Mirvetuximab soravtansine-gynx, a novel antibody-drug conjugate, significantly improved progression-free and overall survival in patients with platinum-resistant, recurrent ovarian cancers that express high levels of folate receptor–alpha (FR-alpha), according to the results of the phase III -MIRASOL trial presented at the 2023 ASCO Annual Meeting.¹ In addition, mirvetuximab soravtansine more than doubled the objective response rates and in general had a more favorable toxicity profile than chemotherapy in the study.

Kathleen N. Moore, MD, MS

“These results are practice-changing. Until now, no targeted therapy has been shown to improve overall survival in ovarian cancer in a phase III trial,” stated lead author Kathleen N. Moore, MD, MS, of Stephenson Cancer Institute at the University of Oklahoma, at a session specially convened to present and discuss this abstract. “This is statistically significant and clinically meaningful. This is the first antibody-drug conjugate with proven efficacy in ovarian cancer and the only approved biomarker-driven therapy for platinum-resistant ovarian cancer.”

Mirvetuximab soravtansine is an antibody-drug conjugate targeting FR-alpha and conjugated to the highly potenttubulin inhibitor, DM4. FR-alpha is ubiquitous in high-grade serous ovarian, primary peritoneal, or fallopian tube cancers (grouped together as ovarian cancer in this report). However, about 35% of patients with ovarian cancer have high FR-alpha expression, and those were the group of patients included in the MIRASOL trial. A previous trial (SORAYA) has recently led to accelerated approval of mirvetuximab soravtansine in platinum-resistant ovarian cancer with high FR-alpha expression.

Study Details

MIRASOL is a global randomized phase III trial conducted for regulatory approval in platinum-resistant ovarian cancer with high FR-alpha expression. At enrollment, all patients had platinum-resistant, high-grade serous ovarian cancer and FR-alpha present in at least 75% of tumor cells. Patients had received one to three prior lines of therapy that may have included prior bevacizumab. If patients had BRCA mutations, they had to be previously treated with a PARP inhibitor. All patients provided tumor samples for further study.

A total of 453 patients were randomly assigned 1:1 to receive the antibody-drug conjugate or investigator’s choice of chemotherapy. The primary endpoint was investigator-assessed progression-free survival. Secondary, analytic endpoints were overall response rate, overall survival, and patient-reported outcomes. There were several exploratory endpoints.

“This presentation focused on progression-free survival per investigator and blinded independent review committee as well as overall response rate, overall survival, and safety. Subsequent findings will be presented in the future,” Dr. Moore told listeners.

Baseline demographics were well balanced between the two arms. Approximately 60% of patients had prior exposure to bevacizumab, and 56% had prior exposure to PARP inhibitors. Stratification factors included one, two, or three lines of prior chemotherapy (14%, 40%, and 46%, respectively). The type of chemotherapy per investigator choice was weekly paclitaxel, pegylated liposomal doxorubicin, or topotecan (41%, 36%, and 23%, respectively).

Key Results

Median progression-free survival was 4.0 months in the investigator’s choice arm (“consistent with the historical benchmark,” she said) vs 5.6 months with the antibody-drug conjugate. This represents a 35% reduction in disease progression or death favoring the experimental arm, which was statistically significant (P < .0001).

“When you look at the morphology of the progression-free survival curve, at first disease assessment, 50% of the patients on the investigator’s choice of chemotherapy experienced disease progression, which is what we typically see with our treatments. But we don’t see that on the experimental arm,” Dr. Moore commented.

For the secondary endpoint of objective response rate, use of the antibody-drug conjugate more than doubled the 16% rate on the control arm, at 42%. This was an absolute difference of 26.4% favoring the new drug that was statistically significant (P < .0001). There were 12 complete responses on the experimental arm vs 0 complete responses on the chemotherapy arm. Partial response was observed in 37% of the experimental arm vs 16% of the investigator’s choice arm.

