A clinical trial at NYU Langone Health’s Perlmutter Cancer Center is evaluating an antibody–drug conjugate for the treatment of recurrent platinum-sensitive ovarian cancer that overexpresses folate receptor-alpha, a protein found in a number of cancers. Platinum-sensitive cancers relapse six months or more after completion of initial treatment with a platinum-based chemotherapy.
Bhavana Pothuri, MD, a gynecologic oncologist and medical director of Perlmutter Cancer Center’s Clinical Trials Office, is leading the phase 3 clinical trial at NYU Langone, which is aimed at assessing the safety and efficacy of the antibody–drug conjugate mirvetuximab soravtansine as maintenance therapy for people with folate receptor-alpha–positive recurrent platinum-sensitive ovarian cancer. This trial is part of the GLORIOSA study, a multicenter trial sponsored by ImmunoGen Inc. in collaboration with the GOG Foundation, which is evaluating mirvetuximab soravtansine in combination with the angiogenesis inhibitor bevacizumab against bevacizumab alone as maintenance therapy in platinum-sensitive ovarian, primary peritoneal, or fallopian tube cancers.
As an antibody–drug conjugate, mirvetuximab soravtansine links a monoclonal antibody, which targets folate receptor-alpha on the surface of tumor cells, with a cytotoxic drug molecule called DM4. Once inside the cancer cell, DM4 disrupts the formation of microtubules, killing the cancer cells and leaving normal cells intact. Expression of folate receptor-alpha is limited in normal tissues, making mirvetuximab soravtansine a potentially highly specific therapeutic drug.
In people with platinum-sensitive recurrent ovarian cancer, studies show that response rates to further platinum-based therapy range from 30 to 90 percent, but median overall survival is only 2 to 3 years. As a result, more treatment options are needed for this patient population.
Earlier studies showed that bevacizumab alone prolongs progression-free survival in first- and second-line treatment for patients with platinum-sensitive ovarian cancer who had not received prior treatment with bevacizumab. In 2020, Dr. Pothuri was lead author of the Society of Gynecologic Oncology’s practice statement on the role of frontline PARP inhibitor (PARPi) maintenance therapy in ovarian cancer, which called PARPi a new standard of care for people with ovarian, fallopian tube, and peritoneal cancer who have had a response to platinum-based therapy.
“As more patients are getting PARPi in the frontline setting, newer maintenance options are needed in the recurrent setting,” said Dr. Pothuri, who is also director of gynecologic oncology clinical trials at Perlmutter Cancer Center. “Adding mirvetuximab soravtansine to bevacizumab makes a lot of rational sense.”
Folate receptor-alpha, one of four receptors through which folate (vitamin B9) is transported into cells, is overexpressed in several malignancies, including ovarian cancer. Folate is a crucial nutrient important for a number of cellular processes, including the synthesis, repair, and methylation of DNA. In ovarian cancer, folate receptor-alpha overexpression is thought to increase uptake of folate, which activates tumor growth signals, enables DNA synthesis, and supports the proliferation of malignant cells. Folate receptor-alpha expression may also induce drug resistance by preventing programmed cell death in tumor cells.
“The U.S. Food and Drug Administration has narrowed the treatment indication with PARPi in the maintenance setting of ovarian cancer, limiting the use of niraparib and rucaparib to patients who have a BRCA gene mutation,” said Dr. Pothuri, who also is a professor in the Departments of Obstetrics and Gynecology and Medicine at NYU Grossman School of Medicine. “Combining mirvetuximab soravtansine and bevacizumab represents a new treatment option for patients who are beyond just having a BRCA mutation, which represents 75 percent of ovarian cancers.”