Gemogenovatucel-T Advantage in Clonal Tumor Mutation Burden-High Ovarian Cancer

Area of Science:

• Oncology
• Genomics
• Clinical Trials

Background:

• Standard frontline treatments for advanced ovarian cancer, including bevacizumab, PARP inhibitors, and PD-1/PD-L1 inhibitors, have not improved overall survival in patients with homologous recombination-proficient (HRP) tumors.
• Identifying specific mutation signatures associated with improved outcomes is crucial for developing more effective therapies.

Purpose of the Study:

• To determine the mechanistic mutation signatures associated with overall survival (OS) advantage in patients with ovarian cancer.
• To evaluate the efficacy of gemogenovatucel-T as maintenance therapy in patients with stage IIIb-IV ovarian cancer who have a homologous recombination-proficient (HRP) profile and high clonal tumor mutation burden (cTMB-H).

Main Methods:

• A whole-exome sequencing bioinformatic pipeline was developed to analyze 91 patients from the VITAL trial.
• Patients with stage IIIb-IV ovarian cancer, HRP profile, and cTMB-H were hypothesized to benefit from gemogenovatucel-T maintenance therapy.
• Overall survival was assessed using the Kaplan-Meier method in a randomized, double-blind, placebo-controlled phase II trial.

Main Results:

• Patients with cTMB-H/HRP ovarian cancer treated with gemogenovatucel-T had a median OS of 68 months compared to 19 months for placebo (hazard ratio [HR], 0.23; 95% CI, 0.06 to 0.83; P = .008).
• No OS advantage was observed in cTMB-H patients with a non-HRP profile (HR, 0.99; 95% CI, 0.39 to 2.47; P = .488).
• No grade 3 treatment-related toxicity was observed in the gemogenovatucel-T group during 8.4 years of follow-up.

Conclusions:

• Maintenance therapy with gemogenovatucel-T demonstrated a significant overall survival advantage in adult females with newly diagnosed, advanced stage ovarian cancer.
• The benefit was observed in patients with HRP status and a cTMB-H profile who achieved complete response after surgery and frontline chemotherapy.
• These findings support gemogenovatucel-T as a potential targeted maintenance therapy for a specific subgroup of ovarian cancer patients.