A Randomized Phase 2 Study Assessing the Efficacy and Safety of Olvimulogene Nanivacirepvec Followed by Platinum-doublet Chemotherapy + Physician's Choice of Immune Checkpoint Inhibitor Compared With Docetaxel in Patients With NSCL Cancer After First Progression While on Front-line Immune Checkpoint Inhibitor-based Maintenance

This Phase 2, open-label, randomized study in non-small-cell lung cancer (NSCLC) is designed to evaluate the efficacy and safety of an intravenously delivered oncolytic vaccinia virus, Olvi-Vec, followed by platinum-doublet chemotherapy + Physician's Choice of Immune Checkpoint Inhibitor (ICI) vs. docetaxel for patients with advanced or metastatic NSCLC who have shown first disease progression (i.e., progressive disease not yet confirmed by further scan after initial scan showing progression) while on front-line treatment or maintenance ICI therapy after front-line treatment with platinum-doublet chemotherapy + ICI as standard of care.

More details:

Olvi-Vec (olvimulogene nanivacirepvec, aka GL-ONC1; laboratory name: GLV-1h68) is an oncolytic vaccinia virus-based immunotherapy that has been shown to have broad infectivity in a wide range of tumor types including non-small-cell lung cancer (NSCLC). In preclinical studies, Olvi-Vec was shown to infect and kill NSCLC cells and tumors in vitro and in vivo, respectively, and resolved and prevented formation of malignant effusion. This study is to test the hypothesis that the combination of Olvi-Vec followed by further platinum-based chemotherapy plus an ICI is particularly effective against established tumors by virus-mediated immune activation and re-sensitization of tumor cells to chemotherapy. Participants will have advanced or metastatic NSCLC (Stage III or Stage IV) squamous or nonsquamous disease without known targetable alterations in Epidermal Growth Factor Receptor (EGFR), Anaplastic Lymphoma Kinase (ALK) or Repressor of Silencing 1 (ROS1). Eligible patients will have first disease progression by radiological assessment (i) while on front-line platinum-doublet chemotherapy and ICI, or (ii) while receiving front-line maintenance ICI-based therapy after completion of front-line therapy, with at least 2 cycles and maximum of 6 cycles of platinum-doublet chemotherapy and ICI, regardless of Programmed death-ligand 1 (PD-L1) expression as the first treatment after being diagnosed. ICI includes anti-programmed death-1 (anti-PD-1) or anti-PD-L1 agents. Other classes of ICI \[e.g., anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4), etc.\] are excluded. Patients will be stratified based on length of time on ICI-based therapy from start date of the first dose, if ICI during front-line therapy, until date of first progression by radiological assessment is either less than or equal to 4 months or greater than 4 months. Patients enrolled in one of the initial 3 cohorts will receive either 3 or 4 days of Olvi-Vec followed by platinum-doublet chemotherapy + Physician's Choice of ICI. The randomization part of the study will start afterwards with the Olvi-Vec dose and schedule selected from one of the 3 cohorts for the Experimental Arm. The Active Comparator Arm (ACA) treatment includes docetaxel. Participants treated in the ACA who subsequently have documented disease progression may cross-over for treatment as per the Experimental Arm following determination of eligibility.

Overview

Olvimulogene nanivacirepvec (Olvi-Vec), also known as GLV-1h68 or GL-ONC1, is an investigational oncolytic vaccinia virus engineered to selectively infect and destroy cancer cells. It is currently under evaluation in clinical trials for various solid tumors, including ovarian cancer and malignant pleural effusion associated with mesothelioma, lung, or breast cancers.

Mechanism of Action

Olvi-Vec is a modified vaccinia virus designed to target and lyse tumor cells while sparing normal tissues. The virus has been engineered with three expression cassettes inserted into specific loci of the vaccinia genome, enhancing its tumor selectivity and safety profile. Upon infection, Olvi-Vec induces oncolysis, leading to the release of tumor antigens and subsequent activation of the immune system against the cancer cells. (en.wikipedia.org)

Efficacy

Ovarian Cancer:

In the Phase 2 VIRO-15 clinical trial involving 27 patients with heavily pretreated platinum-resistant or platinum-refractory ovarian cancer, Olvi-Vec followed by platinum-based chemotherapy, with or without bevacizumab, demonstrated promising results:

• Objective Response Rate (ORR): 54% (13 out of 24 evaluable patients; 95% CI, 33%-74%).
• Median Progression-Free Survival (PFS): 11.0 months (95% CI, 6.7-13.0 months).
• Median Overall Survival (OS): 15.7 months (95% CI, 12.3-23.8 months).

These outcomes suggest a potential reversal of platinum resistance and warrant further investigation in larger trials. (jamanetwork.com)

Malignant Pleural Effusion:

A Phase 1 trial assessed the intrapleural administration of Olvi-Vec in patients with malignant pleural effusion resulting from mesothelioma, lung, or breast cancers. Key findings include:

• Median Overall Survival: 19.5 months for all patients; 22 months for those with malignant pleural mesothelioma.
• Safety Profile: No dose-limiting toxicities were observed, and the maximum tolerated dose was not reached.

