In a statement earlier today, ImmunoGen confirmed that the U.S. Food and Drug Administration (FDA) has advised that a new single-arm study in platinum-resistant ovarian cancer could support accelerated approval for mirvetuximab soravtansine.

Mirvetuximab soravtansine, also know as IMGN853, is the first folate receptor alpha (FRα)-targeting antibody-drug conjugate or ADC. The investigational drug uses a humanized FRα-binding antibody (M9346A, linked via a disulfide-containing cleavable sulfo-SPDB linker to DM4, a potent anti-tumor chemical derivative of maytansine, to target and kill FRα-expressing cancer cells.

Mechanism of Action
After antibody-antigen interaction and internalization, the antibody-drug conjugate 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, including ovarian cancer. The sulfo-SPDB linker prevents cleavage in the bloodstream and may improve this agent’s efficacy in multidrug resistant tumor cells.

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Next steps
Based on the FDA’s guidance, ImmunoGen confirmed that it will initiate a pivotal trial to evaluate mirvetuximab soravtansine monotherapy. The trial, called SORAYA, will study the investigational drug in women with folate receptor alpha (FRα)-high platinum-resistant ovarian cancer who have been previously treated with bevacizumab (Avastin®; Genentech/Roche).

“We have engaged in constructive discussions with FDA and evaluated all avenues to bring mirvetuximab soravtansine to patients more quickly,” explained Mark Enyedy, ImmunoGen’s President and Chief Executive Officer.

“Having aligned with the agency that women with FRα-high platinum-resistant ovarian cancer that has progressed after prior treatment with bevacizumab require better therapeutic options, we are pleased to advance mirvetuximab soravtansine in this patient population with SORAYA, which, if successful, would enable us to submit an application for accelerated approval during the second half of 2021. We anticipate enrolling the first patient in SORAYA next quarter and expect top-line data from the study in mid-2021.”

ImmunoGen’s mirvetuximab soravtansine study program now includes two new trials, SORAYA and MIRASOL, which will enroll concurrently.

Pivotal trial
The pivotal SORAYA study is designed as a single-arm trial with mirvetuximab soravtansine that will enroll approximately 100 patients. To be eligible, patients with platinum-resistant ovarian cancer whose tumors express high levels of FRα using the PS2+ scoring method, and who have been treated with up to three prior regimens – at least one of which included bevacizumab, can enroll. The primary endpoint of this study is overall response rate by investigator assessment and the key secondary endpoint is duration of response.

Confirmatory Trial
MIRASOL, the second study, is a randomized Phase III trial in which 430 patients will be randomized 1:1 to receive either mirvetuximab soravtansine or investigator’s choice of single-agent chemotherapy (weekly paclitaxel, pegylated liposomal doxorubicin, or topotecan).

To be eligible patients need to be diagnosed with platinum-resistant ovarian cancer whose tumors express high levels of FRα using the PS2+ scoring method, and have been treated with up to three prior regimens. The primary endpoint of this study is progression free survival by investigator assessment. The key secondary endpoints include: overall response rate (ORR), overall survival (OS), and patient-reported outcomes.

“We have reviewed the data generated from our Phase I and FORWARD I studies using the PS2+ scoring method and have identified 70 patients who would meet the key eligibility criteria for SORAYA. The overall response rate in these patients was 31.4% with 95% CI (20.9%, 43.6%) and a median duration of response of 7.8 months with 95% CI (3.98, -),” said Anna Berkenblit, MD, Senior Vice President and Chief Medical Officer of ImmunoGen.

“These data compare quite favorably to the response rate seen with single agent chemotherapy in platinum resistant disease, which was 12% in the AURELIA and CORAIL trials, and included patients naïve to and previously treated with bevacizumab,” Berkenblit added.

“Replicating these data in [the] SORAYA [study] would support an application for accelerated approval in advance of the completion of [the] MIRASOL [study], which would thereafter provide the randomized data needed for conversion to full approval. We are delighted to advance both studies as soon as possible,” Berkenblit concluded.

Earlier this year mature data from the FORWARD II expansion cohort evaluating mirvetuximab soravtansine in combination with bevacizumab in patients with FRα-positive platinum-resistant ovarian cancer were presented at the 2019 annual meeting of the  American Society of Clinical Oncology (ASCO) held May 31 – June 4 in Chicago, Illinois. [1]

Clinical trials
Evaluation of Mirvetuximab Soravtansine (IMGN853) in Women With Folate Receptor-α Positive Endometrial Cancer – NCT03832361
Mirvetuximab Soravtansine and Rucaparib Camsylate in Treating Participants With Recurrent Endometrial, Ovarian, Fallopian Tube or Primary Peritoneal Cancer – NCT03552471
A Phase 2 Study of Mirvetuximab Soravtansine (IMGN853) and Pembrolizumab in Endometrial Cancer (EC) – NCT03835819
Mirvetuximab Soravtansine as First Line in Treating Patients With Triple Negative Breast Cancer – NCT03106077
Mirvetuximab Soravtansine and Gemcitabine Hydrochloride in Treating Patients With FRa-Positive Recurrent Ovarian, Primary Peritoneal, Fallopian Tube, Endometrial, or Triple Negative Breast Cancer – NCT02996825
PH3 Study of Mirvetuximab Soravtansine vs Investigator’s Choice of Chemotherapy in Women With FRa+ Adv. EOC, Primary Peritoneal or Fallopian Tube Cancer (FORWARD I) – NCT02631876
First-in-Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Mirvetuximab Soravtansine in Adults With Ovarian Cancer and Other FOLR1-Positive Solid Tumors (IMGN-0401) – NCT01609556
Study of Mirvetuximab Soravtansine in Comb. With Bevacizumab, Carboplatin, PLD, Pembrolizumab, or Bevacizumab + Carboplatin in Adults With FRa + Adv. EOC, Primary Peritoneal or Fallopian Tube Cancer (FORWARD II) – NCT02606305
Mirvetuximab Soravtansine (IMG853) in Folate Receptor Alpha-expressing TNBC (IMGN853) – NCT03045393
Mirvetuximab Soravtansine (IMGN853) and Bevacizumab in Patients With Endometrial Cancer – NCT03836157

[1] O’Malley DM, Matulonis UA, Birrer MJ, Castro CM, Vergote I, Martin LP, Mantia-Smaldone G, Gilbert L, et al. Mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients (pts) with platinum-resistant ovarian cancer: Final findings from the FORWARD II study. J Clin Oncol 37, 2019 (suppl; abstr 5520). 10.1200/JCO.2019.37.15_suppl.5520

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