Infigratinib in Patients with Recurrent Gliomas and FGFR Alterations: A Multicenter Phase II Study

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

ATIM-14. ALLIANCE A071101: A PHASE II RANDOMIZED TRIAL COMPARING THE EFFICACY OF HEAT SHOCK PROTEIN PEPTIDE COMPLEX-96 (HSPPC-96) VACCINE GIVEN WITH BEVACIZUMAB VERSUS BEVACIZUMAB ALONE IN THE TREATMENT OF SURGICALLY RESECTABLE RECURRENT GLIOBLASTOMA

Abstract BACKGROUND Heat shock protein vaccines can be used to stimulate anti-tumor immune responses. An autologous vaccine (HSPPC-96) generated from patient resected tumors has been previously studied in single arm phase I/II trials for newly diagnosed and recurrent GBM. Based on promising survival in these studies, a randomized, multi-centered phase II trial of HSPPC-96 for recurrent GBM compared to bevacizumab was undertaken (NCT01814813). METHODS Patients with 1st/2nd recurrence of resectable GBM were enrolled and underwent surgery with generation of HSPPC-96 from autologous tumors. Post-operative eligibility included a volumetric extent of resection ≥90% (by central review) and sufficient tumor to generate a minimum of 4 vaccine doses. Patients were randomized (1:1:1) to receive HSPPC-96 vaccine followed by bevacizumab at subsequent progression vs. concurrent HSPPC-96 vaccine and bevacizumab vs. bevacizumab alone. The primary endpoint was overall survival (OS) aiming to detect a 36% reduction in HR with 85% power and alpha=0.1 for pooled HSPPC-96 groups vs. bevacizumab alone. Planned enrollment was 165 patients (n=55/arm). An interim analysis was pre-planned at 50% of events (65 deaths). Secondary endpoints included progression-free survival and adverse events. RESULTS At final analysis, 90 patients were enrolled with a distribution of 29:30:31. The study was terminated for futility after the interim analysis. In the intention to treat population, OS for the HSPPC-96 treated groups was 7.5 vs. 10.7 months for bevacizumab alone (HR=2.06 [95% CI 1.18–3.60], p=0.008). Among patients treated per protocol (n=73), OS for HSPPC-96 patients was 8.6 vs. 12.3 months (HR=1.99 [95% CI 1.03–3.81], p=0.03). Trends were similar for progression-free survival between groups. HSPPC-96 toxicity was well tolerated with no attributable serious adverse events. CONCLUSIONS The study failed to demonstrate a survival benefit for patients treated with HSPPC-96 alone or in combination with bevacizumab compared to bevacizumab alone. Correlative analyses are ongoing. SUPPORT: U10CA180882, U10CA180821, U10CA180868, U24CA196171