47MO - The risk index of early relapse defined by MiROvaR, a miRNA-based classifier, is a potential predictive marker for bevacizumab benefit: A MITO-MANGO-ENGOT study

Background

The introduction of PARP inhibitors (PARPi) has greatly changed Ovarian Cancer (OC) patients’ journey. Nonetheless, subgroups of patients still benefit of Bevacizumab (Bev) particularly those at clinical high risk or proficient for BRCA and/or Homologous Recombination. We developed, and validated, a robust and independent miRNA-based molecular predictor, MiROvaR, successfully identifying patients at high risk of early relapse. MiROvaR may contribute in refining poor-prognosis patients predicting those who could greatly benefit from Bev treatment.

Methods

Samples used for the analyses were from two clinical trials: MITO16A-MANGO-Ov2 (MITO16A), single arm including Bev treatment/maintenance in front-line and MITO16B-MANGO-Ov2-ENGOT-Ov17 (MITO16B), randomized phase III including or not Bev treatment/maintenance in platinum sensitive patients relapsing after receiving Bev in front-line. RNA of adequate quality from patient enrolled in MITO16A (n=197) and MITO16B (n=102 standard arm; n=108 experimental arm) was profiled for miRNA expression (Agilent 8x60K miRBase21 version). MiROvaR-Index was derived to classify patients for being at high/low risk of relapse and assess association with clinical/pathological parameters and prognostic/predictive impact.

Results

The biomarker-evaluable populations comprising 49.5% and 51.7% of the intent-to-treat populations of MITO16A and MITO16B respectively had representative baseline characteristics and outcomes. In MITO16A, MiROvaR confirmed its performance in progression-free survival (PFS) and maintained an independent prognostic power in multivariable analysis with residual disease and FIGO stage (HR 1.74, 95% CI 1.131–2.67; P=0.011). In MITO16B, high MiROvaR-Index was predictive of a therapeutic advantage with Bev for PFS (P_interaction = 0.00754) but not for Overall Survival. Patients with high MiROvaR-Index treated with Bev had longer PFS (13 vs. 8 months; log-rank P<0.0001) compared to those in the control arm.

Conclusions

High MiROvaR-Index confirmed its prognostic power of early relapse independently of the treatment schedule and suggested a predictive potential of Bev response.

Clinical trial identification

MITO16A-MANGO-Ov2: EudraCT 2012-003043-29; NCT01706120. MITO16B-MANGO-Ov2-ENGOT-Ov17: NCT01802749 and EudraCT 2012-004362-17.

Legal entity responsible for the study

The authors.

Funding

Fondazione Associazione Italiana per la Ricerca sul Cancro and Italian Ministry of Heath.

