Mirvetuximab Doublet Shows Significant Activity in High FRα—Expressing Ovarian Cancer

David M. O’Malley, MD

Mirvetuximab soravtansine in combination with bevacizumab (Avastin) showed durable responses in patients with high folate receptor α (FRα)– expressing ovarian cancer regardless of platinum sensitivity, according to findings from a phase 1/2 trial (NCT02606305) presented at the 2021 International Gynecologic Cancer Society Annual Global Meeting.¹

“The combination of [mirvetuximab soravtansine] plus [bevacizumab] was highly active in a broad population of recurrent [patients with] ovarian cancer with high folate receptor α expression,” David M. O’Malley, MD, said in a presentation of the final analysis of the study.

More patients are living longer with recurrent ovarian cancer and are in need of treatment alternatives,” noted O’Malley, professor, Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, and director, Division of Gynecologic Oncology, The Ohio State University Comprehensive Cancer Center.

Mirvetuximab soravtansine is an FRα-targeting antibody-drug conjugate (ADC) that delivers the potent tubulin-targeting maytansinoid DM4 directly to the tumor.

Previous reports for the combination regimen showed an objective response rate (ORR) of 39% and a median progression-free survival (PFS) of 6.9 months in patients with FRα-positive, platinum-resistant ovarian cancer.²

The investigators sought to assess preliminary response-based anti-tumor activity for the combination of mirvetuximab soravtansine in combination with bevacizumab in a broader group of women with recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer.¹ All patients in the trial were those for whom a non–platinum-based doublet with bevacizumab would be appropriate and who had tumors with medium or high FRα expression by immunohistochemistry (IHC) staining.

The 60 patients received mirvetuximab soravtansine at 6 mg/kg (adjusted ideal body weight) plus bevacizumab at 15 mg/kg, both given intravenously on day 1 of a 3-week cycle.

Patients had a median age of 60 years (range, 44-83) and recurrent, high-grade disease. Sixty-eight percent of patients had epithelial ovarian cancer, 25% had fallopian tube cancer, and 7% had primary peritoneal cancer. The majority of patients (73%) had an ECOG performance status of 0 and the remainder had a score of 1; most (55%) had high FRα (≥ 75% IHC PS2+ on tumor cells). The median number of prior systemic therapies was 2 (range, 1-4); 32% had received 3 or more prior therapies. Prior therapies included platinum compounds and taxanes in all patients, bevacizumab in 40%, and PARP inhibition in 35%. The platinum-free interval was 6 months or less in 53% of patients, 6 to 12 months in 33%, and more than 12 months in 13%.

The ORR in the total population was 50%. Among patients with high FRα expression, the ORR was 64% in comparison with 33% in patients with medium expression. In those with platinum sensitivity (n = 16), there was an ORR of 69% vs 59% in platinum-resistant patients (n = 17).

Responses were durable in all subgroups. The median duration of response (DOR) was 9.7 months in all patients, 11.8 months in patients with high FRα expression, and 8.3 months in patients with medium FRα expression. In patients with platinum-sensitive tumors, the median DOR was 12.7 months vs 9.4 months in patients with platinum-resistant tumors.

Among all patients with tumors harboring high FRα expression, 97% showed reduction in their tumor burden with the regimen. Reduction was achieved in patients with both platinum-resistant and -sensitive tumors.

O’Malley noted that some patient responses lasted for more than 2 years.

The median PFS was 8.3 months (95% CI, 5.6-10.1) in all patients but was longer among patients with higher FRα expression. The median PFS was 10.6 months (95% CI, 8.3-13.3) in tumors with high FRα expression vs 5.4 months 95% CI, 3.7-6.9) in medium FRα–expressing tumors. For the high expressors, the 6-months PFS rate was 80% and 42% at 1 year.

The median PFS among patients with platinum sensitivity was 13.3 months (95% CI,S 8.3-15.0) in comparison with 9.7 months (95% CI, 5.6-11.0) with platinum recurrence.

Treatment-related emergent adverse events (AEs) were mostly low grade; most frequent were gastrointestinal and ocular events. O’Malley noted that ocular AEs are a class effect of the ADC that can be managed\with eye drops. Thirty percent of patients discontinued treatment with 1 or both agents due to treatment-related AEs after a median of 13 treatment cycles.

The most common AEs of any grade were diarrhea in 62% of patients, blurred vision in 60%, fatigue in 60%, nausea in 57%, keratopathy in 43%, peripheral neuropathy in 40% dry eye in 33%, decreased appetite in 33%, and hypertension in 32%. Grade 3/4 events were infrequent, with the exception of hypertension in 17% and neutropenia in 13%.

O’Malley said that rates of AEs were very similar for the combination in comparison with that of mirvetuximab soravtansine monotherapy.

“Further development of [mirvetuximab soravtansine] in combination with [bevacizumab] is warranted,” O’Malley concluded.

_REFERENCES:

_{1. O’Malley DM, Oaknin A, Matulonis UA, et al. Mirvetuximab soravtansine, a folate receptor alpha-targeting antibody drug conjugate, in combination with bevacizumab in patients with platinum-agnostic ovarian cancer: final analysis. Presented at: 2021 International Gynecologic Cancer Society Annual Global Meeting; August 30 – September 2, 2021; virtual.}

_{2. O’Malley DM, Matulonis UA, Birrer MJ, et al. Phase Ib study of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients with platinum-resistant ovarian cancer. Gynecol Oncol. 2020;157(2):379-385. doi:10.1016/j.ygyno.2020.01.03}7