2021 ASCO Gastrointestinal Cancers Symposium

Infigratinib Offers Second-Line Option for FGFR2-Positive By Mark L. Fuerst

he inhibitor (TKI) infigratinib represents included PFS, disease control rate, overall a new therapeutic option for patients with cholangiocarci- survival, safety, and pharmacokinetics. T noma and FGFR2 fusions as second-line or later therapy. For this study, patients were assigned are rare, aggressive malignancies that are locally to three different cohorts. Cohort 1 in- advanced and metastatic at diagnosis. The 5-year relative survival for cluded patients with FGFR2 gene fusions patients with distant cholangiocarcinomas at diagnosis is 2 percent. or rearrangements. Cohort 2 included “Approximately 70 percent are diagnosed with late-stage disease, patients with FGFR1 and FGFR3 gene for which treatment options are limited,” said lead study author Milind fusions or rearrangements and/or FGFR Javle, MD, Professor in the Department of Gastrointestinal Medical mutations. Cohort 3 included those with Oncology of the Division of Cancer Medicine at The University of FGFR2 gene fusions who had progressed Texas MD Anderson Cancer Center, presenting at the 2021 ASCO after previous treatment with a selective Gastrointestinal Cancers Symposium. FGFR inhibitor beyond infigratinib. Javle First-line treatment with gemcitabine plus cisplatin is the only regi- focused his report on results for cohort iStock men with NCCN level 1 evidence, based on findings of the ABC-02 1 only. study. Second-line options include gemcitabine-based or fluorouracil- In cohort 1, a total of 122 patients were enrolled, but 14 patients based combinations. The ABC-02 study demonstrated superiority of were excluded because they had other genetic alterations, such as modified FOLFOX plus active symptom control after gemcitabine plus FGFR1/3. A total of 108 patients with FGFR2 fusions or rearrange- cisplatin, with limited benefits. ments were included in the protocol-defined analysis population. As of March 31, 2020, 83 patients (77%) with FGFR2 fusions re- ceived infigratinib. About half had received two prior treatment lines. “Infigratinib shows meaningful clinical Median follow-up was 10.6 months. Twelve patients continue on treat- ment, while the rest have discontinued. The majority discontinued due activity against - to disease progression. One patient died on treatment. refractory cholangiocarcinoma with On central review, the ORR was 23.1 percent, including one com- plete response and 24 partial responses. Median DOR was 5 months. FGFR2 fusions.” Among responders, one-third had a DOR of 6 months. Median PFS was 7.3 months. —Milind Javle, MD, Professor at The University In a pre-specified subgroup analysis, the ORR was 34 percent of Texas MD Anderson Cancer Center (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 “The identification of molecular drivers implicated in the devel- appeared to benefit with infigratinib, irrespective of gender, age, base- opment of specific cholangiocarcinoma subtypes is changing the line ECOG performance status, disease stage at time of study entry, standard of care in this disease,” Javle noted. “These include genomic and region. Those who received fewer lines of therapy achieved the alterations in the fibroblast receptor (FGFR), in particu- most benefit. “Interestingly, the clinical activity with infigratinib may lar FGFR2 fusions or rearrangements, which have been shown to drive depend on prior lines of chemotherapy,” said Javle. tumorigenesis in cholangiocarcinoma, as well as in other cancers.” The most common treatment-emergent adverse events (TEAEs) any FGFR gene fusions are found in about 14 percent of intrahepatic grade were hyperphosphatemia (76.9%), eye disorders (67.6%, exclud- cholangiocarcinoma and predict tumor sensitivity to FGFR inhibitors. ing central serous retinopathy/retinal pigment epithelium detachment “Second-line chemotherapy seems to have limited efficacy in patients [CSR/RPED]), stomatitis (54.6%), and fatigue (39.8%). CSR/RPED oc- with cholangiocarcinoma and FGFR2 infusions, similar to that re- curred in 16.7 percent of patients (including one grade 3 event). ported in the general cholangiocarcinoma population,” said Javle. Other common grade 3/4 TEAEs were stomatitis (14.8%, all grade 3), hyponatremia (13%, all grade 3), and hypophosphatemia (13%, 13 Research Findings grade 3, one grade 4). A retrospective analysis of 37 patients with FGFR fusions who received second-line chemotherapy showed a median progression-free survival New Therapeutic Option (PFS) of only 4.6 months and an overall response rate (ORR) of 5.4 “Infigratinib shows meaningful clinical activity against chemother- percent, he noted. apy-refractory cholangiocarcinoma with FGFR2 fusions,” Javle stated. Infigratinib, an ATP-competitive FGFR1–3-selective oral tyrosine “Treatment with infilgratinib was generally well-tolerated in patients kinase inhibitor, has shown preliminary clinical activity against tu- with advanced cholangiocarcinoma. Adverse events were generally mors with FGFR alterations. In early-phase clinical evaluation, infil- reversible and manageable in line with previous observations in this gratinib showed a manageable safety profile and single-agent activity. patient population. Infilgratinib, administered as second-line and Javle reported on an open-label, Phase II study that evaluated adult later-line treatment, represents a new therapeutic option for patients patients with advanced/metastatic cholangiocarcinoma with progres- with cholangiocarcinoma and FGFR2 fusions.” sion on one line of systemic therapy (Abstract 265). The 108 patients, A Phase III study of infigratinib versus gemcitabine plus cisplatin median age 53 years, received infigratinib 125 mg orally for 21 days of is ongoing in the frontline setting in patients with unresectable locally each 28-day cycle until unacceptable toxicity or disease progression. All advanced or metastatic cholangiocarcinoma with FGFR2 gene fusions patients received prophylaxis with the oral phosphate binder sevelamer. or translocations. OT The primary endpoint was ORR by independent central review per RECIST v1.1, with duration of response (DOR). Secondary endpoints Mark L. Fuerst is a contributing writer. oncology-times.com Oncology Times 29