Disclosure

D. Lorusso: Financial Interests, Personal, Advisory Board, Participation in Advisory Boards and Invited Speaker: GSK, Clovis Oncology, PharmaMar; Financial Interests, Personal, Advisory Board, Participation in Advisory Boards and Invited Speakers: AstraZeneca, MSD; Financial Interests, Personal, Other, Consultancy: PharmaMar, AstraZeneca, Clovis Oncology, GSK, MSD, Immunogen, Genmab, Seagen, Novartis; Financial Interests, Personal, Advisory Board, Invited member of advisory board and invited speaker: Seagen, Immunogen, Genmab; Financial Interests, Personal, Advisory Board, Invited member of advisory board: Oncoinvest, Corcept, Sutro; Financial Interests, Institutional, Funding, Grant for founding academic trials: MSD, Clovis Oncology, GSK, PharmaMar; Financial Interests, Institutional, Invited Speaker, ENGOT trial with institutional support for coordination: Clovis Oncology; Financial Interests, Institutional, Invited Speaker, ENGOT trial with institutional support for coordination: Genmab, MSD; Financial Interests, Institutional, Funding, Clinical trial/contracted research: AstraZeneca, Clovis Oncology, GSK, MSD, Seagen; Financial Interests, Institutional, Funding, Clinical trials/contracted research: Genmab, Immunogen, Incyte, Novartis, Roche; Non-Financial Interests, Personal, Principal Investigator, PI of several trials, no compensation received: GSK; Non-Financial Interests, Personal, Principal Investigator, PI of several trials. No personal compensation received: AstraZeneca, Genmab; Non-Financial Interests, Personal, Principal Investigator, PI in several trials. No personal compensation received: MSD; Non-Financial Interests, Personal, Principal Investigator, PI of clinical trial. No personal compensation received: immunogen, Clovis Oncology, Roche, Incyte; Non-Financial Interests, Personal, Principal Investigator, PI of several trials, no personal compensation received: Novartis; Non-Financial Interests, Personal, Principal Investigator, PI of clinical trial, no personal compensation received: Seagen; Non-Financial Interests, Personal, Principal Investigator, PI of clinical trials, no personal compensation received: PharmaMar; Non-Financial Interests, Personal, Member, Board of Directors: GCIG; Other, Personal, Other, Grants for traveling: AstraZeneca, Clovis Oncology, GSK. G. Scambia: Financial Interests, Personal, Invited Speaker, Speaker: Baxter Healthcare, GSK, Intuitive Surgical Inc., AstraZeneca & MSD, Olympus Europa, GSK, AstraZeneca & MSD, Olympus Europa; Financial Interests, Personal, Expert Testimony, Trainer: Covidien AG (Medtronic company); Financial Interests, Institutional, Invited Speaker, ‘IsoMSLN’ in Ovarian Cancer and Malignant Pleural Mesothelioma: Kiromic; Financial Interests, Institutional, Invited Speaker, Roll-over study for patients who have completed a previous cancer study with olaparib and who the investigator believes can benefit from continued treatment - ROSY-O: AstraZeneca; Financial Interests, Institutional, Invited Speaker, CATCH-R: Roll-over study to provide continuous access to clinical therapy with rucaparib.: Clovis Oncology; Financial Interests, Institutional, Invited Speaker, Phase 3, multicenter, placebo-controlled clinical study comparing chemo-immunotherapy (paclitaxel-carboplatin-oregovomab) versus chemotherapy (paclitaxel-carboplatin-placebo) in patients with advanced epithelial ovarian, tubal cancer of fallopian or peritoneal (FLORA-5): Oncoquest Pharmaceuticals Inc.; Financial Interests, Institutional, Invited Speaker, Phase 2b randomized, open-label, active comparator, parallel-group, multicenter study designed to evaluate the efficacy and safety of three different doses of the P2X3 receptor antagonist (BAY 1817080) versus placebo and Elagolix 150 mg in women with symptomatic endometriosis: Bayer AG; Financial Interests, Institutional, Invited Speaker, Usability of ITE transducers for sending electric fields for tumor treatment (TTFields): Novocure Ltd; Financial Interests, Institutional, Invited Speaker, Phase III, multicentre, open-label extension trial to evaluate long-term safety and efficacy in patients with advanced cancers currently undergoing treatment or in follow-up in a pembrolizumab trial.: Merck. J. Alexandre: Financial Interests, Personal, Advisory Board: Eisai, MSD, GSK, Janssen, Pfizer, Seagen; Financial Interests, Personal, Invited Speaker: Eisai, MSD, AstraZeneca, GSK, Novartis; Financial Interests, Institutional, Research Grant: Janssen, GSK, MSD; Financial Interests, Institutional, Invited Speaker: MSD, Eisai, Agenus, GSK, Immunogen, Incyte, Kartos. N. Colombo: Financial Interests, Personal, Advisory Board, Various: Roche, AstraZeneca, MSD/Merck, Clovis Oncology, GSK, Immunogen, Mersana; Financial Interests, Personal, Invited Speaker, Congress, Symposia, Lectures: AstraZeneca; Financial Interests, Personal, Advisory Board, Lectures: Eisai; Financial Interests, Personal, Advisory Board, Advisory role: Nuvation Bio, Pieris; Financial Interests, Personal, Advisory Board, Advisory Role: Onxerna; Financial Interests, Personal, Invited Speaker: MSD/MERCK; Financial Interests, Personal, Invited Speaker, Speaker: GSK; Financial Interests, Institutional, Research Grant: AstraZeneca, Roche, GSK; Non-Financial Interests, Personal, Other, Steering Committee, member Clinical Guidelines: ESMO; Non-Financial Interests, Personal, Leadership Role, Chair, Scientific Committee: ACTO (Alleanza contro il tumore ovarico). G. Tasca: Financial Interests, Personal, Advisory Board: GSK, MSD, Eisai; Financial Interests, Personal, Invited Speaker: GSK, AstraZeneca, GSK; Non-Financial Interests, Personal, Member, Collaborative Group in Gynaecological Oncology: MaNGO; Other, Personal, Other, Travel Grant: PharmaMar. S. Pignata: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, MSD, Clovis, GSK, PharmaMar; Financial Interests, Institutional, Funding: Roche, MSD, Pfizer, AstraZeneca. All other authors have declared no conflicts of interest.