Maintenance Mirvetuximab Soravtansine Plus Bevacizumab Under Exploration in FRα+ Ovarian Cancer

The efficacy of maintenance mirvetuximab soravtansine-gynx (Elahere) plus bevacizumab (Avastin) is being compared with bevacizumab alone in patients with folate receptor alpha (FRα)–positive recurrent platinum-sensitive epithelial ovarian, fallopian tube, or peritoneal cancers that did not progress on second-line triplet therapy in the phase 3 GLORIOSA study (NCT05445778).

The study’s primary end point is investigator-assessed progression-free survival (PFS), which is defined as the time from date of randomization until investigator-assessed progressive disease or death. This end point will be assessed per RECIST v1.1 criteria, and will be evaluated after patients who received platinum-based chemotherapy plus bevacizumab are given maintenance mirvetuximab soravtansine plus bevacizumab vs bevacizumab alone.

In 2022, the ADC mirvetuximab soravtansine received accelerated approval from the FDA for adult patients with FRα-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who previously received 1 to 3 prior systemic regimens.2 This regulatory decision was based on data from the phase 2 SORAYA trial (NCT04296890)​​, in which single-agent mirvetuximab soravtansine elicited an investigator-assessed objective response rate (ORR) of 32.4% (95% CI, 23.6%–42.2%), which included 5 complete responses (CRs).3 The median duration of response (DOR) with the agent was 6.9 months. This result was consistent regardless of the number of prior lines or previous exposure to PARP inhibitors.

Data from the confirmatory phase 3 MIRASOL trial (NCT04209855) indicated that single-agent mirvetuximab soravtansine had clinically meaningful activity and acceptable tolerability in patients with FRα-expressing ovarian cancer.4 In this trial, single-agent mirvetuximab soravtansine (n = 227) resulted in a median PFS of 5.62 months (95% CI, 4.34-5.95) vs 3.98 months (95% CI, 2.86-4.47) with physician’s choice of chemotherapy (n = 226; HR, 0.65; 95% CI, 0.52-0.81; P < .0001); median overall survival (OS) was 16.46 months (95% CI, 14.46-24.57) vs 12.75 months (95% CI, 10.91-14.36), respectively (HR, 0.67; 95% CI, 0.50-0.89; P = .0046); The ORR difference between both arms was 26.4%, in favor of mirvetuximab soravtansine.

Additionally, the phase 3 FORWARD-1/GOG 3011 trial (NCT02631876) showed that the addition of mirvetuximab to bevacizumab led to an ORR of 48% (95% CI, 30%-67%) with a median DOR of 12.7 months.5 Although this trial did not meet its primary end point of PFS, efficacy signals in favor of the combination regimen were observed in the subset of patients with FRα-high, recurrent platinum-sensitive ovarian cancer.

Based on these data, subsequent trials like GLORIOSA were designed to investigate the efficacy and safety of mirvetuximab soravtansine in combination with other standard agents in FRα–positive gynecologic cancers.

The randomized, open-label, phase 3 study is enrolling patients 18 years of age or older with confirmed high-grade serous epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer and FRα detected by immunohistochemistry with PS2+ intensity among at least 75% of viable tumor cells. Patients are also required to have an ECOG performance status of 0 or 1, have received and relapsed after first-line platinum therapy and have platinum-sensitive disease (PFI >6 months). If they have BRCA-mutated disease, they must have been treated with a prior PARP inhibitor.

Additionally, patients must be eligible for, be on, or have completed a platinum-based triplet in the second line, been treated with 4 to 8 cycles of this triplet and have experienced a CR, partial response (PR), or stable disease (SD) after prior treatment with the platinum-based doublet plus bevacizumab. Other key inclusion criteria include being stabilized or having recovered from all prior therapy-related toxicities, with the exception of alopecia; having no major surgeries for at least 4 weeks prior to the first dose of maintenance therapy; and displaying adequate hematologic, liver, and kidney functions.

Patients with endometrioid, clear cell, mucinous, or sarcomatous histology, mixed tumors containing any of the above histologies, or low-grade/borderline ovarian tumor are not eligible to enroll on the study. Other key exclusion criteria include having received more than 1 line of prior chemotherapy; having progressed on or following second-line platinum-based triplet therapy; having active or chronic corneal disorders, a history of corneal transplantation, or active ocular conditions; displaying grade 1 peripheral neuropathy; having a history of bowel obstruction related to underlying disease within 6 months of initiating study treatment; and previous exposure to treatment with mirvetuximab soravtansine or other FRα-targeting agents.

Investigators aim to enroll up to 418 patients on the study, providing 90% power to detect a hazard ratio of 0.7 in statistical tests. Patients may be enrolled either prior to receiving triplet therapy in the run-in portion or following triplet therapy but prior to maintenance therapy in the main study. Those allowed on study during the run-in portion must not have triplet therapy available as the local standard of care. The triplet regimen consists of a platinum-based chemotherapy doublet plus bevacizumab, and is administered for approximately 6 cycles (range, 4-8 cycles). This includes at least 3 cycles of bevacizumab.

