Kathleen N. Moore, MD says the phase 3 MIRASOL results bring a new standard-of-care to the FRα-high, platinum-resistant ovarian cancer landscape.
According to results from the phase 3 MIRASOL trial (NCT04209855), mirvetuximab soravtansine-gynx (Elahere) achieved a 35% reduction in the risk of disease progression or death compared with investigator’s choice of chemotherapy in patients with folate receptor alpha (FRα)-high, platinum-resistant ovarian cancer, according to a press briefing presentation during the 2023 ASCO Annual Meeting.1
Results showed that the median progression-free survival was 5.62 months (95% CI, 4.34-5.95) with mirvetuximab soravtansine compared with 3.98 months (95% CI, 2.86-4.47) with investigator’s choice of chemotherapy (HR, 0.65; 95% CI, 0.52-0.81; P < .0001).
“Mirvetuximab soravtansine is the first novel treatment to demonstrate a benefit in overall survival [OS] in platinum-resistant ovarian cancer in a phase 3 setting,” lead study author Kathleen N. Moore, MD, associate director of clinical research at Stephenson Cancer Center, director of the Oklahoma TSET Phase I Program, and professor in the Section of Gynecologic Oncology at The University of Oklahoma College of Medicine, said during the press briefing. “These data we consider to be practice-changing and position mirvetuximab soravtansine to be the new standard of care for tumors that are FRα-high and platinum-resistant for women with ovarian cancer.”
To date, there has not been a randomized phase 3 trial showing an OS benefit with a novel treatment in platinum-resistant ovarian cancer, Moore said. FRα is expressed in approximately 90% of ovarian cancers, and 35% to 40% of platinum-resistant ovarian cancers are known to have high FRα expression, with at least 75% of tumor cells positive for at least 2+ intensity.
Mirvetuximab soravtansine is an antibody-drug conjugate (ADC) designed with a FRα-binding antibody, cleavable linker, and maytansinoid DM4, which is a potent tubulin-targeting drug. In the single-arm SORAYA trial (NCT04296890), which evaluated mirvetuximab soravtansine in bevacizumab (Avastin)-treated patients with platinum-resistant ovarian cancer, the agent demonstrated a 32.4% objective response rate (ORR) and a 6.9-month median duration of response (DOR; 95% CI, 5.6-9.7).2 Based on these data, the FDA granted accelerated approval in November 2022 to mirvetuximab soravtansine for use in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received 1 to 3 prior systemic treatment regimens.3
The randomized, international MIRASOL trial is the confirmatory study designed to support the continued approval of mirvetuximab soravtansine. The study comprised 453 patients with high-grade serous, platinum-resistant ovarian cancer defined as having a platinum-free interval (PFI) of at least 6 months. Eligible participants also had FRα detected by immunohistochemistry with positive staining intensity of 2+ on at least 75% of viable tumor cells.1
Patients were randomly assigned 1:1 to receive mirvetuximab soravtansine at 6 mg/kg adjusted ideal body weight every 3 weeks or investigator’s choice of chemotherapy, which consisted of paclitaxel, pegylated liposomal doxorubicin (PLD), or topotecan.
Patients were allowed to have had 1 to 3 prior lines of therapy and prior treatment with bevacizumab and PARP inhibitors were permitted. Patients whose disease harbored BRCA mutations were eligible. Those who had a primary PFI less than 3 months were excluded from enrollment.
Stratification factors included chemotherapy choice (paclitaxel, PLD, or topotecan), and prior lines of therapy (1 vs 2 vs 3).
The primary end point was PFS via investigator assessment from a blinded independent central review sensitivity analysis. Key secondary end points were objective response rate (ORR) by investigator review, OS, and patient-reported outcomes. Additional outcome measures included safety and tolerability, DOR, CA-125 response, and time to second disease progression.
Regarding baseline characteristics, the median age was 62.5 years (range, 29-88) and the stage at diagnosis was I to II in 4% of all patients, stage III in 62.5%, and stage IV in 31% of patients. A total 85.5% did not harbor BRCA mutation. Sixty-two percent of patients had prior treatment with bevacizumab and 55.5% had previously received a PARP inhibitor. The primary PFI was within 12 months in 63.5% of patients, and the PFI was within 3 months in 41.5% patients or between 3 and 6 months in 58% of patients.
The breakdown of prior therapies was 1 (14%), 2 (40%), or 3 (46%). For the investigator’s choice of chemotherapy, 41% of patients had received paclitaxel vs 36% who received PLD and 23% who received topotecan.
The data cutoff date was March 6, 2023. Fourteen percent of patients remain on treatment with mirvetuximab soravtansine and 3% remain on treatment in the chemotherapy arm.
