Immunotherapy Shows Promise for Difficult-to-Treat HRP Ovarian Cancer

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A novel immunotherapy provided durable disease control in homologous repair proficient (HRP) ovarian cancer, subgroup data from a small randomized trial showed.

After 3 years of follow-up, median overall survival (OS) had yet to be reached in patients who received gemogenovatucel-T (Vigil), but appeared to exceed 41 months, as compared with a median OS of 26.9 months for placebo-treated patients. Median recurrence-free survival (RFS) was almost twice as long with gemogenovatucel-T versus placebo. An analysis of restricted mean survival time (RMST) showed statistically significant improvement in OS and RFS in favor of patients who received the immunotherapy.

No grade 3/4 adverse events or treatment-related myelodysplastic syndrome or acute myeloid leukemia occurred in the study, reported John Nemunaitis, MD, of drugmaker Gradalis in Carrollton, Texas, and coauthors in Gynecologic Oncology.

“These results are particularly important, given that patients with HRP molecular profile have an unfavorable risk/benefit ratio regarding frontline maintenance therapy,” the authors said in the discussion of their findings.

“Observation that patients with HRP profile appear to demonstrate less benefit to [standard of care] maintenance therapy with PARPi’s [PARP inhibitors], chemotherapy, and/or bevacizumab [Avastin] provide concern regarding risk/benefit ratio,” they continued. “Problematically, chemotherapy, PARPi’s, and bevacizumab elicit moderate toxicity that narrows the therapeutic index for long-term maintenance therapy. This holds true for niraparib [Zejula], the only PARPi indicated for use as frontline maintenance therapy regardless of HR or BRCA tumor status.”

The 3-year follow-up data support the safety and durable efficacy of gemogenovatucel-T and justify a phase III trial of maintenance therapy comparing the immunotherapy with bevacizumab and/or niraparib in patients with HRP ovarian cancer, Nemunaitis’s group added.

Standard of care for newly diagnosed advanced ovarian cancer consists of primary debulking surgery followed by adjuvant chemotherapy or upfront neoadjuvant chemotherapy with interval debulking surgery and additional postoperative chemotherapy. Both approaches achieve complete responses in a majority of patients, but as many as three fourths of patients relapse within 2-3 years, the study authors noted.

Recently, the introduction of maintenance therapy has led to more durable benefits, primarily for patients with BRCA germline or somatic mutations and patients with HR-deficient tumors. Patients who have HRP tumors derive little or no benefit from PARP inhibitor maintenance, the authors explained.

Gemogenovatucel-T is a DNA transfected autologous tumor-based immunotherapy that has three mechanisms of action: personal neoantigen education, suppression of tumor growth factor-β1 and β2, and expression of granulocyte-macrophage colony-stimulating factor in the tumor microenvironment.

The phase IIb VITAL trial showed numerical improvements in RFS and OS with gemogenovatucel-T maintenance therapy versus placebo in newly diagnosed advanced ovarian cancer, but the difference did not achieve statistical significance. A subsequent subgroup analysis showed that patients with HRP tumors benefited most from the immunotherapeutic agent. Nemunaitis and coauthors reported 3-year follow-up data from the subgroup analysis of patients with HRP molecular profile.

The analysis included 45 patients, 25 treated with gemogenovatucel-T. The primary endpoints of VITAL were safety, RFS, and OS. In the gemogenovatucel-T group, 95% confidence intervals for median OS were 41.6 months to not yet reached, representing almost a 60% reduction in the survival hazard ratio (HR 0.417, P=0.020). RMST without covariate adjustment yielded median OS values of 45.7 months vs 32.8 months for gemogenovatucel-T and placebo, respectively (P=0.008).

The RFS analysis showed median values of 10.6 and 5.7 months, respectively, for gemogenovatucel and placebo (HR 0.405, P=0.011). The RMST analysis supported the greater durability of the immunotherapeutic agent (P=0.025).

The authors found no differences in post-relapse disease management that might have biased the OS or RFS results.

Given that the study represented a subgroup analysis, the findings should be considered hypothesis generating, said Don Dizon, MD, of Lifespan Cancer Institute and Brown University in Providence, Rhode Island.

“I think it is promising since we do not have a great maintenance option for people who have homologous recombination proficient ovarian cancer,” Dizon told MedPage Today via email. “It does provide a rationale for a phase III trial enriched for people with HRP ovarian cancer. But for now, my enthusiasm is tempered until a phase III study evaluates the efficacy suggested in this subset analysis.”

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    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined MedPage Today in 2007. Follow

Disclosures

The study was supported by Gradalis.

Nemunaitis is employed by Gradalis. One or more coauthors disclosed relationships with AbbVie, Advaxis, Agenus, Amgen, Aravive, AstraZeneca, Asymmetric Therapeutics, Boston Biomedical, ChemoCare, ChemoID, Circulogene, Clovis, Conjupro, Eisai, Geistlich, Genmab/Seattle Genetics, GOG Foundation, Gradalis, ImmunoGen, Immunomedics, Incyte, Janssen/Johnson & Johnson, Laekna HealthCare, Mateon, Merck, Mersana, Myriad, NuCana, OncoMed, OncoQuest, Oncosec, Perthera, Pfizer, Precision Oncology, Puma, Regeneron, Roche/Genentech, Samumed, Takeda, Tesaro/GlaxoSmithKline, VBL, and Vigeo.

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