Efficacy and safety of STUPP regimen with or without anlotinib for newly diagnosed glioblastoma: Results of a multicenter, double-blind, randomized phase II trial.

Abstract

LBA2000 Background: The standard STUPP regimen (radiotherapy with temozolomide [TMZ] followed by adjuvant TMZ) remains limited in efficacy for newly diagnosed glioblastoma (GBM). Anlotinib, a multi-kinase inhibitor targeting tumor angiogenesis and proliferation, showed promising progression-free survival (PFS) in a prior single-arm trial (NCT04119674). This multicenter, double-blind, randomized phase II trial (NCT04959500) evaluates STUPP plus anlotinib versus STUPP plus placebo. Methods: Eligible patients (≥18 years, ECOG ≤2) are randomized 1:1 to receive anlotinib (10 mg/day, days 1–14 per 21-day cycle) or placebo alongside TMZ-based chemoradiotherapy (54–60 Gy). Patients undergo six TMZ cycles and eight anlotinib/placebo cycles after radiotherapy, then receiving anlotinib/placebo until disease progression or unacceptable toxicity. Key exclusions include brainstem-only tumors, prior GBM therapy, IDH1/2 mutations, or significant intracranial hemorrhage. The primary endpoint is Independent Review Committee (IRC)-assessed PFS. Secondary endpoints include overall survival (OS), investigator-assessed PFS, objective response rate (ORR), and safety. With 150 patients (targeting 110 PFS events), the study has 80% power to detect a hazard ratio of 0.58, at a two-sided alpha level of 5%. Efficacy is analyzed in intent-to-treat populations using Kaplan-Meier estimates and log-rank tests, with ORR 95% CIs calculated via exact binomial methods. Results: A total of 153 patients were randomized in this study, 77 patients were in the anlotinib group and 76 patients were in the placebo group. Baseline characteristics were balanced. In the anlotinib (ALTN) and placebo (PLB) group, the median age was 55.4 and 55.1 years, 64 and 62 patients had an ECOG PS of 0-1, rate of MGMT methylation was 32.47% and 31.58%, respectively. The median follow-up duration was 27.53 months (95% CI 25.46-29.93) and 31.05 months (95% CI 26.25, 32.72) in the ALTN and PLB group. The median PFS evaluated by IRC was 9.89 months (95% CI 9.10, 11.56) in the ALTN group, 5.85 months (95% CI 3.58, 7.69) in the PLB group [HR 0.59 (95% CI 0.42,0.85), p = 0.0043]. The ORR evaluated by IRC was 16.88% (95% CI 9.31,27.14) in the ALTN group, 5.26% (95% CI 1.45,12.93) in the PLB group [ p = 0.0220]. The most frequent grade 3 or higher toxicities in the ALTN and PLB group were thrombocytopenia (7.79% vs 1.32%), neutropenia (6.49% vs 3.95%), lymphocyte count decreased (6.49% vs 7.89%), white blood cell count decreased(6.49% vs 2.63%) and hypertension (5.19% vs 0%). Conclusion: This study had reached the primary endpoint of PFS evaluated by IRC, further data will be analyzed based on molecular pathology when OS data is mature. The combination of ALTN and STUPP regimen showed very good efficacy and favorable safety profile in patients with newly diagnosed GBM, with a simple and feasible treatment process. Clinical trial information: NCT04959500 .