Ovarian cancer is the fifth overall cause for cancer death in women, representing 5% of all cancer deaths in women.  It is also the deadliest of gynecological cancers: According to the American Cancer Society, 19,710 women in the United States will receive a new diagnosis of ovarian cancer in 2023 and about 13,270 women will die from the disease.  In 2018, 44,576 women in Europe  died from ovarian cancer. Most women with ovarian cancer present with Stage III or IV disease, contributing to its high mortality rate. 
Most patients present with late-stage (stage III or stage IV) disease and will typically undergo surgery followed by platinum-based chemotherapy.  Unfortunately, the majority of patients eventually develop platinum-resistant disease, which is difficult to treat. In this setting, standard of care single-agent chemotherapies are associated with low response rates, short durations of response, and significant toxicities, resulting in a major unmet medical need. 
However, ongoing research in the development of novel therapeutic approaches may change this. Among these novel therapeutic approaches are antibody-drug conjugates.
ADCs represent a class of therapeutic agents designed to target specific antigens on tumor cells, combining the specificity of monoclonal antibodies to the cytotoxicity of classic chemotherapy agents.
In November 2022, the US Food and Drug Administration (FDA) granted accelerated approval for mirvetuximab soravtansine-gynx (Elahere®; ImmunoGen), a first-in-class antibody-drug conjugate (ADC) comprising a folate receptor alpha-binding antibody, cleavable linker, and the maytansinoid payload DM4, a potent tubulin inhibitor designed to kill the targeted cancer cells, for the treatment of adult patients with FRα-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received one to three prior systemic treatment regimens based on ORR and duration of response data from the pivotal SORAYA trial (NCT04296890).
As part of the accelerated approval, the FDA required a follow-up confirmatory trial.
Now, positive top-line data from the Phase 3 confirmatory MIRASOL trial (NCT04209855; GOG 3045/ENGOT OV-55) evaluating the safety and efficacy of mirvetuximab soravtansine-gynx compared to chemotherapy in patients with folate receptor alpha (FRα)-positive platinum-resistant ovarian cancer who have received one to three prior lines of therapy.
Based on these data, ImmunoGen plans to submit a Marketing Authorization Application (MAA) in Europe and a supplemental Biologics License Application (sBLA) in the US for the conversion to a regular approval of mirvetuximab soravtansine-gynx.
“I believe the data from the confirmatory MIRASOL trial are practice-changing. They demonstrate mirvetuximab soravtansine’s superiority to chemotherapy based on all efficacy endpoints, in particular overall survival, and build on the clinical benefit of mirvetuximab soravtansine previously reported in the SORAYA trial,” noted Kathleen Moore, Associate Director of Clinical Research and Director of the Oklahoma TSET/Sarah Cannon Phase I Program, Professor of the Section of Gynecologic Oncology at The University of Oklahoma and MIRASOL Principal Investigator.
“[The] accelerated approval of mirvetuximab soravtansine was a paradigm-shifting development in the treatment landscape for this disease and I am confident that, with the MIRASOL data, mirvetuximab soravtansine has the potential to become the new standard of care for patients with FRα-positive, platinum-resistant ovarian cancer,” Moore said.
“FRα status is a ‘must know’ for all ovarian cancer patients and, for those with platinum-resistant disease who test positive, I believe mirvetuximab soravtansine should be their first treatment option,” she added.
The MIRASOL study is a randomized Phase 3 trial of mirvetuximab soravtansine-gynx versus investigator’s choice (IC) of single-agent chemotherapy (weekly paclitaxel, pegylated liposomal doxorubicin, or topotecan). Patients are eligible if they are diagnosed with platinum-resistant ovarian cancer with tumors express high levels of FRα, using the Ventana FOLR1 Assay, and have been treated with up to three prior regimens.
The primary endpoint of this trial is progression-free survival (PFS) by investigator assessment. Key secondary endpoints include objective response rate (ORR) and overall survival (OS).
The study enrolled 453 patients; 14% had one prior line of therapy, 39% had two prior lines of therapy, and 47% had three prior lines of therapy. 62% of patients received prior bevacizumab; 55% received a prior PARP inhibitor. As of the data cutoff on March 6, 2023, the median follow-up time for OS was 13.1 months; 14% of patients on the mirvetuximab soravtansine-gynx arm remained on study drug compared to 3% on the IC chemotherapy arm.
