Mirvetuximab Soravtansine Combination Elicits Durable Responses in Recurrent, Platinum Agnostic Ovarian Cancer

David M O'Malley, MD

Results from the final analysis of the phase 1b FORWARD II trail (NCT02606305), show that mirvetuximab soravtansine (IMGN853) combined with bevacizumab (Avastin) yielded durable responses in patients with recurrent, platinum agnostic ovarian cancer, a population with an unmet need for more effective, non-platinum treatments, according to a presentation given during 2021 ASCO Annual Meeting.¹

Results from the trial indicate that the total patient population (n = 60) achieved an overall response rate (ORR) of 50%. Moreover, patients who had high folate receptor alpha (FRα; n = 33) expression had an ORR of 64% vs 33% in patients with medium levels of FRα expression (n = 27). Patients with platinum-resistant ovarian cancer (n = 17) had an ORR of 59%, while patients with platinum-sensitive disease (n = 16) had an ORR of 69%. Additionally, 97% of patients demonstrated a reduction in tumor burden following treatment.

“These data add to the previously reported [findings] and support the use of mirvetuximab as the partner of choice for bevacizumab in patients with high FRα ovarian cancer following the use of platinum-based treatments,” lead author David M O'Malley, MD, a physician and 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 – James, said in a presentation on the findings. “Further, development of mirvetuximab in combination with bevacizumab is warranted.”

The addition of PARP inhibitors to the treatment paradigm for recurrent ovarian cancer has yielded an increasing population of patients for whom a non-platinum-based regimen would be appropriate. Mirvetuximab, a FRα-targeting antibody-drug conjugate, can deliver tubulin-targeting DM4 directly to tumors, and has demonstrated promising activity in women with platinum-resistant ovarian cancer.^2-4 Additionally, the phase 3 AURELIA trial (NCT00976911), which examined the addition of bevacizumab to chemotherapy in patients with platinum-resistant, recurrent ovarian cancer, demonstrated an improved ORR and progression-free survival (PFS) over chemotherapy alone.⁵

As such, the FORWARD II trial set out to assess the combination of mirvetuximab and bevacizumab as a non-platinum option to address the unmet need for this patient population.

The objective of the study was to the assess preliminary response-based anti-tumor activity of the combination in patients with current ovarian, primary peritoneal, or fallopian tube cancer.

The trial enrolled patients with recurrent ovarian cancer who had previously received up to 3 prior regimens, and allowed for previous treatment with bevacizumab. Additionally, investigators enrolled patients for whom a non-platinum-based doublet regimen with bevacizumab would be appropriate. This included those with platinum-sensitive disease who responded to their last platinum therapy and did not progress, as well as those with platinum-resistant disease who recurred within 6 months of their last dose of platinum-based therapy. Patients also had tumors with medium or high FRα membrane staining with immunohistochemistry PS2-positive scoring.

On the study, patients received 6 mg/kg of mirvetuximab that was adjusted for ideal body weight, and 15 mg/kg of bevacizumab, which was administered intravenously on day 1 of every 3-week cycle.

Patients enrolled on the study had a median age of 60 years old (range, 44-83), and a majority had epithelial ovarian cancer (68%), while the rest had fallopian tube cancer (25%), and primary peritoneal cancer (7%). Most patients also had an ECOG performance status of 0 (73%). Additionally, patients had received a median of 2 prior lines of therapy (range, 1-4), with 33% of receiving 1 prior line of therapy, 35% receiving 3, and 32% receiving 3 or more. All patients had prior exposure to platinum-based compounds and taxanes, while 40% received prior treatment with bevacizumab, and 35% were previously treated with PARP inhibitors. Moreover, 53% of patients had a platinum-free interval of 6 months or less, 33% had 6 months to 12 months or more, and 13% had an interval of more than 12 months.

The total patient population of the study had a median duration of response (DOR) of 9.7 months, while those with medium and high FRα expression had median DORs of 8.3 months and 11.8 months, respectively. Additionally, patients with platinum-resistant disease had a median DOR of 9.4 months, and the platinum-sensitive subgroup had a median DOR of 12.7 months.

“These deep responses are rapid and durable … in patients with platinum-resistant and platinum-sensitive disease,” O’Malley said. “Many of these durable responses continue beyond 6 to 12 months, with some patients’ responses lasting more than 2 years.”

Moreover, patients whose tumors had medium and high FRα expression had a median PFS 5.4 months, and 10.6 months, respectively. The high FRα subgroup, specifically, demonstrated a 6-month PFS rate of 80%, and a 12-month rate of 42%. Additionally, patients within the high FRα cohort who had platinum-sensitive and platinum-resistant ovarian cancer had a median PFS of 13.3 months and 9.7 months, respectively.

“The PFS, [much] like the data from the ORR and DOR, demonstrated that patients with high FRα benefit the most from the combination of mirvetuximab and bevacizumab,” O’Malley explained.

Most adverse effects (AEs) associated with treatment were low grade, the most common being gastrointestinal AEs, as well as ocular AEs that could be managed using eye drops. Grade 3 or higher AEs were infrequent, the most notable of which were hypertension (17%), and neutropenia (13%). In total, 30% of patients discontinued treatment with mirvetuximab and bevacizumab due to treatment-related AEs, and discontinuations occurred after a median of 13 cycles of treatment.

Twenty-three percent of patients discontinued treatment with mirvetuximab, and 18% discontinued bevacizumab. The most common AEs of any grade associated with the treatment were diarrhea (62%), blurred vision (60%), fatigue (60%), and nausea (57%). AE rates were notably similar for the combination vs mirvetuximab alone when adjusted for exposure, with the exceptions of diarrhea, fatigue, hypertension, dysphonia, and weight decrease.

_References

_{1. O’Malley DM, Oaknin A, Matulonis UA, et al. Mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients (pts) with platinum-agnostic ovarian cancer: final analysis. J Clin Oncol. 2021;39(supple 15; abstr 5504). doi:10.1200/JCO.2021.39.15_suppl.5504}

_{2. Moore KN, Matulonis UA, O'Malley DM, et al. Mirvetuximab soravtansine (IMGN853), a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in platinum-resistant epithelial ovarian cancer (EOC) patients (pts): Activity and safety analyses in phase I pooled expansion cohorts. J Clin Oncol. 2017;35(suppl 15):5547-5547. doi:10.1200/JCO.2017.35.15_suppl.5547}

_{3. Moore KN, Oza AM, Oaknin A, et al. FORWARD I (GOG 3011): A Phase III study of mirvetuximab soravtansine, a folate receptor alpha (FRa)-targeting antibody-drug conjugate (ADC), versus chemotherapy in patients (pts) with platinum-resistant ovarian cancer (PROC). Ann Oncol. 2019;30(aupple 5):v403-v434. doi:10.1093/annonc/mdz250}

_{4. 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. Gyn Oncol. 2020;157(2):P379-385. doi:10.1016/j.ygyno.2020.01.037}

_{5. Pujade-Lauraine E, Hilpert F, Weber D, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial. J Clin Oncol. 2014;32(13):1302-1308. doi:10.1200/JCO.2013.51.4489}