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Published on: October 27, 2014
Infigratinib in Patients with Recurrent Gliomas and FGFR Alterations: A Multicenter Phase II Study
Andrew B Lassman1, Juan Manuel Sepúlveda-Sánchez2, Timothy F Cloughesy3
1Division of Neuro-Oncology, Department of Neurology and Herbert Irving Comprehensive Cancer Center, Columbia University Vagelos College of Physicians and Surgeons and NewYork-Presbyterian, New York, New York.
Purpose:
FGFR genomic alterations (amplification, mutations, and/or fusions) occur in ∼8% of gliomas, particularly FGFR1 and FGFR3. We conducted a multicenter open-label, single-arm, phase II study of a selective FGFR1-3 inhibitor, infigratinib (BGJ398), in patients with FGFR-altered recurrent gliomas.
Patients And Methods:
Adults with recurrent/progressive gliomas harboring FGFR alterations received oral infigratinib 125 mg on days 1 to 21 of 28-day cycles. The primary endpoint was investigator-assessed 6-month progression-free survival (PFS) rate by Response Assessment in Neuro-Oncology criteria. Comprehensive genomic profiling was performed on available pretreatment archival tissue to explore additional molecular correlations with efficacy.
Results:
Among 26 patients, the 6-month PFS rate was 16.0% [95% confidence interval (CI), 5.0-32.5], median PFS was 1.7 months (95% CI, 1.1-2.8), and objective response rate was 3.8%. However, 4 patients had durable disease control lasting longer than 1 year. Among these, 3 had tumors harboring activating point mutations at analogous positions of FGFR1 (K656E; n = 2) or FGFR3 (K650E; n = 1) in pretreatment tissue; an FGFR3-TACC3 fusion was detected in the other. Hyperphosphatemia was the most frequently reported treatment-related adverse event (all-grade, 76.9%; grade 3, 3.8%) and is a known on-target toxicity of FGFR inhibitors.
Conclusions:
FGFR inhibitor monotherapy with infigratinib had limited efficacy in a population of patients with recurrent gliomas and different FGFR genetic alterations, but durable disease control lasting more than 1 year was observed in patients with tumors harboring FGFR1 or FGFR3 point mutations or FGFR3-TACC3 fusions. A follow-up study with refined biomarker inclusion criteria and centralized FGFR testing is warranted.
Insights
Infigratinib showed limited efficacy for recurrent gliomas with FGFR alterations. However, some patients with specific FGFR1/FGFR3 mutations or fusions experienced durable disease control, suggesting potential for targeted therapies.
Area of Science:
- Neuro-oncology
- Molecular oncology
- Clinical pharmacology
Background:
- Fibroblast Growth Factor Receptor (FGFR) genomic alterations, including amplification, mutations, and fusions, are present in approximately 8% of gliomas, with FGFR1 and FGFR3 being the most commonly affected.
- Recurrent gliomas with FGFR alterations represent a significant unmet need, driving the investigation of targeted therapies.
Purpose of the Study:
- To evaluate the efficacy and safety of infigratinib, a selective FGFR1-3 inhibitor, in adult patients with recurrent gliomas harboring FGFR genomic alterations.
- To explore potential molecular correlations between FGFR alterations and treatment response.
Main Methods:
- A multicenter, open-label, single-arm, phase II clinical trial was conducted.
- Adult patients with recurrent/progressive gliomas and documented FGFR alterations received oral infigratinib (125 mg daily for 21 days of 28-day cycles).
- The primary endpoint was the 6-month progression-free survival (PFS) rate, assessed by investigator using Response Assessment in Neuro-Oncology criteria. Comprehensive genomic profiling was performed on pretreatment tumor tissue.
Main Results:
- The 6-month PFS rate was 16.0% (95% CI, 5.0-32.5), with a median PFS of 1.7 months (95% CI, 1.1-2.8). The objective response rate was 3.8%.
- Notably, 4 patients achieved durable disease control for over a year. Three of these patients had tumors with activating FGFR1 (K656E) or FGFR3 (K650E) point mutations, and one had an FGFR3-TACC3 fusion.
- Hyperphosphatemia was the most common treatment-related adverse event (76.9% all-grade, 3.8% grade 3), consistent with on-target FGFR inhibition.
Conclusions:
- Monotherapy with infigratinib demonstrated limited overall efficacy in patients with recurrent gliomas and diverse FGFR alterations.
- Durable disease control was observed in a subset of patients with specific FGFR1/FGFR3 point mutations or FGFR3-TACC3 fusions.
- Further investigation with refined biomarker selection and centralized FGFR testing is warranted to optimize patient selection for FGFR-targeted therapies.