No later than 8 weeks after all eligible patients have been treated with the last dose of a second-line platinum-based regimen, they will be randomly assigned 1:1 to mirvetuximab soravtansine and bevacizumab vs bevacizumab alone. At this time, patients will also be stratified according to prior PARP inhibitor, prior bevacizumab, and CR or PR or SD.

In the experimental arm, mirvetuximab soravtansine will be administered intravenously at a dose of 6 mg/kg adjusted ideal body weight plus 15 mg/kg of bevacizumab every 3 weeks. In the control arm, bevacizumab will be administered at 15 mg/kg every 3 weeks. Treatment will continue until patients experience disease progression, unacceptable toxicity, or death, withdraw consent from the study, or the sponsor terminates the study.

Radiological assessments will be conducted every 9 weeks or 72 weeks, and subsequently every 18 weeks.

The key secondary objective in the study is OS, which is defined as the time from randomization to death. Other secondary end points include evaluation of adverse effects; the time from randomization to progression on first subsequent therapy; ORR, including best CR or PR; DOR; disease-free survival; CA-125 response; patient-reported outcomes; and health-related quality of life. Blinded independent central review sensitivity analyses of efficacy end points will also be conducted.

The study is currently open and actively enrolling patients.

Disclosures: Dr O’Malley reported the following disclosures: consulting or advisory roles with Adaptimmune, Agenus, Arcus Biosciences, AstraZeneca, Atossa Therapeutics, BBI Healthcare, Celsion, Clovis Oncology, Corcept Therapeutics, DualityBio, Eisai, Elevar Therapeutics, Genelux, Genentech/Roche, GlaxoSmithKline, GOG Foundation, Immunogen, Imvax, InxMed, Jazz Pharmaceuticals, Laekna Therapeutics, Merck, Mersana, Novartis, Novocure, Novocure, OncoC4, Onconova Therapeutics, Regeneron, Roche, Seagen, Sutro Biopharma, Takeda, Toray Industries, Umoja Biopharma, VBL Therapeutics, Verastem, Vincerx Pharma.

He reported having received research funding from Abbvie, Abbvie/Stemcentrx, Acerta Pharma, Advaxis, Ajinomoto, Ajinomoto, Amgen, Arcus Biosciences, Array BioPharma, AstraZeneca, BBI Healthcare, BeiGene, Bristol-Myers Squibb, Cerulean Pharma, Clovis Oncology, Deciphera, Eisai, EMD Serono, EMD Serono, Ergomed, Exelixis, Genentech/Roche, Genmab, GlaxoSmithKline, Immunogen, Immunogen, Incyte, Iovance Biotherapeutics, Janssen Research & Development, Karyopharm Therapeutics, Leap Therapeutics, Ludwig Institute for Cancer Research, Merck, Mersana, Novartis, NovoCure, OncoQuest, Pfizer, PharmaMar, Precision Therapeutics, Regeneron, Roche, Sanofi, SeaGen, Seagen, Sumitomo Dainippon Pharma Oncology, Inc., Sutro Biopharma, Tesaro, TRACON Pharma, Verastem.

References

1. O'Malley DM, Myers T, Zamagni C, et al. GLORIOSA: A randomized, open-label, phase 3 study of mirvetuximab soravtansine with bevacizumab vs. bevacizumab as maintenance in platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer. J Clin Oncol. 2023;41(suppl 16):TPS5622. doi:10.1200/JCO.2023.41.16_suppl.TPS5622
2. FDA grants accelerated approval to mirvetuximab soravtansine-gynx for FRα positive, platinum-resistant epithelial ovarian, fallopian tube, or peritoneal cancer. FDA. November 14, 2022. Accessed August 31, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-mirvetuximab-soravtansine-gynx-fra-positive-platinum-resistant
3. Matulonis UA, Lorusso D, Oaknin A, et al. Efficacy and safety of mirvetuximab soravtansine in patients with platinum-resistant ovarian cancer with high folate receptor alpha expression: results from the SORAYA study. J Clin Oncol. 2023;41(13):2436-2445. doi:10.1200/JCO.22.01900
4. Moore K, Angelergues A, Konecny G, 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. J Clin Oncol. 2023;41(suppl 17):LBA5507. doi:10.1200/JCO.2023.41.17_suppl.LBA5507
5. Moore K, Oza A, Colombo N, et al. FORWARD I (GOG 3011): A Phase III study of mirvetuximab soravtansine, a folate receptor alpha (FRa)-targeting antibody-drug conjugate, versus chemotherapy in patients with platinum-resistant ovarian cancer. Ann Oncol. 2019;30(suppl 5):V403. doi:10.1093/annonc/mdz250