The United States Food and Drug Administration (FDA) has recommended that ImmunoGen conducts a new Phase III randomized trial to evaluate the safety and efficacy of mirvetuximab soravtansine (IMGN853) in patients with high folate receptor alpha (FRα)-positive, platinum-resistant ovarian cancer as part of a Type C meeting held earlier this week.

Mirvetuximab soravtansine is the first folate receptor alpha (FRα)-targeting ADC which uses a humanized FRα-binding antibody (M9346A) against folate receptor 1 (FOLR1) conjugated, via the disulfide-containing cleavable linker sulfo-SPDB, to the cytotoxic maytansinoid DM4.

The anti-FOLR1 monoclonal antibody moiety of mirvetuximab soravtansine targets and binds to the cell surface antigen FOLR1. After antibody-antigen interaction and internalization, the immunoconjugate releases DM4, which binds to tubulin and disrupts microtubule assembly/disassembly dynamics, thereby inhibiting cell division and cell growth of FOLR1-expressing tumor cells. FOLR1, a member of the folate receptor family is overexpressed on a variety of epithelial-derived cancer cells. The sulfo-SPDB linker prevents cleavage in the bloodstream and may improve this agent’s efficacy in multidrug resistant tumor cells.

ImmunoGen requested the meeting with the FDA to discuss the results of the Phase III FORWARD I trial and a potential path to registration for mirvetuximab monotherapy. The agency advised that, because FORWARD I (NCT02631876) did not meet its primary endpoint under the pre-specified statistical analysis plan, the data generated assessing the secondary endpoints from the study could not be used to support an application for accelerated approval.[1]

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Platinum Resistant Ovarian Cancer
However, the FDA acknowledged that platinum-resistant ovarian cancer is a disease with unmet need and provided guidance regarding the design and endpoints of a potential registration study. Representatives of the FDA encouraged the Immunogen to return to discuss a proposed study design.

The FORWARD I is a Phase III trial randomized 366 patients 2:1 to receive either mirvetuximab soravtansine or the physician’s choice of single-agent chemotherapy (pegylated liposomal doxorubicin, topotecan, or weekly paclitaxel). Eligible patients were diagnosed with platinum-resistant ovarian cancer that expresses medium or high levels of FRα and were treated with up to three prior regimens. The primary endpoint of this study was progression free survival (PFS), which was assessed in the entire study population and in the subset of patients with high FRα expression. ImmunoGen estimates that 12,000-14,000 patients per year in the U.S. meet these criteria, with a comparable number in the major markets in Europe.

ImmunoGen partnered with the GOG Foundation Inc., a leader in clinical research in gynecologic malignancies, on FORWARD I, which was conducted in North America and Europe.

“We are encouraged by the consistent signal of anti-tumor activity and the favorable benefit-risk profile in patients with high FRα expression in our Phase 3 FORWARD I trial,” said Anna Berkenblit, MD, Senior Vice President and Chief Medical Officer of ImmunoGen.

“We appreciate the constructive engagement with FDA and look forward to aligning with the agency on the design of a new registration trial in this population.”

“Our meeting with FDA enabled us to clarify a regulatory path forward for mirvetuximab and we are evaluating all avenues to bring this promising therapy to ovarian cancer patients,” said Mark Enyedy, ImmunoGen’s President and Chief Executive Officer.

“The mirvetuximab combination cohorts continue to advance and, with approximately US $270 million on the balance sheet as of the end of Q1, we remain focused on developing innovative ADC therapeutics and delivering more good days to people with cancer.”

[1] Phase III Study of Mirvetuximab Soravtansine vs Investigator’s Choice of Chemotherapy in Women With FRa+ Adv. EOC, Primary Peritoneal or Fallopian Tube Cancer (FORWARD I).

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