FORWARD I (GOG 3011): A phase III study of mirvetuximab soravtansine, a folate receptor alpha (FRa)-targeting antibody-drug conjugate (ADC), versus chemotherapy in patients (pts) with platinum-resistant ovarian cancer (PROC)

Abstract Background Mirvetuximab soravtansine (MIRV) is an ADC comprising a FRα-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent. FORWARD I, a phase III study, evaluated the safety and efficacy of MIRV compared to chemotherapy in pts with PROC. Methods Pts with PROC, 1-3 prior lines of therapy, and FRα positivity by immunohistochemistry (stratified by predefined medium or high expression) were enrolled. Pts were randomized 2:1 to MIRV (6 mg/kg, adjusted ideal body weight) once every 21 days or investigators’ choice chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary endpoint was progression-free survival (PFS) by blinded independent review committee, in both the intention-to-treat (ITT) population (medium and high FRα expression) and, separately, in pts with high FRα. Secondary endpoints included objective response rate (ORR) and overall survival (OS). Median follow-up time was 12.5 months. Results Of 366 pts randomized, 248 received MIRV and 118 chemotherapy. Baseline characteristics were well balanced across arms. In the ITT population, the PFS hazard ratio (HR) was 0.981 (median PFS of 4.1 vs 4.4 months for MIRV and chemotherapy, respectively). For the high FRα pt subset (n = 218), additional outcomes favored MIRV over chemotherapy: PFS HR of 0.693 (4.8 vs 3.3 months; p = 0.049, not significant by Hochberg procedure), ORR (24% vs 10%), and interim OS (83/213 events (34%); median not reached vs 11.8 months; HR, 0.618). The most common adverse events (AEs) observed with MIRV were nausea (54%), diarrhea (44%), and blurred vision (43%). Fewer high grade (≥ 3) events, dose modifications, and discontinuations due to AEs were seen with MIRV. Conclusions While the study did not meet the primary endpoint, promising and consistent efficacy measures were observed in the predefined subset of high FRα PROC pts treated with MIRV. Along with favorable tolerability and differentiated safety, these findings suggest a favorable benefit-risk profile for MIRV in this biomarker-defined and difficult-to-treat population. Clinical trial identification NCT02631876. Legal entity responsible for the study ImmunoGen, Inc. Funding ImmunoGen, Inc. Disclosure K.N. Moore: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Clovis; Advisory / Consultancy: ImmunoGen; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Tesaro; Advisory / Consultancy: VBL Therapeutics; Advisory / Consultancy: Aravive. A. Oaknin: Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: PharmaMar; Advisory / Consultancy, Travel / Accommodation / Expenses: Clovis; Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy: ImmunoGen. D. Lorusso: Advisory / Consultancy, Research grant / Funding (institution): Tesaro; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Clovis; Advisory / Consultancy: Merrimack. C.G. Murphy: Advisory / Consultancy: Janssen; Advisory / Consultancy: Roche; Advisory / Consultancy: Nordic Pharma; Travel / Accommodation / Expenses: Ipsen; Travel / Accommodation / Expenses: Pfizer. J.A. Konner: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Clovis; Advisory / Consultancy: ImmunoGen. M. Prasad Hayes: Research grant / Funding (institution): AstraZeneca. S.K. Kim: Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: AbbVie; Advisory / Consultancy: Cytomx; Advisory / Consultancy: ImmunoGen; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy, Travel / Accommodation / Expenses: Astellas/Agensys. J. Wang: Full / Part-time employment: ImmunoGen Inc. P. Pautier: Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Clovis; Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro. M.J. Birrer: Advisory / Consultancy: Tesaro; Advisory / Consultancy: Clovis; Advisory / Consultancy: Merck Sharp & Dome; Advisory / Consultancy: Genentech USA; Advisory / Consultancy: AstraZeneca. All other authors have declared no conflicts of interest.