Effect of Vocimagene Amiretrorepvec in Combination With Flucytosine vs Standard of Care on Survival Following Tumor Resection in Patients With Recurrent High-Grade Glioma

Abstract

IMPORTANCE New treatments are needed to improve the prognosis of patients with recurrent high-grade glioma.OBJECTIVE To compare overall survival for patients receiving tumor resection followed by vocimagene amiretrorepvec (Toca 511) with flucytosine (Toca FC) vs standard of care (SOC). DESIGN, SETTING, AND PARTICIPANTSA randomized, open-label phase 2/3 trial (TOCA 5) in 58 centers in the US, Canada, Israel, and South Korea, comparing posttumor resection treatment with Toca 511 followed by Toca FC vs a defined single choice of approved (SOC) therapies was conducted from November 30, 2015, to December 20, 2019. Patients received tumor resection for first or second recurrence of glioblastoma or anaplastic astrocytoma.INTERVENTIONS Patients were randomized 1:1 to receive Toca 511/FC (n = 201) or SOC control (n = 202). For the Toca 511/FC group, patients received Toca 511 injected into the resection cavity wall at the time of surgery, followed by cycles of oral Toca FC 6 weeks after surgery. For the SOC control group, patients received investigators' choice of single therapy: lomustine, temozolomide, or bevacizumab. MAIN OUTCOMES AND MEASURESThe primary outcome was overall survival (OS) in time from randomization date to death due to any cause. Secondary outcomes reported in this study included safety, durable response rate (DRR), duration of DRR, durable clinical benefit rate, OS and DRR by IDH1 variant status, and 12-month OS. RESULTSAll 403 randomized patients (median [SD] age: 56 [11.46] years; 62.5% [252] men) were included in the efficacy analysis, and 400 patients were included in the safety analysis (3 patients on the SOC group did not receive resection). Final analysis included 271 deaths (141 deaths in the Toca 511/FC group and 130 deaths in the SOC control group). The median follow-up was 22.8 months. The median OS was 11.10 months for the Toca 511/FC group and 12.22 months for the control group (hazard ratio, 1.06; 95% CI 0.83, 1.35; P = .62). The secondary end points did not demonstrate statistically significant differences. The rates of adverse events were similar in the Toca 511/FC group and the SOC control group.CONCLUSIONS AND RELEVANCE Among patients who underwent tumor resection for first or second recurrence of glioblastoma or anaplastic astrocytoma, administration of Toca 511 and Toca FC, compared with SOC, did not improve overall survival or other efficacy end points.

Interstitial Photodynamic Therapy Using 5-ALA for Malignant Glioma Recurrences

“…Despite recent advances in the treatment of malignant glioma, prognosis remains poor with a median overall survival (OS) of less than two years in IDH-wildtype glioblastomas [ 1 , 2 ]. Upon inevitable tumor recurrence, median post-recurrence survival (PRS) is limited to 7–12 months in most recent studies [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. Salvage treatment options include resurgery, reirradiation protocols, chemotherapy and any combination thereof.…”

SUMOylation Regulator-Related Molecules Can Be Used as Prognostic Biomarkers for Glioblastoma

“…Studies have shown that the 5-year survival rate is only approximately 5% (Stupp et al, 2009;Ostrom et al, 2017). Due to the high cost of treatment of glioblastoma and poor treatment effect, it has always been one of the difficulties in tumor treatment (Cloughesy et al, 2020;Faria et al, 2020;Reardon et al, 2020). Therefore, it is of great importance to find effective molecular targets and improve the prognosis of glioblastoma.…”

Current Approaches for Glioma Gene Therapy and Virotherapy

“…Vocimagene amiretrorepvec (Toca 511) or Toca 511 with flucytosine (Toca FC) have been evaluated in Phase I clinical trials which demonstrated safety and good tolerability, with tumor regression at the site of infusion and durable responses in patients with recurrent high-grade glioma (Cloughesy et al, 2018 ). However, a recent phase III clinical trial (NCT02414165) revealed that among 403 randomized patients who underwent tumor resection for first or second recurrence of GBM or anaplastic astrocytoma, administration of Toca511 or Toca FC compared with standard of care did not improve overall survival or other efficacy end points (Cloughesy et al, 2020 ).…”