Phase II VIRO-15: Vaccinia Virus Plus Chemo Doublet Exceeds Expected Outcomes in Platinum-Resistant/Refractory Ovarian Cancer

In the phase II VIRO-15 trial, viral therapy with olvimulogene nanivacirepvec—a modified oncolytic vaccinia virus—followed by doublet chemotherapy with or without bevacizumab, led to objective response in 54% and a median progression-free survival (PFS) of 11 months in women with platinum-resistant or platinum-refractory ovarian cancer (PRROC) with a median of four prior lines of therapy, and clinically reversed platinum resistance and refractoriness.

These results exceeded expectations set by previous trials, and are published in JAMA Oncology.

"Olvimulogene nanivacirepvec…is a modified oncolytic vaccinia virus that selectively infects malignant cells and replicates especially well in ovarian and lung cancers. Because ovarian cancer usually metastasizes throughout the peritoneal cavity, it is amenable to intraperitoneal (IP) virotherapy given the large peritoneal surface area of carcinomatosis. [Olvimulogene nanivacirepvec] activates both innate immunity via proinflammatory response and adaptive immunity, which modify the tumor microenvironment and promote a condition wherein reversal of platinum resistance is potentially realized," they added.

In their accompanying editorial "Vaccinia (Smallpox) for the Treatment of Ovarian Cancer—Turning an Old Foe Into a Friend," Erica S. Tsang, MD, MPH, and Pamela N. Munster, MD, both of the Division of Hematology and Oncology, University of California San Francisco, presented a brief synopsis of the use of modified viruses as treatments for cancer.

"Historical cases of impressive, albeit brief, tumor regression in the setting of natural virus infections have spurred the hope for genetically modified viruses as oncolytic therapy. Oncolytic viruses are of interest not only for their potential to infect tumor cells and by excessive viral replication that induces direct tumor cell death, but also for their ability to trigger tumor-directed immune activation for lasting tumor control. Such effects have been successfully shown in several tumor models," they wrote.

"The specific oncolytic virus evaluated in this issue of JAMA Oncology in the phase II nonrandomized clinical trial by Holloway and colleagues, GLV-1h68 (olvimulogene nanivacirepvec), is a triple-modified replication-competent vaccinia based on the Lister strain. Extensive preclinical studies in multiple tumor types, including breast, cholangiocarcinoma, and lung, suggested a substantially improved infection specificity for the modified virus with pre-clinical antitumor activity in many models," added Tsang and Munster.

Incidentally, the vaccinia virus Lister strain was one of the vaccine strains used to eradicate smallpox.

For their open-label, non-randomized phase II study, Holloway and colleagues assessed the clinical activity of immunotherapy with olvimulogene nanivacirepvec followed by platinum-doublet chemotherapy with or without bevacizumab in women with PRROC.

Holloway and colleagues included 27 heavily pretreated patients with PRROC who had disease progression after their last prior line of treatment. All patients received olvimulogene nanivacirepvec via a temporary intraperitoneal dialysis catheter, given as two consecutive daily doses of 3 × 10⁹ plaque-forming units, followed by platinum-doublet chemotherapy with or without bevacizumab. The platinum-doublet chemotherapy was investigator-chosen from gemcitabine, taxane, or pegylated liposomal doxorubicin coupled with carboplatin or cisplatin. Patients received a median of 6 cycles of platinum-based therapy, which was begun a median of 6 weeks after olvimulogene nanivacirepvec administration.

Patients were a median age of 62 years, and had a median of four prior lines of therapy.

After a median follow-up of 47.0 months, the ORR according to Response Evaluation Criteria in Solid Tumors version (RECIST) 1.1 criteria in the 24 evaluable patients was 54% (95% CI, 33%-74%), and per cancer antigen 125 (CA-125) assay, 85% (95% CI, 65%-96%). Duration of response was 7.6 months (95% CI, 3.7-9.6) and the disease control rate was 88%.

Median PFS according to RECIST 1.1 was 11.0 months (95% CI, 6.7-13.0 months), and 6-month PFS was 77%. In the 14 patients with platinum-resistant disease, median PFS was 10.0 months (95% CI,6.4-NA months), and in the 13 patients with platinum-refractory disease, 11.4 months (95% CI, 4.3-13.2 months).