“Patients care about any degree of tumor shrinkage, and the waterfall plot shows clear differences between treatment arms. A total of 80% of patients on the experimental arm had some degree of tumor shrinkage compared with 55% of those randomly assigned to chemotherapy,” Dr. Moore told the audience.

A sensitivity analysis of both progression-free survival and objective response rate by a blinded independent review committee showed that rates were consistent with both key endpoints as assessed by investigators.

A preplanned interim analysis of overall survival was conducted at 13.1 months of follow-up, with 68% of expected events having occurred. Median overall survival was 16.6 months in the experimental arm vs 12.8 months in the chemotherapy-alone arm. This represents a 33% reduction in the hazard ratio for death (P = .0046).

An exploratory analysis of progression-free survival and overall survival in bevacizumab-naive and bevacizumab-treated patients revealed a consistent magnitude of benefit for mirvetuximab soravtansine over chemotherapy irrespective of prior exposure to bevacizumab.

Safety Profile

The rate of grade 3 or higher treatment-related adverse events (42% vs 54%, respectively), as well as that of serious adverse events (24% vs 33%, respectively), was lower with mirvetuximab soravtansine than with chemotherapy. Almost half as many patients treated with mirvetuximab soravtansine discontinued treatment because of treatment-related adverse events compared with chemotherapy (9% vs 16%, respectively).

“There was virtually no hematologic toxicity with mirvetuximab soravtansine compared with chemotherapy,” she said. “There was less neuropathy compared with paclitaxel, and no alopecia.” Both treatment arms had similar rates and grades of nausea.

The key toxicity with mirvetuximab soravtansine is ocular. Blurred vision was reported in 41% of patients; keratopathy was diagnosed in 32%; and dry eye, in 28%. A total of four patients discontinued the antibody-drug conjugate because of ocular adverse events. “These events are reversible, and there are effective mitigation strategies,” Dr. Moore noted.

“This medication works, and it is less toxic than chemotherapy. Patients are in much better shape when they come off this antibody-drug conjugate, which is not the case for chemotherapy. This improves our ability to continue to treat patients over the long term with other drugs, because they may withstand toxicity better,” she explained. “Hopefully, this is the first of many examples.” 

DISCLOSURE: Dr. Moore reported having a leadership role with GOG Partners and NRG Oncology; has received honoraria from Great Debates and Updates, Physicians’ Education Resource, Prime Oncology, and Research To Practice; has served as a consultant or advisor to Aadi Bioscience, Alkermes, AstraZeneca, Blueprint Medicines, Caris Life Sciences, Clovis Oncology, Eisai, Genentech/Roche, GlaxoSmithKline/Tesaro, Hengrui Pharmaceutical, I-Mab, Immunogen, InxMed, Iovance Biotherapeutics, Merck, Mereo BioPharma, Mersana, Myriad Genetics, Novartis, Novartis/Pfizer, Onconova Therapeutics, OncXerna Therapeutics, VBL Therapeutics, and Verastem/Pharmacyclics; has received institutional research funding from Agenus, Amgen, artios, AstraZeneca, Bolt Biotherapeutics, Bristol Myers Squibb, Clovis Oncology, cyteir, Daiichi Sankyo/Lilly, Genentech, Immunocore, Immunogen, Eli Lilly, Lilly Foundation, Merck, Novartis Pharmaceuticals UK Ltd, Novogen, PTC Therapeutics, Regeneron, Takeda, Tesaro, and Verastem; has patents, royalties, and other intellectual property with UpToDate; and has received reimbursement for travel, accommodations, expenses from AstraZeneca and GlaxoSmithKline.

REFERENCE

1. Moore KN, Angelergues A, Konecny GE, et al: Phase III MIRASOL (GOG 3045/ENGOT-ov55) study: Initial report 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. 2023 ASCO Annual Meeting. Abstract LBA5507. Presented June 4, 2023.