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Gemogenovatucel-T (Vigil) maintenance immunotherapy: 3-year survival benefit in homologous recombination proficient (HRP) ovarian cancer

Open AccessPublished:October 23, 2021DOI:https://doi.org/10.1016/j.ygyno.2021.10.004

      Highlights

      • Treatment options for HRP ovarian cancer are limited and associated with significant toxicity and limited clinical benefit.
      • Previously, Vigil has shown both safety and efficacy in the BRCA wild type, homologous recombination proficient patients.
      • Continued 3 year follow up has shown Vigil demonstrates durable clinical benefit to prolong OS and RFS in HRP patients.

      Abstract

      Objective

      Previously, Vigil demonstrated clinical benefit to prolong relapse free and overall survival in the BRCA wild-type (BRCA-wt), homologous recombination proficient (HRP) patient population. Here we provide long term follow up of 3 years in the HRP patient population enrolled in the Phase 2b VITAL study.

      Methods

      HRP patients treated with Vigil (n = 25) or placebo (n = 20) who were enrolled in the Phase 2b, double-blind, placebo-controlled (VITAL study, NCT02346747) were followed for safety, OS and RFS. OS and RFS from time of randomization (immediately prior to maintenance therapy) and from debulking tissue procurement time points were analyzed by Kaplan-Meier (KM) and restricted mean survival time (RMST) analysis.

      Results

      OS for Vigil treated patients at 3 years has not yet reached median OS time point (95% CI 41.6 months to not achieved) compared to 26.9 (95% CI 17.4 months to not achieved) in placebo treated patients (HR 0.417 p = 0.020). Three year RFS also showed benefit to Vigil (stratified HR 0.405, p = 0.011) and no long term toxicity to Vigil was observed. Three year OS for Vigil of 70% vs. 40% for placebo from time of randomization was observed (p = 0.019). RMST analysis was also significant for OS (45.7 vs. 32.8 months, p = 0.008) and RFS (p = 0.025).

      Conclusion

      In conclusion, results suggest durable activity of Vigil on RFS and OS and support further evaluation of Vigil in HRP ovarian cancer.

