To evaluate the combination of intratumoral oncolytic viral therapy and checkpoint blockade in the challenging GBM setting, Nassiri et al. tested a cancer cell-replicating variant of adenovirus (DNX-2401) and anti-PD-1 in 48 patients with recurrent disease. Treatment was well tolerated, except for discontinuation due to brain edema in one patient (which resolved). The prespecified primary endpoint of overall response rate was not met, but the secondary endpoint of 12-month survival was met (55% vs 20%). 3 patients showed durable CRs, and 3 patients were alive after 45 months. Clinical benefit correlated best with a moderately immune inflamed tumor at baseline.
Contributed by Ed Fritsch
ABSTRACT: 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).
Author Info: (1) Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada. Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. (2) Princess Ma
Author Info: (1) Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada. Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. (2) Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. (3) Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. (4) Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. (5) Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. (6) Department of Human Genetics, University of California Los Angeles, Los Angeles, CA, USA. (7) Department of Human Genetics, University of California Los Angeles, Los Angeles, CA, USA. (8) Division of Neuro-oncology, University of California San Francisco, San Francisco, CA, USA. (9) UCLA Neuro-Oncology Program, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. (10) Huntsman Cancer Institute and Department of Neurosurgery, University of Utah, Salt Lake City, UT, USA. (11) Department of Neurology, Division of Neuro-Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. (12) Department of Neurosurgery, University of Minnesota, Minneapolis, MI, USA. (13) Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, USA. (14) Department of Neurology, Texas Oncology, Austin, TX, USA. (15) Division of Neuro-Oncology, Department of Neurology, the Ohio State University Wexner Medical Center, Columbus, Ohio, USA. (16) Department of Neurological Surgery, Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY, USA. (17) Department of Neuro-Oncology, Neuro-Oncology Program, Moffitt Cancer Center, Tampa, FL, USA. (18) Division of Medical Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. (19) Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (20) Department of Internal Medicine, Baylor University Medical Center, Dallas, TX, USA. (21) The Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH, USA. (22) Department of Neurosurgery, University of Arkansas for Medical Sciences, Little Rock, AK, USA. (23) Department of Pediatrics, University of Michigan, Ann Arbor Beaumont Children's Hospital, Royal Oak, MI, USA. (24) Lehigh Valley Topper Cancer Institute, Allentown, PA, USA. (25) Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (26) Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA. (27) Department of Laboratory Medicine and Pathobiology, University Health Network, Toronto, Ontario, Canada. (28) Department of Pathology, Clnica Universidad de Navarra, Pamplona, Spain. Navarra Institute for Health Research (IdISNA), Pamplona, Spain. (29) Department of Pathology, Clnica Universidad de Navarra, Pamplona, Spain. Navarra Institute for Health Research (IdISNA), Pamplona, Spain. (30) Navarra Institute for Health Research (IdISNA), Pamplona, Spain. Department of Pediatrics, Clnica Universidad de Navarra, Pamplona, Spain. Program of Solid Tumors, Center for the Applied Medical Research (CIMA), Pamplona, Spain. (31) Department of Human Genetics, University of California Los Angeles, Los Angeles, CA, USA. (32) DNATrix Inc., Carlsbad, CA, USA. (33) Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. (34) Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. (35) Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. Department of Medicine, Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. (36) Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (37) Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (38) Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (39) Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada. gelareh.zadeh@uhn.ca. Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. gelareh.zadeh@uhn.ca. Department of Surgery, University of Toronto, Toronto, Ontario, Canada. gelareh.zadeh@uhn.ca.