The study also documented Olvi-Vec infection of tumor cells, associated with reduced tumor cell density and increased immune cell infiltration, confirming its dual mechanism of direct oncolysis and immune activation. (investors.genelux.com)

Safety

In the VIRO-15 trial, treatment-related adverse events (TRAEs) were generally manageable. The most common TRAEs included:

• Pyrexia (fever): 63% of patients (3.7% Grade 3).
• Abdominal pain: 51.9% of patients (7.4% Grade 3).

No Grade 4 TRAEs or treatment-related deaths were reported. (jamanetwork.com)

Further Reading

• 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
• Genelux Corporation Announces Publication of Phase I Trial Results of Intrapleural Administration of Olvi-Vec in Patients with Malignant Pleural Effusion from Mesothelioma, Lung or Breast Cancers in Frontiers in Immunology
• Genelux Corporation Receives FDA Fast Track Designation for Olvi-Vec in Platinum Resistant/Refractory Ovarian Cancer

Last updated: Apr 2025

Clinical and News Coverage Summary

Company and Industry Announcements

Most available news and online coverage related to clinical trial NCT06463665 centers on company press releases and industry reports. The trial has been highlighted in company communications as a significant step for patients with non-small cell lung cancer (NSCLC) who have progressed after first-line immune checkpoint inhibitor-based treatment. According to these sources, this patient population represents a high unmet medical need due to limited effective treatment options following progression on immunotherapy maintenance.

The investigational regimen, involving olvimulogene nanivacirepvec (an oncolytic virus therapy), followed by chemotherapy and physician's choice of immune checkpoint inhibitor, is positioned as a potential new approach that could address "immunotherapy resistance," a primary challenge for these patients. The company emphasized the rationale of building on immune priming and overcoming resistance mechanisms as key reasons for this trial's design.

No clinical trial results (efficacy or safety) have been released for NCT06463665 to date, and no independent expert or patient advocacy commentary was identified outside of company materials. The trial is mentioned as part of ongoing efforts to evaluate new immunotherapeutic strategies after progression, but no additional insights or early data are publicly available.

Key References

• Genosco Initiates Phase 2 Study of Olvimulogene Nanivacirepvec in NSCLC — BusinessWire, Jan 2024
• Korea Biomedical Review – Phase 2 trial launch news — Jan 2024
• BioSpace: Genosco Announces First Patient Dosed in Phase II Study — Jan 2024

No published or peer-reviewed early data or third-party analyses are available as of June 2024.

Last updated: Apr 2025

Inclusion Criteria:

* Male or female 18 years or older.

* ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1.

* Have histologically or cytologically confirmed advanced or metastatic NSCLC.

* Histologically confirmed Stage III or IV squamous or nonsquamous \[American Joint Committee on Cancer (AJCC) 8th edition\].

* Received at least 2 cycles and maximum of 6 cycles of front-line platinum-based chemotherapy with ICI-based therapy, regardless of PD-L1 expression.

* Reached first disease progression by radiological assessment while receiving front-line or maintenance ICI.

* At least one measurable target tumor lesion anywhere except the brain per RECIST 1.1 by Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) scan.

* Have adequate renal, hepatic, bone marrow function as well as adequate coagulation tests \[International Normalized Ratio (INR)\] and adequate immune function by lymphocyte count.

* Women of child-bearing potential must have a negative serum pregnancy test prior to initiating study dosing.

* Be willing and able to comply with scheduled visits, the treatment plan, imaging and laboratory tests.

Exclusion Criteria:

* Active and untreated urinary tract infection, pneumonia, or other systemic infections.

* Current symptomatic central nervous system (CNS) metastasis.

* Any uncontrolled systemic disease, condition or comorbidity that, in the opinion of the Investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results.

* Persistent toxicities \[Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥ 3\] caused by previous anticancer therapy; alopecia and vitiligo are excluded toxicities.

* Required the use of additional immunosuppression other than corticosteroids for the management of an adverse event or have experienced recurrence of an adverse event if re-challenged, or currently require maintenance doses of \>10 mg prednisone or equivalent per day.

* Receiving concurrent antiviral agent active against vaccinia virus (e.g., cidofovir, vaccinia immunoglobulin, imatinib, tecovirimat, or other agents with known anti-vaccinia activities).

* Underwent major surgery within 4 weeks, or have insufficient recovery from surgical-related trauma or wound healing, prior to the planned first dose of treatment in either Arm.

* Have received prior virus-based gene therapy or therapy with cytolytic virus of any type.

* Vaccination against smallpox or monkeypox within 1 year of study therapy.

* Any non-oncology vaccine therapy used for prevention of infectious diseases, such as seasonal (influenza) vaccinations, corona virus disease (COVID) vaccination or other vaccines, within 2 weeks of the planned first dose of study drug.

* Clinically significant skin disease as assessed by the Investigator (e.g., severe eczema, psoriasis, or any unresolved skin injury or ulcer).

* Known hypersensitivity to carboplatin, cisplatin, paclitaxel or nab-paclitaxel, docetaxel, or any of the constituents of Olvi-Vec (i.e., gentamicin).

* Had severe hypersensitivity (CTCAE Grade ≥ 3) to ICI and/or any of its excipients previously.

* Dementia or altered mental status that would prohibit informed consent, and/or psychiatric illness/social situations that might interfere or limit compliance with study requirements.