In all patients, median overall survival (OS) was 15.7 months (95% CI, 12.3-23.8 months), with a median of 18.5 months (95% CI, 11.3-23.8 months) in platinum-resistant patients and 14.7 months (95% CI, 10.8-33.6 months) in platinum-refractory patients.

Regarding BRCA1/2 mutations, Holloway and colleagues wrote, "Prior studies have shown that BRCA1/2 variants are associated with increased sensitivity to platinum-based therapy. However, in this study, ORR by RECIST was 29% (2/7) in patients with BRCA1/2 variants vs 65% (11/17) in those with wild-type BRCA, indicating response was not driven by BRCA1/2 variation."

Pyrexia and abdominal pain were the most common treatment-related adverse events (TRAEs), with an incidence of 63.0% for any grade pyrexia, and 3.7% for grade 3 pyrexia, and 51.9% and 7.4%, respectively, for the two grades of abdominal pain. No grade 4 TRAEs occurred, and there were no treatment-related deaths or treatment discontinuations.

"Previous data support the staggered approach of viral immunotherapy and chemotherapy. Virus-mediated tumor cell lysis may induce immune priming by increasing T-cell response through cross-presentation of the tumor (neo) antigens, and being further boosted by subsequent cytotoxic chemotherapy. In this population, [olvimulogene nanivacirepvec] was associated with an influx of CD4-positive and CD8-positive tumor-infiltrating lymphocytes in paired tumor biopsy samples, which was a positive prognostic factor in patients with ovarian cancer. Overall, [olvimulogene nanivacirepvec] may convert immunologically ’cold’ to ’hot’ tumors by modifying the tumor microenvironment and abrogate platinum resistance," concluded Holloway and fellow researchers.

Editorialists Tsang and Munster added a few caveats to these results.

"The presented strategy shows promising efficacy in this platinum-refractory/resistant patient population and a clinically relevant PFS for this stage of disease and prior therapy. While platinum resistance was carefully described, prior exposure and the potential response to the allowable chemotherapy doublet (gemcitabine, taxane, pegylated liposomal doxorubicin) were less clear. Only 24 of 27 patients had measurable disease by RECIST, version 1.1, further limiting the assessable patient number. This study was terminated early after reaching prespecified early efficacy stopping rules; thus, it enrolled a limited number of patients," they noted.

Tsang and Munster also commented on lower ORRs seen in patients with BRCA-variant tumors, and the use of CT scans to assess efficacy after treatment administration and before chemotherapy initiation. "Therefore, the tumor response to the virus alone cannot be assess. Furthermore, tumor flares induced by the virus could affect the response assessment," Tsang and Munster added.

A phase III trial of olvimulogene nanivacirepvec is currently enrolling women with PRROC from nearly 30 sites in the U.S.

"In the absence of demonstrated single-agent activity of GL-ONC1, the true effect of vaccinia virus on reversing chemotherapy resistance and enhancing response durability can only be determined in randomized clinical trials. The undertaking of this stringent randomized phase 3 trial as proposed should clearly define the contribution of [olvimulogene nanivacirepvec] to standard therapy in ovarian cancer. The outcomes of the phase 3 trial are anxiously awaited by patients and clinicians," concluded Tsang and Munster.

Limitations of the trial cited by researchers included the small number of patients enrolled.

This study was funded by Genelux Corporation.

Holloway reported advisory board membership for a phase 3 protocol development from Genelux, Inc; and stock options given in lieu of hourly advisory fees during the conduct of the study.

Tsang and Munster reported no disclosures.

Holloway RW, et al "Clinical activity of olvimulogene nanivacirepvec–primed immunochemotherapy in heavily pretreated patients with platinum-resistant or platinum-refractory ovarian cancer: The nonrandomized phase II VIRO-15 clinical trial" JAMA Oncol 2023; DOI: 10.1001/jamaoncol.2023.1007.

Tsang ES and Munster PN "Vaccinia (smallpox) for the treatment of ovarian cancer—Turning an old foe into a friend?" JAMA Oncol 2023; DOI: 10.1001/jamaoncol.2023.0983.