      Keywords

      1. Introduction

      Standard of care for newly diagnosed advanced ovarian cancer (Stage IIIb-IV) involves either primary debulking surgery followed by adjuvant chemotherapy with paclitaxel and carboplatin or neoadjuvant chemotherapy with interval debulking surgery followed by adjuvant chemotherapy [
      • Jelovac D.
      • Armstrong D.K.
      Recent progress in the diagnosis and treatment of ovarian cancer.
      ,
      • Gogineni V.
      • et al.
      Current ovarian cancer maintenance strategies and promising new developments.
      ]. Although the majority of patients achieve complete remission with either approach, 60–75% still relapse within 2–3 years with no significant difference in OS between the treatment options. Within the past few years, maintenance therapy has demonstrated benefits with optimal frontline maintenance including bevacizumab, niraparib or olaparib/bevacizumab combination [
      • Gogineni V.
      • et al.
      Current ovarian cancer maintenance strategies and promising new developments.
      ,
      • Gonzalez-Martin A.
      • et al.
      Niraparib in patients with newly diagnosed advanced ovarian cancer.
      ,
      • Devanaboyina M.
      • et al.
      Immune response role of angiogenesis inhibitors.
      ], but most durable clinical response are seen in patients with either BRCA germline or somatic mutations [
      • Moore K.
      • et al.
      Maintenance Olaparib in patients with newly diagnosed advanced ovarian cancer.
      ,
      • LaFargue C.J.
      • et al.
      Exploring and comparing adverse events between PARP inhibitors.
      ] as well as HRD molecular profiles [
      • Gonzalez-Martin A.
      • et al.
      Niraparib in patients with newly diagnosed advanced ovarian cancer.
      ]. HRP patients demonstrate no to minimal benefit with PARPi therapy [
      • Gonzalez-Martin A.
      • et al.
      Niraparib in patients with newly diagnosed advanced ovarian cancer.
      ,
      • Ray-Coquard I.
      • et al.
      Olaparib plus Bevacizumab as first-line maintenance in ovarian cancer.
      ].
      Olaparib (with bevacizumab) confers no benefit as maintenance in frontline management of HRP ovarian cancer patients [
      • Ray-Coquard I.
      • et al.
      Olaparib plus Bevacizumab as first-line maintenance in ovarian cancer.
      ]. Bevacizumab as frontline maintenance was not prospectively evaluated with regard to BRCA or HRP tumor status; however, retrospective assessment of OS by Tewari et al. [
      • Marchetti C.
      • et al.
      First-line treatment of women with advanced ovarian cancer: focus on bevacizumab.
      ,
      • Tewari K.S.
      • et al.
      Final overall survival of a randomized trial of Bevacizumab for primary treatment of ovarian cancer.
      ] revealed lower survival of HRP patients by over 20 months compared to HRD patients with use of bevacizumab as frontline maintenance [
      • Marchetti C.
      • et al.
      First-line treatment of women with advanced ovarian cancer: focus on bevacizumab.
      ,
      • Tewari K.S.
      • et al.
      Final overall survival of a randomized trial of Bevacizumab for primary treatment of ovarian cancer.
      ]. Niraparib, which is indicated as maintenance therapy for ovarian cancer patients regardless of BRCA status, also is of limited benefit in the HRP subset (2.7 months improvement in PFS over placebo without evidence of OS advantage). Additionally, in the HRP setting use of bevacizumab and niraparib maintenance therapy is further limited due to adverse risk/benefit ratio given that over 65% of these patients will develop Grade 3/4 product related adverse events, necessitating dose modification. Dose modification of niraparib occurred at a rate of 79.5% [
      • Gonzalez-Martin A.
      • et al.
      Niraparib in patients with newly diagnosed advanced ovarian cancer.
      ] in the recently completed trial which led to niraparib registration in the United States. [
      • Gonzalez-Martin A.
      • et al.
      Niraparib in patients with newly diagnosed advanced ovarian cancer.
      ]. Additional toxicity concern includes long term follow up with olaparib and niraparib in frontline use and rare occurrence of treatment-associated acute myeloid leukemia (tAML) and myelodysplastic syndrome (tMDS) that ranges from 1 to 2% [
      • Gogineni V.
      • et al.
      Current ovarian cancer maintenance strategies and promising new developments.
      ,
      • GlaxoSmithKline
      Niraparib Package Insert.
      ] and up to 6.9% of patients with long term follow-up [
      • Todisco E.
      • et al.
      Clinical presentation, diagnosis and management of therapy-related hematological disorders in women with epithelial ovarian cancer treated with chemotherapy and poly-ADP-ribose polymerase inhibitors: a single-center experience.
      ].
      Vigil is a triple function DNA transfected autologous tumor based immunotherapy which contains three independent mechanisms of immune mediated anticancer activity. These include (1) provision of personal neoantigen education, (2) TGFβ1 and TGFβ2 suppression through bi-functional short-hairpin RNA construct targeted to furin and (3) GMCSF expression within a localized microenvironment at the intradermal injection site. All three of these mechanisms will combine to generate a systemic anticancer immune response [
      • Rocconi R.P.
      • et al.
      Gemogenovatucel-T (Vigil) immunotherapy as maintenance in frontline stage III/IV ovarian cancer (VITAL): a randomised, double-blind, placebo-controlled, phase 2b trial.
      ,
      • Senzer N.
      • et al.
      Phase I trial of “bi-shRNAi(furin)/GMCSF DNA/autologous tumor cell” vaccine (FANG) in advanced cancer.
      ,
      • Oh J.
      • et al.
      Phase II study of Vigil(R) DNA engineered immunotherapy as maintenance in advanced stage ovarian cancer.
      ]. TGF-β is known to be highly expressed in ovarian cancer and correlates with poor prognosis by driving proliferation and metastasis [
      • Bristow R.E.
      • et al.
      Altered expression of transforming growth factor-beta ligands and receptors in primary and recurrent ovarian carcinoma.
      ,
      • Riester M.
      • et al.
      Risk prediction for late-stage ovarian cancer by meta-analysis of 1525 patient samples.
      ,
      • Kang Y.
      • Massagué J.
      Epithelial-mesenchymal transitions: twist in development and metastasis.
      ]. Phase IIb trial (VITAL study) demonstrated RFS and OS advantage with Vigil vs. placebo maintenance therapy in BRCA-wt newly diagnosed Stage IIIb-IV resectable ovarian cancer patients achieving complete response with adjuvant chemotherapy [
      • Rocconi R.P.
      • et al.
      Gemogenovatucel-T (Vigil) immunotherapy as maintenance in frontline stage III/IV ovarian cancer (VITAL): a randomised, double-blind, placebo-controlled, phase 2b trial.
      ]. Subsequent analysis demonstrated that the HRP population was most sensitive to Vigil maintenance therapy compared to BRCA-m or HRD population [
      • Rocconi R.P.
      • et al.
      Gemogenovatucel-T (Vigil) immunotherapy demonstrates clinical benefit in homologous recombination proficient (HRP) ovarian cancer.
      ]. Specifically, RFS and OS from randomization was done (just before maintenance treatment) to compare Vigil and placebo which demonstrated a clinical benefit to Vigil (HR = 0.386, p = 0.007; HR = 0.342, p = 0.019, respectively). Two-year RFS and OS also revealed long term advantage to Vigil (36% vs. 11%, p = 0.031; 88% vs. 56%, p = 0.012, respectively).
      We now provide 3-year follow up of RFS and OS involving HRP patients entered into the VITAL trial.

