FGFR2 Inhibitor Infigratinib Active in Chemotherapy-Refractory Cholangiocarcinoma

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The novel targeted agent infigratinib (BGJ398) showed clinically meaningful activity against chemotherapy-refractory cholangiocarcinoma in patients with fibroblast growth factor receptor (FGFR2) fusions and rearrangements. The confirmed overall response rate was 23% (34% confirmed/unconfirmed), the median duration of response was 5 months, and the median progression-free survival was 7.3 months.1

“Infigratinib is an ATP-competitive FGFR1-3–competitive oral tyrosine kinase inhibitor. Administered as a second-line or later treatment regimen, it represents a new therapeutic option for patients with cholangiocarcinoma and FGFR fusions/rearrangements,” said lead investigator Milind M. Javle, MD, of The University of Texas MD Anderson Cancer Center, Houston, who presented the findings from a phase II study at the 2021 Gastrointestinal Cancers Symposium.

Milind M. Javle, MD

Milind M. Javle, MD


Cholangiocarcinoma has a poor prognosis. For patients with distant disease, 5-year survival at diagnosis is about 2%. Nearly three-quarters of patients are diagnosed with late-stage disease, and they have few safe and effective treatment options, he said.

First-line treatment is gemcitabine plus cisplatin, based on the findings of the ABC-02 study.2,3 Second-line options include gemcitabine- or fluorouracil-based combinations. 

“The identification of molecular drivers implicated in the development of specific cholangiocarcinoma subtypes is now changing the standard of care in this disease,” Dr. Javle said. “They include genomic alterations in FGFR, particularly FGFR2 fusions or rearrangements, which have been shown to drive tumorigenesis in this and other cancers.”

FGFR fusions are found in up to 14% of intrahepatic cholangiocarcinoma cases and predict sensitivity to FGFR inhibitors. In such patients, second-line chemotherapy has limited efficacy, as shown in a retrospective analysis led by Dr. Javle. In this analysis, the median progression-free survival was just 4.6 months, and only 5.4% of patients responded to treatment.4 These discouraging outcomes indicate a need for improved ­treatments.

Phase II Study

Dr. Javle presented the phase II study, which enrolled 140 previously treated patients with advanced cholangiocarcinoma into three cohorts: (1) 120 patients with FGFR2 gene fusions/rearrangements; (2) 20 patients with FGFR1 and FGFR3 fusions/rearrangements and/or FGFR mutations; and (3) 20 patients with FGFR2 gene fusions who have experienced disease progression after prior treatment with a selective FGFR inhibitor other than infigratinib.

Patients are being treated with infigratinib monotherapy, at 125 mg/d for 21 days in 28-day cycles. The primary endpoints are objective response rate and duration of response.

Dr. Javle reported on the results for Cohort 1, who had FGFR2 fusions/rearrangements and had experienced disease progression on gemcitabine-based therapy but had not received prior treatment with another FGFR inhibitor. The final sample for the protocol-defined analysis included 108 patients; 88 (81%) had fusions and 20 (19%) had gene rearrangements. The most common fusion partner was BICC1 (25%), with a variety of other mutations observed at a frequency of up to 4%. Of note, 44% of patients had a novel fusion partner.

“The vast majority of patients (99%) had stage IV disease at diagnosis. This was an extensively pretreated population, with a median of two prior lines of therapy,” he noted.

Response Rates

By blinded independent central review, the confirmed objective response rate was 23.1% (95% confidence interval = 15.6%–32.2%). This included 1 patient with a complete response and 24 with partial responses; 66 patients had stable disease, and 11 had progressive disease as best response. The best overall response rate (confirmed/unconfirmed) was 34.3%, and the disease control rate was 84.3%. The median time to response was 3.6 months, the median progression-free survival was 7.3 months, and the median overall survival was 12.2 months.

“All subtypes seemed to benefit, particularly those who had fewer lines of therapy,” Dr. Javle commented. “For instance, the objective response rate for patients with one or fewer lines of therapy was 34%, as compared with 13% for those who had received two or more. This also translated to a best overall response rate that was superior in those who had received less chemotherapy, and a disease control rate of 88% in those with one or fewer lines, as compared with 81% in those with two or more lines of therapy. There was no difference, however, in terms of the duration of response or the median progression-free survival.”

Most treatment-related adverse events were grade 1 or 2; they were reversible and easily managed, Dr. Javle reported. The most common adverse events were “mechanism-based,” including alterations in calcium and phosphate homeostasis, tissue calcification, vascular calcifications, and ocular effects.

“On-target toxicities were managed with dose interruptions or reductions, supportive care, dietary modification, and concomitant medications. Hyperphosphatemia was manageable with dietary modifications and use of phosphate binders, which is in line with previous observations in this patient population. No patients discontinued treatment because of hyperphosphatemia,” he said.

“Eye disorders, mostly dry eyes, were generally reversible and could be managed with the use of eye drops. Gastrointestinal side effects, such as those reported for FGFR4 inhibitors, were relatively uncommon, which is consistent with the low affinity of infigratinib for FGFR4,” Dr. Javle pointed out. 

DISCLOSURE: Dr. Javle has served as a consultant or advisor to AstraZeneca, EMD Serono, Incyte, Merck, Mundi, OncoSil Medical, and QED Therapeutics and has held other relationships with Bayer, BeiGene, Incyte, Merck, Merck Serono, Novartis, Pieris Pharmaceuticals, QED Therapeutics, Rafael Pharmaceuticals, and Seattle Genetics.


1. Javle MM, Roychowdhury S, Kelley RK, et al: Final results from a phase II study of infigratinib (BGJ398), an FGFR-selective tyrosine kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma containing FGFR2 fusions/rearrangements. 2021 Gastrointestinal Cancers Symposium. Abstract 265. Presented January 17, 2021.

2. Lamarca A, Ross P, Wasan HS, et al: Advanced intrahepatic cholangiocarcinoma: Post hoc analysis of the ABC-01, -02, and -03 clinical trials. J Natl Cancer Inst 112:200-210, 2020.

3. Lamarca A, Palmer DH, Singh Wasan HS, et al: ABC-06: A randomised phase III, multi-centre, open-label study of Active Symptom Control (ASC) alone or ASC with oxaliplatin/5-FU chemotherapy for patients with locally advanced/metastatic biliary tract cancers previously treated with cisplatin/gemcitabine chemotherapy. 2019 ASCO Annual Meeting. Abstract 4003. Presented June 2, 2019.

4. Javle MM, Sadeghi S, El-Khoueiry AB, et al: A retrospective analysis of post second-line chemotherapy treatment outcomes for patients with advanced or metastatic cholangiocarcinoma and FGFR2 fusions. ASCO20 Virtual Scientific Program. Abstract 4591.


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