Additionally, the ORR with mirvetuximab soravtansine was 42% (95% CI, 5.8%-49.0%) vs 16% (95% CI, 11.4%-21.4%) with chemotherapy (odds ratio, 3.81; 95% CI, 2.44-5.94; P < .0001), which Moore described as statistically significant and clinically meaningful. In the experimental arm, the complete response rate was 5%, the partial response rate was 37%, the stable disease rate was 38%, the progressive disease rate was 14%, and 6% of patients’ response were not evaluable. In the chemotherapy arm, these rates were 0%, 16%, 40%, 27%, and 16%, respectively.
Further findings showed that the maximum percentage change in target lesion size from baseline, via investigator assessment, was 80% and 55% in the mirvetuximab soravtansine and chemotherapy arms, respectively.
OS was planned as an interim analysis at the time of PFS, Moore said. At a median follow-up of 13.11 months, the median OS was 16.46 months (95% CI, 14.46-24.57) and 12.75 months (95% CI, 10.91-14.36) with chemotherapy (HR, 0.67; 95% CI, 0.50-0.89; P = .0046). “This represents a 33% reduction in the hazard of death for patients who received mirvetuximab [soravtansine] compared with investigator’s choice chemotherapy and this is both clinically and statistically significant,” Moore said.
Investigators also evaluated PFS and OS in patients who had received prior bevacizumab and had not. In bevacizumab-naïve patients, the median PFS was 7.0 months (95% CI, 5.6-8.4) and 5.6 months (95% CI, 3.0-6.5) in the mirvetuximab soravtansine and chemotherapy arms, respectively (HR, 0.66; 95% CI, 0.46-0.94; P = .0210). The median OS was 20.2 months (95% CI, 14.8-not estimable) and 14.4 months (95% CI, 11.8-16.7), respectively (HR, 0.51; 95% CI, 0.31-0.86; P = .0099).
For patients who received prior bevacizumab, the median PFS with mirvetuximab soravtansine was 4.4 months (95% CI, 4.0-5.8) and 3.0 months (95% CI, 2.5-4.3) with chemotherapy (HR, 0.64; 95% CI, 0.49-0.84; P = .0011). The median OS in this subgroup was 15.4 months (95% CI, 11.3-17.5) and 10.9 months (95% CI, 9.4-13.3), respectively (HR, 0.74; 95% CI, 0.54-1.04; P = .0789).
Regarding safety, any-grade treatment-emergent adverse events (TEAEs) were reported in 96% and 94% of mirvetuximab soravtansine–(n = 218) and chemotherapy-treated patients (n = 207), respectively; grade 3 or higher TEAEs occurred in 42% and 54%, respectively. Serious AEs occurred in 24% of patients on mirvetuximab soravtansine and in 33% of those on chemotherapy. Two deaths occurred in each arm, all of which occurred within 30 days of the last dose of therapy.
More patients on mirvetuximab soravtansine required dose reductions due to TEAEs (34%) vs those on chemotherapy (24%); dose delays occurred in 54% of patients on each arm. Treatment discontinuation rates were 9% with mirvetuximab soravtansine vs 16% with chemotherapy.
Specific to mirvetuximab soravtansine, grade 3 or higher ocular TEAEs included keratopathy (9%), blurred vision (8%), dry eye (3%). Other grade 3 or higher AEs with the ADC included nausea (2%), peripheral neuropathy (1%), and diarrhea (1%).
Roisin E. O’Cearbhaill, MD, research director of gynecologic medical oncology, and section head of the Solid Tumor, Cell Therapy Service at Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, was a discussant on the MIRASOL study following Moore’s presentation of the data. She cited the remaining tasks of identifying optimal sequencing and as well as the optimal level of FRα expression and cutoffs as a predictive biomarker for this class of drugs in the platinum-resistant ovarian cancer population.
“We need to minimize toxicity; that can be achieved through disease control but also by preemptive mitigation strategies,” O’Cearbhaill said. “We definitely need to understand the mechanisms of resistance […] and [consider] what are the rescue strategies that we might propose in advance or at the time of developmental resistance?”
1. Moore KN, Angelergues A, Konecny GE, et al. Phase III MIRASOL (GOG 3045/ENGOT-ov55) study: 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 (FRα) expression. J Clin Oncol. 2023;41(suppl 17):LBA5507.
2. 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
3. ImmunoGen announces FDA accelered approval of Elahere (mirvetuximab soravtansine-gynx) for the treatment of platinum-resistant ovarian cancer. News release. ImmunoGen Inc. November 14, 2022. Accessed June 3, 2023. https://www.businesswire.com/news/home/20221104005657/en/ImmunoGen-Announces-FDA-Accelerated-Approval-of-ELAHERE%E2%84%A2-mirvetuximab-soravtansine-gynx-for-the-Treatment-of-Platinum-Resistant-Ovarian-Cancer