      2. Methods

      2.1 Patient population and study design

      Vigil plasmid construction, cGMP manufacturing, tissue processing and transfection were carried out as previously described [
      • Senzer N.
      • et al.
      Phase I trial of “bi-shRNAi(furin)/GMCSF DNA/autologous tumor cell” vaccine (FANG) in advanced cancer.
      ,
      • Oh J.
      • et al.
      Phase II study of Vigil(R) DNA engineered immunotherapy as maintenance in advanced stage ovarian cancer.
      ,
      • Rocconi R.P.
      • et al.
      Gemogenovatucel-T (Vigil) immunotherapy demonstrates clinical benefit in homologous recombination proficient (HRP) ovarian cancer.
      ,
      • Maples P.
      • et al.
      FANG vaccine: autologous tumor cell vaccine genetically modified to express GM-CSF and block production of Furin.
      ]. The VITAL study was a randomized, Phase IIb, double-blind, placebo-controlled trial. Patient population and study design were previously published [
      • Rocconi R.P.
      • et al.
      Gemogenovatucel-T (Vigil) immunotherapy as maintenance in frontline stage III/IV ovarian cancer (VITAL): a randomised, double-blind, placebo-controlled, phase 2b trial.
      ]. Patients received 1x10e7 cells/injection of Vigil or placebo once per month for a minimum of 4 and maximum of 12 doses. Treatment continued until product exhaustion or disease progression. All 45 HRP patients entered into the VITAL trial were followed for RFS, OS and late adverse events including development of hematologic malignancy. Continued independent third party assessment by radio-imaging was monitored by World Care Clinical (Boston, MA, USA) using response evaluation criteria in solid tumors version 1.1 [
      • Rocconi R.P.
      • et al.
      Gemogenovatucel-T (Vigil) immunotherapy as maintenance in frontline stage III/IV ovarian cancer (VITAL): a randomised, double-blind, placebo-controlled, phase 2b trial.
      ,
      • Rocconi R.P.
      • et al.
      Gemogenovatucel-T (Vigil) immunotherapy demonstrates clinical benefit in homologous recombination proficient (HRP) ovarian cancer.
      ]. Reports of late adverse events were provided by patient caretaker.

      2.2 HRP analysis

      BRCA1/2 mutation, HRD and HRP status were determined as previously described in 91 patients [
      • Rocconi R.P.
      • et al.
      Gemogenovatucel-T (Vigil) immunotherapy as maintenance in frontline stage III/IV ovarian cancer (VITAL): a randomised, double-blind, placebo-controlled, phase 2b trial.
      ,
      • Rocconi R.P.
      • et al.
      Gemogenovatucel-T (Vigil) immunotherapy demonstrates clinical benefit in homologous recombination proficient (HRP) ovarian cancer.
      ]. Twenty-five patients were identified as HRP in the Vigil arm and 20 were HRP in the placebo arm. Per assay guidelines using MyChoice® CDx (Myriad, Inc., Salt Lake City, UT) a score of ≥42 was used to identify patients who were HRD, and < 42 threshold was used to define HRP. Demographics of the 45 HRP patients which have previously been published [
      • Rocconi R.P.
      • et al.
      Gemogenovatucel-T (Vigil) immunotherapy demonstrates clinical benefit in homologous recombination proficient (HRP) ovarian cancer.
      ] revealed a higher number of Stage IV presenting disease and poor performance status (ECOG 1) patients in the Vigil arm.

