al. 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. Lancet Gastroenterol Hepatol. Published online August 3, 2021. doi:10.1016/ S2468-1253(21)00196-5
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