DNX-2401 plus Pembrolizumab Is Safe in Recurrent Glioblastoma

Patients with recurrent glioblastoma (GBM) have limited treatment options, with immune checkpoint blockade (ICB) demonstrating limited clinical efficacy as a monotherapy due to an immunosuppressive microenvironment. However, combination of ICB with oncolytic viruses could recondition the microenvironment to one that is more immunologically “hot,” and use of the conditionally replicative oncolytic adenovirus DNX-2401 has demonstrated promise in treating high-grade gliomas in a previous phase I study. To evaluate intratumoral injection of DNX-2401 along with systemic pembrolizumab in recurrent GBM, Nassiri and colleagues conducted a phase I/II clinical trial (CAPTIVE) in 48 patients with recurrent GBM in which the primary endpoints of the study were overall safety and objective response rate. The secondary endpoint was overall survival. The safety endpoint was met, as no dose-limiting toxicities were observed leading to the maximal dose tested (5 × 10¹⁰ viral particles) being used for the dose-expansion phase of the study. Treatment-related adverse events were mostly grade 1 or 2 events and included brain edema, headache, and fatigue. Evaluation of the efficacy and survival endpoints indicated that two patients had a complete response and three patients had a partial response, leading to an objective response rate of 10.4%, which was not significantly different than the prespecified control rate of 5%. The median duration of response was 9.4 months in patients who showed an objective response. Additionally, overall survival at 12 months was 52.7%, which was significantly greater than the prespecified control rate of 20%, and median overall survival was determined as 12.5 months, with patients with objective responses having longer survival. Moreover, three patients who had objective responses were alive at 45, 48, and 60 months after the study interval. Exploratory biomarker characterization using gene expression data and immunophenotypic analyses indicated that a balance between expression of checkpoint molecules and immune cell infiltration could provide information on response and potential resistance mechanisms. In conclusion, the results of this trial indicate that the combination of DNX-2401 and pembrolizumab is safe and may have efficacy in a subset of patients with GBM.

Nassiri F, Patil V, Yefet LS, Singh O, Liu J, Dang RMA, et al. Oncolytic DNX-2401 virotherapy plus pembrolizumab in recurrent glioblastoma: a phase 1/2 trial. Nat Med 2023 May 15 [Epub ahead of print].

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