      2.3 Statistical analysis

      The primary endpoint of the VITAL study was recurrence free survival from time of randomization. Post-hoc analysis of recurrence free and overall survival of Vigil vs. placebo in HRP patients was performed via Kaplan-Meier analysis. The distributions of RFS and OS were compared using stratified log-rank test with one-sided p values reported. Hazard ratios and 90% CIs were estimated via a Cox proportional hazards model stratified by the randomization factors. Stratification factors included residual disease (at time of debulking surgery) and chemotherapy schedule. Grambsch and Therneau's test was done at the two-sided 0.05 significance level to check the proportional hazards assumption for the Cox model with stratification. Restricted mean survival time (RMST) difference analysis was performed as a sensitivity analysis. A truncation point equal to the minimum of the longest follow-up time of each group was used and was performed without covariate adjustment. Three-year OS was calculated using one-sided Z test. Fisher's exact test (2-sided) was used to compare post Vigil/placebo therapy.

      3. Results

      3.1 Patients and safety

      Patient demographics are listed in Table 1 and were previously published [
      • Rocconi R.P.
      • et al.
      Gemogenovatucel-T (Vigil) immunotherapy demonstrates clinical benefit in homologous recombination proficient (HRP) ovarian cancer.
      ]. No Grade 3, 4, or 5 adverse events felt to be related to Vigil were reported. No treatment related myelodysplastic syndrome or acute myeloid leukemia was observed. Median follow up from first dose of Vigil was 38.6 months (IQR 33.6–43.5) and placebo was 38.4 months (IQR 34.1–43.2).
      Table 1Patient demographics and baseline characteristics.
      CharacteristicGemogenovatucel-TPlacebo
      No. of patients2520
      Age, years
       Median (IQR)64.0 (58.0–71.0, 13.0)64.0 (52.5–68.5, 16.0)
       Mean64.562.5
       Range51.0–84.046.0–79.0
       <6513 (52.0%)11 (55.0%)
       ≥ 6512 (48.0%)9 (45.0%)
      FIGO Stage
       III18 (72.0%)17 (85.0%)
       IV7 (28.0%)3 (15.0%)
      ECOG
       012 (48.0%)15 (75.0%)
       113 (52.0%)5 (25.0%)
      Frontline chemotherapy
       Neoadjuvant4 (16.0%)1 (5.0%)
       Adjuvant21 (84.0%)19 (95.0%)
       Range5–66–7
      Frontline surgery residual disease status
       Macroscopic8 (32.0%)6 (30.0%)
       Microscopic/NED17 (68.0%)14 (70.0%)
      Gender
       Female2520
      Race
       American Indian or Alaska native00
       Asian00
       Black or African American02 (10%)
       Native Hawaiian or other Pacific Islander00
       White25 (100%)18 (90%)
       Not reported00
       Unknown00
      Ethnicity
       Hispanic or Latino00
       Not Hispanic or Latino25 (100%)19 (95%)
       Missing01 (5%)

      3.2 Endpoint analysis

      OS Kaplan Meier (KM) analysis from randomization (n = 45) is shown in Fig. 1A . Vigil median OS was not achieved (NA, 95% CI 41.6 months – NA), placebo median OS was 26.9 months (95% CI 17.4 months – NA), HR = 0.417 (90% CI 0.202–0.860, p = 0.020).
      Fig. 1
      Fig. 1OS KM analysis on 04/07/2021 database lock from randomization (A) and procurement (B).
      Three-year OS from randomization was 70% (95% CI 53.9–91.4%) for Vigil vs. 40% (95% CI 23.4–68.4%) for placebo (p = 0.019, Z test). The assumption of non-proportionality using the Grambsch–Therneau test was significant (p = 0.044). RMST without covariate adjustment was 45.7 months vs. 32.8 months. The estimated RMST difference was 12.8 months (90% CI 4.1–21.6, p = 0.008). RFS from randomization revealed Vigil median RFS of 10.6 (95% CI 5.9-NA) to placebo median of 5.7 (95% CI 5.6–19.6) months (stratified HR 0.405, p = 0.011). RMST further verified durable effect (p = 0.025).
      OS KM analysis from procurement (n = 45) is shown in Fig. 1B. Vigil median OS was not achieved (95% CI 48.9 months - NA) and placebo median OS was 32.5 months (95% CI 23.8 months - NA), HR = 0.417 (90% CI 0.202–0.860 p = 0.020. Three-year OS was 83% (95% CI 69.7–99.7) Vigil vs. 40% (95% CI 23.4–68.4) for placebo (p = 0.0006, Z test). The assumption of non-proportionality using the Grambsch–Therneau test was significant (p = 0.035). RMST without covariate adjustment was 52.0 months vs. 39.1 months. The estimated RMST difference was 12.9 months (90% CI 4.3–21.5, p = 0.007). RFS from procurement revealed Vigil median RFS of 18 (95% CI 14.5-NA) to placebo median of 12 (95% CI 11.4–26.1) months (stratified HR 0.38, p = 0.007). RMST was also significant and further verified durable effect (p = 0.032).
      No difference in long term post relapse disease management that could potentially bias OS or RFS interpretation was observed between placebo and Vigil. Proportion of placebo vs. Vigil patients receiving chemotherapy was 75% vs. 60% (p = 0.35, Fisher's exact test), PARPi 40% vs. 44% (p = 1.0, Fisher's exact test), immunotherapy 25% vs. 12% (p = 0.43, Fisher's exact test) and angiogenesis inhibitor 35% vs. 44% (p = 0.76, Fisher's exact test). Key demographics and stratification factors related to OS and RFS from time of randomization and procurement are listed in Fig. 2.
      Fig. 2
      Fig. 2OS from randomization (A), procurement (B) and RFS from randomization (C), procurement (D) for key subgroups of the per protocol population.

