In patients with recurrent ovarian cancer, the antibody-drug conjugate mirvetuximab soravtansine, given with bevacizumab, showed antitumor activity leading to durable responses in platinum-agnostic patients with strong expression of folate receptor alpha (FRα), researchers reported at the 2021 ASCO Annual Meeting.1
The combination led to a response rate of 64%, a median duration of response of 11.8 months, and a median progression-free survival of 10.6 months in patients with high FRα expression in the phase Ib FORWARD II trial, said David M. O’Malley, MD, Professor, Director of Gynecologic Oncology, and Co-Director of the Gynecologic Oncology Phase I Program of The Ohio State University Wexner Medical Center and James Cancer Hospital, Columbus.
“The progression-free survival…demonstrated that patients with high FRα benefit the most from the combination of mirvetuximab [soravtansine] and bevacizumab.”— David M. O’Malley, MD
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“These data add to the previously reported findings2 and support the use of mirvetuximab as the partner of choice for bevacizumab in patients with high FRα [expression] ovarian cancer following the use of platinum-based treatments,” Dr. O’Malley said. “Further, development of mirvetuximab in combination with bevacizumab is warranted.”
About Mirvetuximab Soravtansine
Mirvetuximab soravtansine is a first-in-class antibody-drug conjugate comprising an FRα-binding antibody, cleavable linker, and the maytansinoid DM4 (a potent tubulin-targeting agent). The combination of mirvetuximab soravtansine and bevacizumab was evaluated in patients with FRα-positive (medium/high expression; ≥ 50%/≥ 75% of cells with PS2+ staining intensity), platinum-agnostic ovarian cancer for whom a nonplatinum doublet would be appropriate. Patients with platinum-agnostic ovarian cancer were defined as having either platinum-resistant disease (recurrence within 6 months of last platinum dose) or platinum-sensitive disease (response to platinum and no disease progression within 6 months).
Mirvetuximab soravtansine at 6 mg/kg plus bevacizumab at 15 mg/kg was given on day 1 of a 21-day cycle to 60 patients, who had received a median of two prior lines of therapy and were followed for a median of 17.5 months. Many patients (68%) had epithelial ovarian cancer, whereas the rest had fallopian tube cancer (25%) and primary peritoneal cancer (7%). All patients had prior exposure to platinum-based compounds and taxanes, 40% had previously received bevacizumab, and 35% had exposure to poly (ADP-ribose) polymerase inhibitors.
By platinum sensitivity, there were 32 patients (53%) with platinum-resistant disease and 28 (47%) with platinum-sensitive disease. The primary endpoint was investigator-assessed response.
Response Rates Improved
In the overall patient population, high response rates and durability were observed, especially among patients with high FRα expression (Table 1). “These deep responses are rapid and durable…in patients with platinum-resistant and platinum-sensitive disease. Many of these durable responses continued beyond 6 to 12 months, with some patients’ responses lasting more than 2 years,” Dr. O’Malley said.
“Much like the data for the objective response rate and duration of response, the progression-free survival demonstrated that patients with high FRα [expression] benefit the most from the combination of mirvetuximab and bevacizumab,” he said.
KEY POINTS
- The phase Ib FORWARD II trial evaluated the antibody-drug conjugate mirvetuximab soravtansine plus bevacizumab in patients with ovarian cancer who had disease progression after treatment with a platinum agent.
- Activity was strong in patients with high expression of folate receptor alpha (FRα), with a response rate of 64%, a median duration of response of 11.8 months, and a median progression-free survival of 10.6 months.
- In patients with high FRα expression and platinum-sensitive recurrence, the response rate was 69%, the median duration of response was 12.7 months, and the median progression-free survival was 13.3 months.
Median progression-free survival was 10.6 months in the subgroup with high FRα expression and 5.4 months in the subgroup with medium FRα expression. For high expressors, 80% had not experienced disease progression at 6 months, and 42% had no disease progression at 12 months.
Safety Profile
The adverse events observed with the doublet were manageable and consistent with the side-effect profiles of each agent, according to Dr. O’Malley. Treatment-related toxicities were generally low grade, with diarrhea (62%), blurred vision (60%), fatigue (60%), and nausea (57%) being the most common. The most common grade ≥ 3 events were hypertension (17%) and neutropenia (13%). In total, 30% of patients discontinued treatment with mirvetuximab soravtansine and bevacizumab due to treatment-related adverse events; the median time to treatment discontinuation was 13 cycles.
“The strength of these mature data warrant further development of this novel, targeted combination, and I look forward to evaluating this regimen in earlier lines of therapy,” Dr. O’Malley concluded.
DISCLOSURE: The study was funded by ImmunoGen. Dr. O’Malley has served as a consultant or advisor to AbbVie, Agenus, Ambry Genetics, Arquer Diagnostics, AstraZeneca, BBI, Celsion, Clovis Oncology, Eisai, Elevar Therapeutics, Genelux, Genentech/Roche, GlaxoSmithKline, GOG Foundation, ImmunoGen, InxMed, Iovance Biotherapeutics, Janssen Oncology, Leap Therapeutics, Marker Therapeutics, Myriad Genetics, Novartis, Novocure, OncoQuest, Regeneron, Roche Diagnostics MSA, Rubius Therapeutics, Seagen, Sorrento Therapeutics, Takeda, Tarveda Therapeutics, Tesaro, Toray Medical, and Translational Genomics/Cordgenics; and has received institutional research funding from AbbVie, AbbVie/Stemcentrx, Agenus, Ajinomoto, Amgen, Array BioPharma, AstraZeneca, BBI, Bristol Myers Squibb, Cerulean Pharma, Clovis Oncology, Eisai, EMD Serono, Ergomed, Genentech/Roche, Genmab, Iovance Biotherapeutics, ImmunoGen, Janssen Research & Development, Leap Therapeutics, Merck, Mersana, PharmaMar, Regeneron, Seattle Genetics, Sumitomo Dainippon Pharma Oncology, Tesaro, and TRACON Pharma.
REFERENCES
1. O’Malley DM, Oaknin A, Matulonis UA, et al: Mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate, in combination with bevacizumab in patients with platinum-agnostic ovarian cancer: Final analysis. 2021 ASCO Annual Meeting. Abstract 5504. Presented June 7, 2021.
2. Moore K, Oza A, Colombo N, et al: FORWARD I (GOG 3011): A phase III study of mirvetuximab soravtansine, a folate receptor alpha (FRa)-targeting antibody-drug conjugate, versus chemotherapy in patients with platinum-resistant ovarian cancer. Ann Oncol 30(suppl 5):v403, 2019.
