Treatment with the folate receptor alpha (FRα)-targeted antibody-drug conjugate mirvetuximab soravtansine-gynx benefited patients with FRα-high, platinum-resistant ovarian cancer, even after multiple lines of prior therapy, according to an updated analysis of the SORAYA trial presented at the Society of Gynecologic Oncology (SGO) 2023 Annual Meeting on Women’s Cancer.1 Predictably, the highest response rates were achieved when mirvetuximab soravtansine was used as a first-line treatment for platinum-resistant disease.
The sequence-of-therapy and final overall analysis were presented by Robert L. Coleman, MD, Chief Medical Officer of the Sarah Cannon Research Institute, Nashville, and a gynecologic oncologist with Texas Oncology, part of US Oncology Research.
Based on an earlier analysis of SORAYA,2 the first-in-class mirvetuximab soravtansine was approved by the U.S. Food and Drug Administration in November 2022 for patients with high levels of FRα expression. More than 90% of ovarian cancers overexpress FRα, a biomarker for worse clinical outcomes, and about 30% to 35% of patients overexpress FRα at a level to be eligible for mirvetuximab.
“These results position mirvetuximab soravtansine to become a practice-changing, biomarker-driven, standard- of-care treatment option for patients with FRα-positive, platinum-resistant ovarian cancer.”— Robert L. Coleman, MD
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“The totality of data supports the regulatory action that made this drug available to us under accelerated approval,” Dr. Coleman said.
In the platinum-resistant population, median overall survival was 15 months; at 24 months, 37% of patients were alive. The objective response rate for the entire cohort was 32.4%, a rate that compares favorably with those for other single-agent therapies (around 4%–13%), with responses consistent regardless of the number of prior lines of therapy or previous exposure to PARP inhibitors, Dr. Coleman said. “These results position mirvetuximab soravtansine to become a practice-changing, biomarker-driven, standard-of-care treatment option for patients with FRα-positive, platinum-resistant ovarian cancer,” he said.
SORAYA was a single-arm, phase III study that enrolled 106 patients with platinum-resistant, high-grade, serous histology ovarian cancer (40% stage IV) who had received one to three prior lines of therapy, including bevacizumab in 48% of patients (16% in the platinum-resistant setting). All patients had tumors with FRα-high membrane staining by the Ventana FOLR1 assay, with at least 75% of viable tumor cells exhibiting at least 2+ staining intensity with immunohistochemistry. Patients received mirvetuximab soravtansine at 6 mg/kg once every 3 weeks.
As previously reported, the investigator-assessed objective response rate was 32.4% with mirvetuximab soravtansine, and the median duration of response was 6.9 months. Of the 34 responses, 5 were complete responses.
“With the addition of new agents for the treatment of ovarian cancer, sequence of therapies may be important to optimize patient outcomes,” he said. In the new analysis, Dr. Coleman and colleagues evaluated response based on prior therapies and timing of exposure to bevacizumab.
Response by Sequence
“Benchmarking against the primary endpoint in the overall population, objective response was slightly higher when mirvetuximab soravtansine was administered as a first treatment in the platinum-resistant setting and in patients who had received bevacizumab in a platinum-sensitive setting,” he reported.
He cited response rates of 34.8% as a first-line treatment as compared with 28.2% when given after other therapies. The response rate was 34.0% in patients who received bevacizumab while they had platinum-sensitive disease compared with 17.6% in patients who received bevacizumab in the platinum-resistant setting. More than 70% of patients had at least some reduction in tumor burden, and 51% achieved disease control for at least 12 weeks.
To put this into context, Dr. Coleman noted that the response rate to chemotherapy after two or more prior therapies has been between 3% and 8% in the bevacizumab-naive population. “Overall responses in each subgroup exceeded our expectations for single-agent chemotherapy,” he commented.
Among all patients, the median overall survival was 15.0 months. At 24 months, 37% of patients were alive. In patients who received mirvetuximab soravtansine after only one or two prior therapies, the median overall survival was 18.7 months, compared with 11.6 months in patients who had received three prior lines of treatment.
Most of the adverse events were low-grade and included reversible ocular and gastrointestinal events. About one-third of patients experienced a treatment-related adverse event that led to a dose delay, and one-fifth required a dose reduction. Treatment was discontinued in 9% of patients. One death, from respiratory failure, was considered possibly related to the study drug.
The toxicities of special interest with mirvetuximab soravtansine are ocular. More than half (52%) of patients experienced blurred vision or keratopathy of any grade. These effects are reversible, have a predictable onset (usually by the second cycle), and can be managed with dose modifications. At the time of data cutoff, 96% of patients with grade ≥ 2 ocular events had seen them resolve completely or to grade 1, and 1 of 106 patients discontinued treatment because of an ocular abnormality. There were no corneal ulcers or corneal perforations, and no patient had permanent ocular sequelae, Dr. Coleman reported.
Conundrums Related to Patient Selection
After the presentation, audience member Joshua G. Cohen, MD, of City of Hope, Orange County, California, said that he sees many patients getting FOLR1 testing with numbers in the 60% to 65% range. He questioned the fact that “FRα-high” is defined as membrane staining of at least 75%.
Joshua G. Cohen, MD
“For these patients who don’t have great options, how do you counsel them, and where do you see the future going for patients who don’t meet that cutoff?” Dr. Cohen asked. Dr. Coleman acknowledged that “this question comes up a lot” and noted that FRα-high is “not a dichotomous variable.”
“We know there are responders among patients with less than [the FRα-high cutoff]. Your safest bet in counseling patients is that you have to follow the label,” Dr. Coleman said. “Data will emerge with new studies evaluating lower expression…. [W]e are going to have other compounds and opportunities with new antibody-drug conjugates that won’t require the highest level of FRα expression.”
DISCLOSURE: Dr. Coleman reported financial relationships with AstraZeneca, GSK, ImmunoGen,Novocure, OncXerna, Onconova, Epsilogen, Pfizer, Merck, Alkermes, Gradalis, Agenus, Mersana, Karyopharm, Deciphera, Roche Genentech, Genelux, Eisai, and VBL Therapeutics.
1. Coleman RL, Oaknin A, Pignata S, et al: Mirvetuximab soravtansine in patients with platinum-resistant ovarian cancer with high folate receptor alpha expression: Evaluation of sequence of therapy on anti-tumor activity in the SORAYA study. Society of Gynecologic Oncology 2023 Annual Meeting on Women’s Cancer. Presented March 25, 2023.
2. Matulonis UA, Lorusso D, Oaknin A, et al: Efficacy and safety of mirvetuximab soravtansine in patients with platinum-resistant ovarian cancer with high folate receptor alpha expression: Results from the SORAYA Study. J Clin Oncol. January 30, 2023 (early release online).
Debra L. Richardson, MD
Debra L. Richardson, MD, Associate Professor and Chief of the Section of Gynecologic Oncology, Oklahoma TSET Phase I Program, at the Stephenson Cancer Center, University of Oklahoma, Oklahoma City, discussed the emerging field of antibody-drug conjugates at a session...