      4. Discussion

      Results at 3 years of follow-up demonstrate OS and RFS advantage to Vigil over placebo and support durable benefit of Vigil used as maintenance in newly diagnosed Stage IIIb-IV ovarian cancer patients with resectable disease and HRP molecular profile. Importantly, Vigil continued to exhibit safety, with no Grade 3/4 or 5 treatment related adverse events or tMDS/tAML reported. Two statistical analyses, KM with Cox proportional hazards model and RMST, were used to assess overall survival advantage in Vigil treated patients versus placebo. RMST analysis looks at survival data using the area under the KM curve over a prespecified time and overcomes limitations in the utilization of traditional KM based hazard ratio through Log-rank test and Cox Proportional Hazards models [
      • Rahmadian A.P.
      • et al.
      Quantifying the survival benefits of oncology drugs with a focus on immunotherapy using restricted mean survival time.
      ]. This approach is particularly useful for analysis of immune based therapies, as the treatment effect may be delayed and unequal over time [
      • Mick R.
      • Chen T.T.
      Statistical challenges in the design of late-stage cancer immunotherapy studies.
      ,
      • Liang F.
      • et al.
      Treatment effects measured by restricted mean survival time in trials of immune checkpoint inhibitors for cancer.
      ].
      Dendritic cell (DC) vaccines have also been explored in ovarian cancer due to the increased presence of ineffective DC infiltration into the tumor microenvironment [
      • Harimoto H.
      • et al.
      Inactivation of tumor-specific CD8+ CTLs by tumor-infiltrating tolerogenic dendritic cells.
      ]. DC vaccines have been loaded with specific antigens including p53, Her-2/neu, MUC1 and also autologous tumor cell lysate (reviewed in [
      • Zhang X.
      • et al.
      Dendritic cell vaccines in ovarian cancer.
      ]). Autologous DC vaccines have also demonstrated benefit in combination with chemotherapy following surgical debulking. Interestingly, patients with low CD8+ T-cell counts had improved PFS and OS gains in response to enhancing activity of DC therapy [
      • Rob L.
      • et al.
      Dendritic cell vaccine (DCVAC) combined with chemotherapy (CMT) in patients with newly diagnosed epithelial ovarian carcinoma (EOC) after primary debulking surgery (PDS): Biomarker exploratory analysis of a phase 2, open-label, randomized, multicenter trial.
      ].
      Systemic immune response following Vigil treatment has been demonstrated by ELISPOT assay of circulating mononuclear cells [
      • Oh J.
      • et al.
      Phase II study of Vigil(R) DNA engineered immunotherapy as maintenance in advanced stage ovarian cancer.
      ,
      • Oh J.
      • et al.
      Long-term follow-up of phase 2A trial results involving advanced ovarian cancer patients treated with Vigil(R) in frontline maintenance.
      ]. Antitumor activity correlates with γ-IFN positive ELISPOT response even months after Vigil discontinuation [
      • Senzer N.
      • et al.
      Long term follow up: phase I trial of “bi-shRNA furin/GMCSF DNA/autologous tumor cell” immunotherapy (FANGTM) in advanced cancer.
      ]. In addition, CD3+/CD8+ circulating mononuclear cells has been shown to be elevated in several solid tumor patients following Vigil treatment [
      • Herron J.
      • et al.
      Vigil: personalized immunotherapy generating systemic cytotoxic T cell response.
      ]. Mounting an effective anti-tumor response is dependent on T cell priming, activation and expansion. Moreover, it has been reported that T cells preferentially recognize clonal neoantigens over subclonal neoantigens which may not be present on every tumor cell or maybe diluted in visibility or access in relationship to subclonal neoantigen expression [
      • McGranahan N.
      • et al.
      Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade.
      ]. Vigil, by providing the relevant tumor neoantigens, may prime and expand the T cell population while also stimulating memory T cell generation. Generation of memory T cells is important for robust and durable tumor control. The presence of resident memory T cells within the tumor microenvironment is correlated with increased response to checkpoint inhibitors and survival [
