The tyrosine kinase inhibitor (TKI) infigratinib represents a new therapeutic option for patients with cholangiocarcinoma and FGFR2 fusions as second-line or later therapy. Cholangiocarcinomas are rare, aggressive malignancies that are locally advanced and metastatic at diagnosis. The 5-year relative survival for patients with distant cholangiocarcinomas at diagnosis is 2 percent.
"Approximately 70 percent are diagnosed with late-stage disease, for which treatment options are limited," said lead study author Milind Javle, MD, Professor in the Department of Gastrointestinal Medical Oncology of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, presenting at the 2021 ASCO Gastrointestinal Cancers Symposium.
First-line treatment with gemcitabine plus cisplatin is the only regimen with NCCN level 1 evidence, based on findings of the ABC-02 study. Second-line options include gemcitabine-based or fluorouracil-based combinations. The ABC-02 study demonstrated superiority of modified FOLFOX plus active symptom control after gemcitabine plus cisplatin, with limited benefits.
"The identification of molecular drivers implicated in the development of specific cholangiocarcinoma subtypes is changing the standard of care in this disease," Javle noted. "These include genomic alterations in the fibroblast growth factor receptor (FGFR), in particular FGFR2 fusions or rearrangements, which have been shown to drive tumorigenesis in cholangiocarcinoma, as well as in other cancers."
FGFR gene fusions are found in about 14 percent of intrahepatic cholangiocarcinoma and predict tumor sensitivity to FGFR inhibitors. "Second-line chemotherapy seems to have limited efficacy in patients with cholangiocarcinoma and FGFR2 infusions, similar to that reported in the general cholangiocarcinoma population," said Javle.
Research Findings
A retrospective analysis of 37 patients with FGFR fusions who received second-line chemotherapy showed a median progression-free survival (PFS) of only 4.6 months and an overall response rate (ORR) of 5.4 percent, he noted.
Infigratinib, an ATP-competitive FGFR1-3-selective oral tyrosine kinase inhibitor, has shown preliminary clinical activity against tumors with FGFR alterations. In early-phase clinical evaluation, infilgratinib showed a manageable safety profile and single-agent activity.
Javle reported on an open-label, Phase II study that evaluated adult patients with advanced/metastatic cholangiocarcinoma with progression on one line of systemic therapy (Abstract 265). The 108 patients, median age 53 years, received infigratinib 125 mg orally for 21 days of each 28-day cycle until unacceptable toxicity or disease progression. All patients received prophylaxis with the oral phosphate binder sevelamer.
The primary endpoint was ORR by independent central review per RECIST v1.1, with duration of response (DOR). Secondary endpoints included PFS, disease control rate, overall survival, safety, and pharmacokinetics.
For this study, patients were assigned to three different cohorts. Cohort 1 included patients with FGFR2 gene fusions or rearrangements. Cohort 2 included patients with FGFR1 and FGFR3 gene fusions or rearrangements and/or FGFR mutations. Cohort 3 included those with FGFR2 gene fusions who had progressed after previous treatment with a selective FGFR inhibitor beyond infigratinib. Javle focused his report on results for cohort 1 only.
In cohort 1, a total of 122 patients were enrolled, but 14 patients were excluded because they had other genetic alterations, such as FGFR1/3. A total of 108 patients with FGFR2 fusions or rearrangements were included in the protocol-defined analysis population.
As of March 31, 2020, 83 patients (77%) with FGFR2 fusions received infigratinib. About half had received two prior treatment lines. Median follow-up was 10.6 months. Twelve patients continue on treatment, while the rest have discontinued. The majority discontinued due to disease progression. One patient died on treatment.
On central review, the ORR was 23.1 percent, including one complete response and 24 partial responses. Median DOR was 5 months. Among responders, one-third had a DOR of 6 months. Median PFS was 7.3 months.
In a pre-specified subgroup analysis, the ORR was 34 percent (17/50) in the second-line setting and 13.8 percent (8/58) in the third-line or later setting (3-8 prior treatments). All subgroups of patients appeared to benefit with infigratinib, irrespective of gender, age, baseline ECOG performance status, disease stage at time of study entry, and region. Those who received fewer lines of therapy achieved the most benefit. "Interestingly, the clinical activity with infigratinib may depend on prior lines of chemotherapy," said Javle.
The most common treatment-emergent adverse events (TEAEs) any grade were hyperphosphatemia (76.9%), eye disorders (67.6%, excluding central serous retinopathy/retinal pigment epithelium detachment [CSR/RPED]), stomatitis (54.6%), and fatigue (39.8%). CSR/RPED occurred in 16.7 percent of patients (including one grade 3 event).
Other common grade 3/4 TEAEs were stomatitis (14.8%, all grade 3), hyponatremia (13%, all grade 3), and hypophosphatemia (13%, 13 grade 3, one grade 4).
New Therapeutic Option
"Infigratinib shows meaningful clinical activity against chemotherapy-refractory cholangiocarcinoma with FGFR2 fusions," Javle stated. "Treatment with infilgratinib was generally well-tolerated in patients with advanced cholangiocarcinoma. Adverse events were generally reversible and manageable in line with previous observations in this patient population. Infilgratinib, administered as second-line and later-line treatment, represents a new therapeutic option for patients with cholangiocarcinoma and FGFR2 fusions."
A Phase III study of infigratinib versus gemcitabine plus cisplatin is ongoing in the frontline setting in patients with unresectable locally advanced or metastatic cholangiocarcinoma with FGFR2 gene fusions or translocations.
Mark L. Fuerst is a contributing writer.