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Treatment options for HRP ovarian cancer are limited and associated with significant toxicity and limited clinical benefit.
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Previously, Vigil has shown both safety and efficacy in the BRCA wild type, homologous recombination proficient patients.
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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.
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 [
]. 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 [
]. 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. [
]. 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% [
]. 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% [
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 [
Gemogenovatucel-T (Vigil) immunotherapy as maintenance in frontline stage III/IV ovarian cancer (VITAL): a randomised, double-blind, placebo-controlled, phase 2b trial.
]. 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 [
Gemogenovatucel-T (Vigil) immunotherapy as maintenance in frontline stage III/IV ovarian cancer (VITAL): a randomised, double-blind, placebo-controlled, phase 2b trial.
]. 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 [
]. The VITAL study was a randomized, Phase IIb, double-blind, placebo-controlled trial. Patient population and study design were previously published [
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 [
Gemogenovatucel-T (Vigil) immunotherapy as maintenance in frontline stage III/IV ovarian cancer (VITAL): a randomised, double-blind, placebo-controlled, phase 2b trial.
Gemogenovatucel-T (Vigil) immunotherapy as maintenance in frontline stage III/IV ovarian cancer (VITAL): a randomised, double-blind, placebo-controlled, phase 2b trial.
]. 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 [
] 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 [
]. 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.
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. 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. 2OS from randomization (A), procurement (B) and RFS from randomization (C), procurement (D) for key subgroups of the per protocol population.
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 [
Dendritic cell (DC) vaccines have also been explored in ovarian cancer due to the increased presence of ineffective DC infiltration into the tumor microenvironment [
]). 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 [
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.
]. 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 [
]. 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 [
]. 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 [
]. 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 [
]. 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 [
]. 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 [
] 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 [
]. 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 [
]. 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.
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.
Gemogenovatucel-T (Vigil) immunotherapy as maintenance in frontline stage III/IV ovarian cancer (VITAL): a randomised, double-blind, placebo-controlled, phase 2b trial.
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.
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