      • Craig D.J.
      • et al.
      Resident memory T cells and their effect on cancer.
      ,
      • Byrne A.
      • et al.
      Tissue-resident memory T cells in breast cancer control and immunotherapy responses.
      ]. Additionally, in a prior publication we showed that recurrent ovarian cancer patients MHC-II upregulation and TISHIGH gene expression profile by NanoString at baseline had correlation with clinical benefit to Vigil [
      • Rocconi R.P.
      • et al.
      Long-term follow-up of Gemogenovatucel-T (Vigil) survival and molecular signals of immune response in recurrent ovarian cancer.
      ]. Further exploration of these signals in the frontline ovarian cancer patients presented here is underway. Prior results combined with prolonged durable benefit demonstrated here with Vigil treatment suggest memory T cell generation [
      • Craig D.J.
      • et al.
      Resident memory T cells and their effect on cancer.
      ]. However, while benefit is durable it may not be infinite. Tumor growth and evolution may lead to antigen shifts which would change the neoantigen landscape of the tumor resulting in new clonal neoantigens. Alternatively, the prolonged activation of memory T cells may result in terminally exhausted T cells that have decreased capacity for tumor targeting [
      • Ando M.
      • et al.
      Memory T cell, exhaustion, and tumor immunity.
      ]. To overcome both of these possibilities, manufacturing a second Vigil vaccine from tissue harvested at recurrence would be feasible and may provide further benefit.
      These results are particularly important, given that patients with HRP molecular profile have an unfavorable risk/benefit ratio regarding frontline maintenance therapy. A recent meta-analysis of ovarian cancer patients [
      • Xu K.
      • Yang S.
      • Zhao Y.
      Prognostic significance of BRCA mutations in ovarian cancer: an updated systematic review with meta-analysis.
      ] confirmed that inefficient DNA repair mechanisms in patients with BRCA-m tumors and HRD molecular profile predict improved response rates to platinum chemotherapy and PARPi therapy as compared to BRCA-wt tumors [
      • Gonzalez-Martin A.
      • et al.
      Niraparib in patients with newly diagnosed advanced ovarian cancer.
      ,
      • Faraoni I.
      • Graziani G.
      Role of BRCA mutations in cancer treatment with poly(ADP-ribose) polymerase (PARP) inhibitors.
      ]. Observation that patients with HRP profile appear to demonstrate less benefit to SOC maintenance therapy with PARPi's, chemotherapy and/or bevacizumab provide concern regarding risk/benefit ratio. Problematically, chemotherapy, PARPi's, and bevacizumab elicit moderate toxicity that narrows the therapeutic index for long term maintenance therapy. This holds true for niraparib, the only PARPi indicated for use as frontline maintenance therapy regardless of HR or BRCA tumor status, which demonstrates Grade 3/4 adverse events in up to 65% of patients, evidence of tMDS/tAML over time and no OS benefit [
      • Gonzalez-Martin A.
      • et al.
      Niraparib in patients with newly diagnosed advanced ovarian cancer.
      ]. Olaparib/bevacizumab combination has similar toxicity profile but is not indicated in in HRP patients [
      • Moore K.
      • et al.
      Maintenance Olaparib in patients with newly diagnosed advanced ovarian cancer.
      ]. These observations generate concerns from physicians treating newly diagnosed ovarian cancer patients with HRP profile, occasionally resulting in the decision not to use maintenance therapy in this patient population when considering overall risk/benefit. Consequently, HRP profile tumors remain a subset of ovarian cancer with suboptimal risk/benefit balance observed with currently available therapies. These considerations prompted the performance of a post-hoc analysis of VITAL study results with regard to tumor HRP status. Results of 3-year follow up now further support evidence of safety and durable benefit to Vigil justifying further consideration of Vigil use against bevacizumab and/or niraparib in a Phase 3 trial maintenance therapy of HRP profile in Stage IIIb/Iv ovarian cancer patients who achieve complete response after adjuvant chemotherapy and debulking surgery.

