Oncolytic DNX-2401 virotherapy plus pembrolizumab in recurrent glioblastoma: a phase 1/2 trial
Farshad Nassiri 1 2 , Vikas Patil 2 , Leeor S Yefet 2 , Olivia Singh 2 , Jeff Liu 2 , Rachel M A Dang 3 , Takafumi N Yamaguchi 3 , Mariza Daras 4 , Timothy F Cloughesy 5 , Howard Colman 6 , Priya U Kumthekar 7 , Clark C Chen 8 , Robert Aiken 9 , Morris D Groves 10 , Shirley S Ong 11 , Rohan Ramakrishna 12 , Michael A Vogelbaum 13 , Simon Khagi 14 , Thomas Kaley 15 , Jason M Melear 16 , David M Peereboom 17 , Analiz Rodriguez 18 , Maxim Yankelevich 19 , Suresh G Nair 20 , Vinay K Puduvalli 21 , Kenneth Aldape 22 , Andrew Gao 23 , Álvaro López-Janeiro 24 25 , Carlos E de Andrea 24 25 , Marta M Alonso 25 26 27 , Paul Boutros 3 , Joan Robbins 28 , Warren P Mason 2 , Adam M Sonabend 29 30 , Roger Stupp 29 30 31 32 , Juan Fueyo 21 , Candelaria Gomez-Manzano 21 , Frederick F Lang 33 , Gelareh Zadeh 34 35 36
Immune-mediated anti-tumoral responses, elicited by oncolytic viruses and augmented with checkpoint inhibition, may be an effective treatment approach for glioblastoma.
Here in this multicenter phase 1/2 study we evaluated the combination of intratumoral delivery of oncolytic virus DNX-2401 followed by intravenous anti-PD-1 antibody pembrolizumab in recurrent glioblastoma, first in a dose-escalation and then in a dose-expansion phase, in 49 patients. The primary endpoints were overall safety and objective response rate. The primary safety endpoint was met, whereas the primary efficacy endpoint was not met.
There were no dose-limiting toxicities, and full dose combined treatment was well tolerated. The objective response rate was 10.4% (90% confidence interval (CI) 4.2-20.7%), which was not statistically greater than the prespecified control rate of 5%.
The secondary endpoint of overall survival at 12 months was 52.7% (95% CI 40.1-69.2%), which was statistically greater than the prespecified control rate of 20%. Median overall survival was 12.5 months (10.7-13.5 months). Objective responses led to longer survival (hazard ratio 0.20, 95% CI 0.05-0.87). A total of 56.2% (95% CI 41.1-70.5%) of patients had a clinical benefit defined as stable disease or better.
Three patients completed treatment with durable responses and remain alive at 45, 48 and 60 months. Exploratory mutational, gene-expression and immunophenotypic analyses revealed that the balance between immune cell infiltration and expression of checkpoint inhibitors may potentially inform on response to treatment and mechanisms of resistance.
Overall, the combination of intratumoral DNX-2401 followed by pembrolizumab was safe with notable survival benefit in select patients (ClinicalTrials.gov registration: NCT02798406).
CITATION Nat Med. 2023 May 15. doi: 10.1038/s41591-023-02347-y