Mirvetuximab soravtansine-gynx is a first-in-class antibody–drug conjugate targeting folate receptor α (FRα). Efficacy and safety assessments in the confirmatory, randomised, phase III MIRASOL study that involved patients with platinum-resistant, FRα-positive ovarian cancer show that treatment with mirvetuximab soravtansine-gynx, as compared with chemotherapy, was associated with significant benefits in terms of progression-free survival (PFS), objective response, and overall survival (OS). No new safety signals were observed.
The results further reinforce the potential for mirvetuximab soravtansine-gynx to alter the treatment landscape for platinum-resistant ovarian cancer, a disease with historically poor prognosis according to Dr. Kathleen N. Moore, and colleagues of the Gynecologic Oncology Group Partners and the European Network of Gynaecological Oncological Trial Groups, who published the findings in the 7th December 2023 issue of The New England Journal of Medicine.
Platinum-resistant ovarian cancer has a poor prognosis with few effective treatment options, none of which have shown a substantial OS benefit. Current treatment in platinum-resistant ovarian cancer consists primarily of non-platinum chemotherapy administered either as a single agent or in combination with bevacizumab. Challenges in the treatment also include the lack of meaningful, predictive biomarkers, as well as chemotherapy-associated haematologic and gastrointestinal side effects and cumulative neuropathy.
FRα is a biomarker that is commonly overexpressed on ovarian cancers and minimally expressed on normal tissues. Studies with a single-agent mirvetuximab soravtansine-gynx have shown anticancer activity and a safety profile that primarily included low-grade gastrointestinal, neurosensory, and reversible ocular adverse events. On 14 November 2022, based on the positive results of the pivotal single-group SORAYA study, the US Food and Drug Administration granted accelerated approval to mirvetuximab soravtansine-gynx for adult patients with FRα-positive (as assessed by an FDA-approved test), platinum-resistant ovarian cancer who had previously received 1 to 3 systemic treatments.
In a previous phase III, open-label, randomised, controlled FORWARD I study that compared mirvetuximab soravtansine-gynx with chemotherapy in patients with platinum-resistant ovarian cancer with FRα expression, as determined according to the 10× scoring method (i.e., ≥50% of tumour cells with observable staining at 10× magnification), who had previously received 1 to 3 lines of treatment, mirvetuximab soravtansine-gynx did not result in a significant improvement in PFS which was the the primary endpoint.
However, results for the secondary endpoints consistently favoured mirvetuximab soravtansine-gynx, particularly in a prespecified population with high FRα tumour expression. Furthermore, exploratory rescoring of FRα expression levels with an alternative scoring method referred to as PS2+ showed that the 10× scoring method used for screening diluted the treatment effect of mirvetuximab soravtansine-gynx by allowing enrolment of participants with lower-than-expected levels of FRα expression. These findings supported the use of the PS2+ scoring method for determining FRα expression levels in subsequent studies.
The MIRASOL investigators conducted a phase III, global, confirmatory, open-label, randomised, controlled study to compare the efficacy and safety of mirvetuximab soravtansine-gynx with the investigator’s choice of chemotherapy in the treatment of platinum-resistant, high-grade serous ovarian cancer. Participants who had previously received 1 to 3 lines of treatment and had high FRα tumour expression (≥75% of cells with ≥2+ staining intensity) were randomly assigned in a 1:1 ratio to receive mirvetuximab soravtansine-gynx or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary endpoint was investigator-assessed PFS, and key secondary endpoints included objective response, OS, and patient-reported outcomes.
A total of 453 participants were randomised, of whom 227 in the mirvetuximab soravtansine-gynx group and 226 in the chemotherapy group. The median PFS was 5.62 months (95% confidence interval [CI] 4.34 to 5.95) with mirvetuximab soravtansine-gynx and 3.98 months (95% CI 2.86 to 4.47) with chemotherapy (p < 0.001).
An objective response occurred in 42.3% of the participants in the mirvetuximab soravtansine-gynx group and in 15.9% of those in the chemotherapy group (odds ratio 3.81, 95% CI 2.44 to 5.94; p < 0.001). Results for PFS and objective response, as determined by blinded independent central review, were concordant with the investigator-assessed results. OS was significantly longer with mirvetuximab soravtansine-gynx than with chemotherapy with median 16.46 months versus 12.75 months (hazard ratio for death 0.67, 95% CI 0.50 to 0.89; p = 0.005).
During the treatment period, fewer adverse events of grade 3 or higher occurred with mirvetuximab soravtansine-gynx than with chemotherapy (41.7% versus 54.1%), as did serious adverse events of any grade (23.9% versus 32.9%) and events leading to treatment discontinuation (9.2% versus 15.9%).
The safety findings reinforce the known safety profile of mirvetuximab soravtansine-gynx, which consists primarily of low-grade gastrointestinal, neurosensory, and reversible ocular adverse events. This study further shows that ocular adverse events are common with mirvetuximab soravtansine-gynx; thus, recommended prophylactic and mitigative measures should be adhered to by patients and healthcare professionals.
The authors concluded that platinum-resistant ovarian cancer is a lethal disease with few efficacious, targeted treatments. Mirvetuximab soravtansine-gynx appears to be capable of inducing responses and improving survival in this setting.
The study was funded by ImmunoGen.
Reference
Moore KN. Angelergues A, Konecny GE, et al. for Gynecologic Oncology Group Partners and the European Network of Gynaecological Oncological Trial Groups. Mirvetuximab Soravtansine in FRα-Positive, Platinum-Resistant Ovarian Cancer. N Engl J Med 2023;389:2162-2174.
