Clinical Activity of Olvimulogene Nanivacirepvec-Primed Immunochemotherapy in Heavily Pretreated Patients With Platinum-Resistant or Platinum-Refractory Ovarian Cancer: The Nonrandomized Phase 2 VIRO-15 Clinical Trial.

Importance: Patients with platinum-resistant or platinum-refractory ovarian cancer (PRROC) have limited therapeutic options, representing a considerable unmet medical need. Objective: To assess antitumor activity and safety of intraperitoneal (IP) olvimulogene nanivacirepvec (Olvi-Vec) virotherapy and platinum-based chemotherapy with or without bevacizumab in patients with PRROC. Design, Setting, and Participants: This open-label, nonrandomized multisite phase 2 VIRO-15 clinical trial enrolled patients with PRROC with disease progression following their last prior line of therapy from September 2016 to September 2019. Data cutoff was on March 31, 2022, and data were analyzed between April 2022 and September 2022. Interventions: Olvi-Vec was administered via a temporary IP dialysis catheter as 2 consecutive daily doses (3 × 109 pfu/d) followed by platinum-doublet chemotherapy with or without bevacizumab. Main Outcomes and Measures: Primary outcomes were objective response rate (ORR) via Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) and cancer antigen 125 (CA-125) assay, and progression-free survival (PFS). Secondary outcomes included duration of response (DOR), disease control rate (DCR), safety, and overall survival (OS). Results: Twenty-seven heavily pretreated patients with platinum-resistant (n = 14) or platinum-refractory (n = 13) ovarian cancer were enrolled. The median (range) age was 62 (35-78) years. The median (range) prior lines of therapy were 4 (2-9). All patients completed both Olvi-Vec infusions and chemotherapy. Median follow-up duration was 47.0 months (95% CI, 35.9 months to NA). Overall, ORR by RECIST 1.1 was 54% (95% CI, 33%-74%), with a DOR of 7.6 months (95% CI, 3.7-9.6 months). The DCR was 88% (21/24). The ORR by CA-125 was 85% (95% CI, 65%-96%). Median PFS by RECIST 1.1 was 11.0 months (95% CI, 6.7-13.0 months), and the PFS 6-month rate was 77%. Median PFS was 10.0 months (95% CI, 6.4-NA months) in the platinum-resistant group and 11.4 months (95% CI, 4.3-13.2 months) in the platinum-refractory group. The median OS was 15.7 months (95% CI, 12.3-23.8 months) in all patients, with a median OS of 18.5 months (95% CI, 11.3-23.8 months) in the platinum-resistant group and 14.7 months (95% CI, 10.8-33.6 months) in the platinum-refractory group. Most frequent treatment-related adverse events (TRAEs) (any grade, grade 3) were pyrexia (63.0%, 3.7%, respectively) and abdominal pain (51.9%, 7.4%, respectively). There were no grade 4 TRAEs, and no treatment-related discontinuations or deaths. Conclusions and Relevance: In this phase 2 nonrandomized clinical trial, Olvi-Vec followed by platinum-based chemotherapy with or without bevacizumab as immunochemotherapy demonstrated promising ORR and PFS with a manageable safety profile in patients with PRROC. These hypothesis-generating results warrant further evaluation in a confirmatory phase 3 trial. Trial Registration: ClinicalTrials.gov Identifier: NCT02759588.

A phase 1b study of intraperitoneal oncolytic viral immunotherapy in platinum-resistant or refractory ovarian cancer.

OBJECTIVE: Our objective was to assess safety and adverse events associated with intraperitoneal Olvi-Vec virotherapy in patients with platinum-resistant or refractory ovarian cancer (PRROC). Secondary objectives included objective response rate (ORR) per RECIST 1.1 and progression-free survival (PFS). METHODS: Olvi-Vec is a modified vaccinia virus that causes oncolysis and immune activation. An open-label phase 1b trial using a 3 + 3 dose escalation was conducted. Intraperitoneal Olvi-Vec was given as monotherapy in two consecutive daily doses. Translational analyses included anti-virus antibody levels, viral shedding, circulating tumor cells (CTCs) and T cells. RESULTS: Twelve patients (median age: 69 years, range: 45-77) with median 5 prior therapies (range: 2-10) and 2 prior platinum lines (range: 1-5) were enrolled. There were three dose level cohorts: 3 × 109 (n = 6), 1 × 1010 (n = 5), and 2.5 × 1010 (n = 1) plaque forming units (PFU)/day on two consecutive days. Treatment-related adverse events (TRAEs) included G1/G2 nausea (n = 6), fever (n = 6), abdominal distention (n = 5), and abdominal pain (n = 4). There were no Grade 4 TRAEs, no dose relationship to TRAEs, and no deaths attributed to Olvi-Vec. The ORR was 9% (1/11). Stable disease (SD) was 64% (7/11), and SD ≥15 weeks was 46% (5/11). Median PFS was 15.7 weeks (95%CI: 5.7-34.5), including extended PFS in four patients (23.2, 34.5, 59.4+ and 70.8 weeks). Three patients had extended overall survival (deceased 33.6 months, and alive with disease at 54 and 59 months). CTCs diminished in 6/8 (75%) baseline-positive patients. Immune activation was demonstrated from virus-enhanced tumor infiltration of CD8+ T-cells and activation of tumor-specific T-cells in peripheral blood. CONCLUSIONS: Oncolytic viral therapy with intraperitoneal Olvi-Vec showed promising safety, clinical activities, and immune activation in patients with PRROC, warranting further clinical investigation.