Vebreltinib for Previously Treated Astrocytoma, IDH -Mutant, Grade 4, and Glioblastoma, IDH Wild-Type with PTPRZ1–MET Fusion Gene: A Multicenter, Phase III Randomized, Open-Label Trial

Background: High-grade gliomas, including isocitrate dehydrogenase ( IDH )-mutant astrocytoma and IDH wild-type glioblastoma, have a poor prognosis and limited treatment options. The PTPRZ1–MET ( ZM ) fusion gene is a potential therapeutic target. This study evaluated vebreltinib, a highly selective, adenosine-triphosphate-competitive inhibitor of the mesenchymal–epithelial transition factor ( MET ), in patients with ZM -fusion-positive glioma. Methods: In this multicenter, open-label ZM FUsion GENe (FUGEN) trial, patients with previously treated astrocytoma, IDH -mutant, grade 4, or glioblastoma, IDH wild-type, harboring the ZM fusion were randomized in a 1:1 ratio to receive vebreltinib (300 mg orally twice daily) or control treatment (temozolomide or cisplatin plus etoposide) in 28-d cycles. The primary end point was overall survival (OS). Key secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety analyses. Results: Eighty-one patients (42 in the vebreltinib group and 39 in the control group) were included in the full analysis set. As of 2023 April 1, the median follow-up duration was 5.9 (range, 0.8 to 44.7) months in the vebreltinib group and 3.4 (range, 0.5 to 40.5) months in the control group. Median OS was significantly longer in the vebreltinib group than in the control group (6.3 months versus 3.4 months; hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.32 to 0.85; stratified log-rank P = 0.007). In the IDH -mutant subgroup, median OS was 7.7 months in the vebreltinib group and 3.3 months in the control group (HR, 0.48; 95% CI, 0.28 to 0.80; stratified log-rank P = 0.005). Among patients with a baseline tumor diameter of ≤3.0 cm, median OS was 32.5 months in the vebreltinib group versus 4.2 months in the control group (HR, 0.27; 95% CI, 0.07 to 1.06; stratified log-rank P = 0.046). Median PFS was also longer in the vebreltinib group (1.9 months versus 1.1 months; HR, 0.54; 95% CI, 0.33 to 0.88; stratified log-rank P = 0.012). The ORR was 9.5% with vebreltinib and 2.6% with control treatment. The incidence of grade ≥3 adverse events was comparable between groups, and no treatment-related deaths were reported. Conclusion: Vebreltinib significantly improved OS in patients with previously treated high-grade glioma harboring the ZM fusion, particularly in the subgroup with IDH -mutant astrocytoma, and the safety profile was manageable. Trial registration: This study was registered with the Chinese Drug Clinical Trial Registry ( ChinaDrugTrials.org.cn ) under the identifier, CTR20181664 (registration date: 2018 September 19).