The combination of the antibody-drug conjugate mirvetuximab soravtansine-gynx and the immune checkpoint inhibitor pembrolizumab showed notable activity in patients with recurrent or persistent microsatellite-stable endometrial cancer, according to new findings presented by Porter et al at the American Association for Cancer Research (AACR) Annual Meeting 2024 (Abstract CT008).
Background
Serous endometrial cancers—accounting for about 5% of all endometrial cancer cases but about 40% of deaths from the disease—is an aggressive cancer subtype with poor outcomes. Approximately 30% of patients with serous endometrial cancer have tumors expressing folate receptor–alpha.
Antibody-drug conjugates such as mirvetuximab soravtansine work by pairing a potent anticancer drug with an antibody that directs the drug to cells that express certain markers like folate receptor–alpha. Previous studies have shown that serous endometrial cancers likely have the highest expression of folate receptor–alpha and that mirvetuximab soravtansine and pembrolizumab might be synergistic.
Immune checkpoint inhibitors, which allow antitumor T cells to attack cancer cells, don’t tend to be active in patients with microsatellite stable/mismatch repair–proficient serous endometrial cancer on their own. However, preclinical evidence suggested that mirvetuximab soravtansine can alter immune cells in the tumor microenvironment in ways that could increase T-cell infiltration into the tumor and enhance the effects of the immune checkpoint inhibitors.
“We had a strong rationale for the combination and hoped it would be better than either drug alone,” explained lead study author Rebecca Porter, MD, PhD, a medical oncologist in the Gynecological Oncology Program at the Susan F. Smith Center for Women’s Cancers at Dana-Farber Cancer Institute.
Study Methods and Results
In the new phase II study, Dr. Porter and her colleagues designed the two-stage trial as a single-arm study in which all patients received the same treatment. The researchers first assigned 16 patients with recurrent or persistent folate receptor–alpha–positive microsatellite stable/mismatch repair–proficient serous endometrial cancer who received one to four prior lines of therapy to receive mirvetuximab soravtansine plus pembrolizumab. The second stage of the study would proceed to enroll additional patients if there were at least two objective responses or two cases of 6-month, progression-free survival in the first stage.
The researchers found that 37.5% (n = 6/16) of the patients who received the combination therapy achieved objective responses, 31.3% (n = 5) of them achieved partial responses, and 6.3% (n = 1) of them achieved a complete response. Additionally, 31.3% (n = 5) of the patients had stable disease. Therefore, the study met its primary endpoint, demonstrating the benefit of continuing to study the novel combination therapy. The researchers also noted that 12.5% (n = 2) of the patients experienced progression-free survival for over 6 months—one for nearly 12 months and the other for more than 18 months.
Conclusions
“This is a really encouraging response rate. Almost two-thirds of these patients had three or four lines of therapy, so these results are notable. Some of these responses are what we would call exceptional,” emphasized Dr. Porter. “This study underscores the potential benefits of combining antibody-drug conjugates with immunotherapies for this patient group,” she added.
The researchers plan to conduct further analyses exploring whether there are molecular changes in the tumors or features of the microenvironment that can predict either response or resistance to the combination therapy.
“Our next steps are to dive deeper into the potential mediators of the differences in response we’re seeing. Our goal is to improve the duration of response for those who do respond to the combination,” Dr. Porter concluded.
Disclosure: The research in this study was funded by Dana-Farber Cancer Institute, ImmunoGen, and Merck. For full disclosures of the study authors, visit abstractsonline.com.