- Mirvetuximab soravtansine-gynx demonstrated a statistically significant and clinically meaningful improvement in OS compared to IC chemotherapy. With 204 OS events reported as of March 6, 2023, the median OS was 16.46 months in the mirvetuximab soravtansine arm, compared to 12.75 months in the IC chemotherapy arm, with a hazard ratio (HR) of 0.67, p=0.0046. This represents a 33% reduction in the risk of death in the mirvetuximab soravtansine arm in comparison to the IC chemotherapy arm.
- Mirvetuximab soravtansine-gynx demonstrated a statistically significant and clinically meaningful improvement in PFS by investigator assessment compared to IC chemotherapy, with a hazard ratio of 0.65 (p<0.0001), which represents a 35% reduction in the risk of tumor progression or death in the mirvetuximab soravtansine arm compared to the IC chemotherapy arm. The median PFS in the mirvetuximab soravtansine-gynx arm was 5.62 months, compared to 3.98 months in the IC chemotherapy arm.
- ORR by investigator assessment in the mirvetuximab soravtansine arm was 42.3%, including 12 complete responses (CRs), compared to 15.9%, with no CRs, in the IC chemotherapy arm.
- PFS and ORR results by blinded independent central review were concordant with investigator assessment.
- The safety profile of mirvetuximab soravtansine-gynx continues to consist predominantly of low-grade ocular and gastrointestinal events. No new safety signals were identified. Compared with IC chemotherapy, mirvetuximab soravtansine was associated with lower rates of:
- Grade 3 or greater treatment-emergent adverse events (TEAEs) (42% vs 54%);
- Serious adverse events (24% vs 33%); and
- TEAEs leading to discontinuation of study drug (9% vs 16%).
“We are elated with the positive top-line results from MIRASOL. We believe the impressive efficacy data and consistent safety data reinforce mirvetuximab soravtansine’s benefit for patients with platinum-resistant ovarian cancer,” said Anna Berkenblit, MD, Senior Vice President and Chief Medical Officer of ImmunoGen.
“Importantly, mirvetuximab soravtansine is the first drug to show an overall survival benefit in this patient population. These results are remarkable and we extend our appreciation to all of the patients and physicians who participated in MIRASOL. We look forward to presenting full data from the trial at a medical meeting later this year.”
“These MIRASOL data shows that mirvetuximab soravtansine-gynx is a first-in-class, biomarker-driven ADC for the treatment of FRα-positive platinum-resistant ovarian cancer and mark a significant milestone for patients and our organization,” said Mark Enyedy, ImmunoGen’s President and Chief Executive Officer.
“We believe these data will provide the foundation for pursuing a marketing authorization in Europe and elsewhere, and seeking full approval in the US, support our goal of delivering mirvetuximab soravtansine to FRα-positive patients worldwide, and reinforce our conviction in our clinical development program to move this therapy into broader populations, including platinum-sensitive disease. Mirvetuximab soravtansine-gynx ’s differentiated safety and efficacy data provides further validation of our leading ADC platform and broad clinical pipeline of novel ADCs for solid tumors and hematologic malignancies.”
A Study of Mirvetuximab Soravtansine in Platinum-Resistant, Advanced High-Grade Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancers With High Folate Receptor-Alpha Expression (SORAYA) – NCT04296890
A Study of Mirvetuximab Soravtansine vs. Investigator’s Choice of Chemotherapy in Platinum-Resistant, Advanced High-Grade Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancers With High Folate Receptor-Alpha Expression (MIRASOL) – NCT04209855
Highlights of Prescribing Information
Mirvetuximab soravtansine-gynx (Elahere®; ImmunoGen)[Prescribing Information]
RxDx Diagnostic Assay
VENTANA FOLR1 (FOLR1-2.1) RxDx Assay [Predictive IHC assay]
Indication and Usage
Mirvetuximab soravtansine-gynx is indicated for the treatment of adult patients with folate receptor-alpha (FRα) positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received one to three prior systemic treatment regimens. Select patients for therapy based on an FDA-approved test.This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
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 National Cancer Institute. Surveillance, Epidemiology and End Results Program. Cancer Stat Facts: Ovarian Cancer. Online. Last accesses on May 1, 2023
 WHO. IARC: ovarian cancer estimated incidence, mortality and prevalence. Online. Last accesses on May 1, 2023.
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