Mirvetuximab soravtansine plus bevacizumab ‘highly active’ in ovarian cancer subset
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Mirvetuximab soravtansine in combination with bevacizumab demonstrated antitumor activity with durable responses and favorable tolerability among women with high folate receptor-alpha recurrent ovarian cancer, according to study results.
“Interestingly, poly(ADP-ribose) polymerase (PARP) inhibitors are moving into earlier lines of therapy as maintenance therapy and in larger defined populations. The use of maintenance therapies is extending the platinum-free interval, thus leading to additional lines of platinum-based therapy and ... a higher occurrence of platinum hypersensitivity,” David M. O’Malley, MD, professor in the department of obstetrics and gynecology at The Ohio State University College of Medicine, and director of the division of gynecologic oncology at The Ohio State University Comprehensive Cancer Center — Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, said in a presentation during the virtual ASCO Annual Meeting. “More patients are living longer with recurrent ovarian cancer and are in need of treatment alternatives, especially after platinum therapies are no longer an option.”
Mirvetuximab soravtansine (IMGN853, ImmunoGen), an antibody-drug conjugate, delivers the potent tubulin-target agent maytansinoid DM4 directly to the tumor in women with folate receptor (FR)-alpha-positive ovarian cancer, according to O’Malley.
“[This agent] has demonstrated significant activity in platinum-resistant ovarian cancer — both as monotherapy and in combination with bevacizumab [Avastin, Genentech], with overall response rates of up to 50%,” he said.
O’Malley and colleagues evaluated the combination as part of the phase 1b FORWARD II trial, which enrolled 60 women (median age, 60 years) with FR-alpha-positive, platinum-resistant (53%) or platinum-sensitive (47%) ovarian cancer who received a median two (range, 1-4) prior lines of systemic therapy.
All women received 6 mg/kg mirvetuximab soravtansine, adjusted to ideal body weight, plus 15 mg/kg bevacizumab on day 1 of a 21-day cycle.
Median follow-up was 17.5 months.
Results showed 28 women experienced an objective response, for a confirmed ORR of 47% (95% CI, 34-60). Median duration of response was 9.7 months (95% CI, 6.7-12.9) and median PFS was 8.3 months (95% CI, 5.6-10.6).
Among those with high FR-alpha expression (n = 33), defined as expression on at least 75% of cells with PS2+ staining intensity, researchers observed a confirmed ORR of 64% (95% CI, 45-80), median duration of response of 11.8 months (95% CI, 6.7-13.7) and median PFS of 10.6 months (95% CI, 8.3-13.3).
“Ninety-seven percent of patients with high FR-alpha expression demonstrated tumor burden reduction,” O’Malley said. “Patients experienced rapid tumor shrinkage, with early responses achieved and durable benefits observed among patient with platinum-resistant and platinum-sensitive ovarian cancer.”
Among women with FR-alpha-high platinum-resistant ovarian cancer, who experienced recurrence within 6 months of their last platinum dose, researchers reported a confirmed ORR of 59% (95% CI, 33-82), median duration of response of 9.4 months (95% CI, 4-not reached) and median PFS of 10.1 months (95% CI, 5.6-12.9). Women with FR-alpha-high platinum-sensitive ovarian cancer, who responded to their last platinum therapy and did not experience progression within 6 months, had a higher confirmed ORR (69%; 95% CI, 41-89) and longer median duration of response (12.7 months; 95% CI, 6.5-15.7) and median PFS (13.3 months; 95% CI, 8.3-18.3).
Common all-grade treatment-related adverse events included diarrhea (62%), blurred vision (60%), fatigue (58%) and nausea (57%). Grade 3 to grade 4 treatment-related adverse events, which occurred infrequently, included hypertension (17%) and neutropenia (13%). Eighteen women (30%) discontinued either or both agents after a median 13 treatment cycles due to treatment-related adverse events.
“The combination of mirvetuximab soravtansine plus bevacizumab was highly active in a broad population of patients with recurrent ovarian cancer with high FR-alpha expression,” O’Malley said. “These are very exciting and compelling findings and support mirvetuximab soravtansine as the combination partner of choice for bevacizumab in this patient population following the use of platinum-based treatments. Further development of mirvetuximab soravtansine in combination with bevacizumab is warranted.”
Perspective
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Robert L. Coleman, MD, FACOG, FACS
Mirvetuximab soravtansine is one of several novel antibody drug conjugates that have been evaluated in many solid tumor types, including ovarian cancer. As a single agent, mirvetuximab soravtansine demonstrated impressive objective responses among patients with FR-alpha-positive tumors in the phase 2 and phase 3 settings and is currently under evaluation in biomarker-positive recurrent ovarian cancer. Given the impact of mirvetuximab soravtansine as a cytotoxic agent, it was rational and desired to evaluate its activity in combination with bevacizumab to help further the clinical development program. In this context, researchers enrolled both platinum-sensitive and platinum-resistant women with FR-alpha-positive tumors. The clinical activity (objective response, duration of response and PFS), in both settings, was above what might be expected with single-agent mirvetuximab soravtansine. Although the range of expected response in platinum-sensitive ovarian cancer can be quite variable, the efficacy in platinum-resistant ovarian cancer was notable, particularly given that women receiving the combination would not have been eligible for chemotherapy-bevacizumab combinations under current FDA approvals. The safety assessment was consistent with prior reports for each single agent and with the preliminary report published in 2020. The data help to define opportunities in primary and recurrent ovarian cancer.
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Rebecca L. Porter, MD, PhD
Based upon the activity of mirvetuximab soravtansine in platinum-resistant ovarian cancer in the FORWARD I study and improved response rates and PFS with the addition of bevacizumab to chemotherapy in platinum-resistant ovarian cancer in the AURELIA trial, the FORWARD II study is testing the combination of mirvetuximab soravtansine and bevacizumab among women with platinum-agnostic recurrent ovarian cancer. These current results by O’Malley and colleagues suggest very promising activity of the combination in women with FR-alpha-high recurrent high-grade serous ovarian cancer, possibly filling an unmet need for novel, nonplatinum targeted therapies in the recurrent setting. Future studies are likely to address the activity of this combination earlier in the treatment paradigm for ovarian cancer.
References:
Moore KN, et al. Abstract 9920. Presented at: European Society for Medical Oncology; Sept. 27-Oct. 1, 2019; Barcelona, Spain.
Pujade-Lauraine E, et al. J Clin Oncol. 2014;doi:10.1200/JCO.2013.51.4489.
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O’Malley DM, et al. Abstract 5504. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
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