      Author Contribution

      AW, RPR, BKM, TJH, RLC, JN were involved conceptualization, data curation, formal analysis and writing- review and editing. LM, EB, GW, PA, SH, MT, LS were involved in data curation, formal analysis, investigation, project administration, Writing- original draft and review and editing.

      Declaration of Competing Interest

      RPR reports sponsored research related to this work. BJM reports personal fees from Abbvie, Advaxis, Agenus, Amgen, Aravive, AstraZeneca, Asymmetric Therapeutics, Boston Biomedical, ChemoCare, ChemoID, Circulogene, Clovis, Conjupro, Easai, Geistlich, Genmab/Seattle Genetics, GOG Foundation, Gradalis, ImmunoGen, Immunomedics, Incyte, Janssen/ Johnson & Johnson, Laekna Health Care, Mateon (formally Oxigene), Merck, Mersana, Myriad, Nucana, Oncomed, Oncoquest, Oncosec, Perthera, Pfizer, Precision Oncology, Puma, Regeneron, Roche/ Genentech, Samumed, Takeda, Tesaro/GSK, VBL, and Vigeo, outside the submitted work. All other authors declare no competing interests.

      Acknowledgement

      We would like to thank Brenda Marr for her assistance in the preparation of the manuscript.

      References

        • Jelovac D.
        • Armstrong D.K.
        Recent progress in the diagnosis and treatment of ovarian cancer.
        CA Cancer J. Clin. 2011; 61: 183-203
        • Gogineni V.
        • et al.
        Current ovarian cancer maintenance strategies and promising new developments.
        J. Cancer. 2021; 12: 38-53
        • Gonzalez-Martin A.
        • et al.
        Niraparib in patients with newly diagnosed advanced ovarian cancer.
        N. Engl. J. Med. 2019; 381: 2391-2402
        • Devanaboyina M.
        • et al.
        Immune response role of angiogenesis inhibitors.
        Clin. Oncol. Res. 2021; 4: 4-13
        • Moore K.
        • et al.
        Maintenance Olaparib in patients with newly diagnosed advanced ovarian cancer.
        N. Engl. J. Med. 2018; 379: 2495-2505
        • LaFargue C.J.
        • et al.
        Exploring and comparing adverse events between PARP inhibitors.
        Lancet Oncol. 2019; 20: e15-e28
        • Ray-Coquard I.
        • et al.
        Olaparib plus Bevacizumab as first-line maintenance in ovarian cancer.
        N. Engl. J. Med. 2019; 381: 2416-2428
        • Marchetti C.
        • et al.
        First-line treatment of women with advanced ovarian cancer: focus on bevacizumab.
        Onco Targets Ther. 2019; 12: 1095-1103
        • Tewari K.S.
        • et al.
        Final overall survival of a randomized trial of Bevacizumab for primary treatment of ovarian cancer.
        J. Clin. Oncol. 2019; 37: 2317-2328
        • GlaxoSmithKline
        Niraparib Package Insert.
        2020
        • Todisco E.
        • et al.
        Clinical presentation, diagnosis and management of therapy-related hematological disorders in women with epithelial ovarian cancer treated with chemotherapy and poly-ADP-ribose polymerase inhibitors: a single-center experience.
        Int. J. Cancer. 2021; 148: 170-177
        • Rocconi R.P.
        • et al.
        Gemogenovatucel-T (Vigil) immunotherapy as maintenance in frontline stage III/IV ovarian cancer (VITAL): a randomised, double-blind, placebo-controlled, phase 2b trial.
        Lancet Oncol. 2020; 21: 1661-1672
        • Senzer N.
        • et al.
        Phase I trial of “bi-shRNAi(furin)/GMCSF DNA/autologous tumor cell” vaccine (FANG) in advanced cancer.
        Mol. Ther. 2012; 20: 679-686
        • Oh J.
        • et al.
        Phase II study of Vigil(R) DNA engineered immunotherapy as maintenance in advanced stage ovarian cancer.
        Gynecol. Oncol. 2016; 143: 504-510
        • Bristow R.E.
        • et al.
        Altered expression of transforming growth factor-beta ligands and receptors in primary and recurrent ovarian carcinoma.
        Cancer. 1999; 85: 658-668
        • Riester M.
        • et al.
        Risk prediction for late-stage ovarian cancer by meta-analysis of 1525 patient samples.
        J. Natl. Cancer Inst. 2014; 106
        • Kang Y.
        • Massagué J.
        Epithelial-mesenchymal transitions: twist in development and metastasis.
        Cell. 2004; 118: 277-279
        • Rocconi R.P.
        • et al.
        Gemogenovatucel-T (Vigil) immunotherapy demonstrates clinical benefit in homologous recombination proficient (HRP) ovarian cancer.
        Gynecol. Oncol. 2021; 161: 676-680
        • Maples P.
        • et al.
        FANG vaccine: autologous tumor cell vaccine genetically modified to express GM-CSF and block production of Furin.
        Bioprocess. J. 2010; 8: 4-14
        • Rahmadian A.P.
        • et al.
        Quantifying the survival benefits of oncology drugs with a focus on immunotherapy using restricted mean survival time.
        J. Natl. Compr. Cancer Netw. 2020; 18: 278-285
        • Mick R.
        • Chen T.T.
        Statistical challenges in the design of late-stage cancer immunotherapy studies.
        Cancer Immunol. Res. 2015; 3: 1292-1298
        • Liang F.
        • et al.
        Treatment effects measured by restricted mean survival time in trials of immune checkpoint inhibitors for cancer.
        Ann. Oncol. 2018; 29: 1320-1324
        • Harimoto H.
        • et al.
        Inactivation of tumor-specific CD8+ CTLs by tumor-infiltrating tolerogenic dendritic cells.
        Immunol. Cell Biol. 2013; 91: 545-555
        • Zhang X.
        • et al.
        Dendritic cell vaccines in ovarian cancer.
        Front. Immunol. 2021; 11
        • Rob L.
        • et al.
        Dendritic cell vaccine (DCVAC) combined with chemotherapy (CMT) in patients with newly diagnosed epithelial ovarian carcinoma (EOC) after primary debulking surgery (PDS): Biomarker exploratory analysis of a phase 2, open-label, randomized, multicenter trial.
        J. Clin. Oncol. 2021; 39: 5521
        • Oh J.
        • et al.
        Long-term follow-up of phase 2A trial results involving advanced ovarian cancer patients treated with Vigil(R) in frontline maintenance.
        Gynecol. Oncol. Rep. 2020; 34: 100648
        • Senzer N.
        • et al.
        Long term follow up: phase I trial of “bi-shRNA furin/GMCSF DNA/autologous tumor cell” immunotherapy (FANGTM) in advanced cancer.
        J. Vaccines Vaccin. 2013; 4: 209
        • Herron J.
        • et al.
        Vigil: personalized immunotherapy generating systemic cytotoxic T cell response.
        Cancer Sci. Res. 2020; 3: 1-4
        • McGranahan N.
        • et al.
        Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade.
        Science. 2016; 351: 1463-1469
        • Craig D.J.
        • et al.
        Resident memory T cells and their effect on cancer.
        Vaccines (Basel). 2020; 8
        • Byrne A.
        • et al.
        Tissue-resident memory T cells in breast cancer control and immunotherapy responses.
        Nat. Rev. Clin. Oncol. 2020; 17: 341-348
        • Rocconi R.P.
        • et al.
        Long-term follow-up of Gemogenovatucel-T (Vigil) survival and molecular signals of immune response in recurrent ovarian cancer.
        Vaccines. 2021; 9: 894
        • Ando M.
        • et al.
        Memory T cell, exhaustion, and tumor immunity.
        Immunol. Med. 2020; 43: 1-9
        • Xu K.
        • Yang S.
        • Zhao Y.
        Prognostic significance of BRCA mutations in ovarian cancer: an updated systematic review with meta-analysis.
        Oncotarget. 2017; 8: 285-302
        • Faraoni I.
        • Graziani G.
        Role of BRCA mutations in cancer treatment with poly(ADP-ribose) polymerase (PARP) inhibitors.
        Cancers (Basel). 2018; 10: 1-20