Mirvetuximab Soravtansine Plus Pembrolizumab Generates Reponses in pMMR FRα+ Serous Endometrial Cancer

The combination of mirvetuximab soravtansine-gynx (Elahere) and pembrolizumab (Keytruda) showed clinical activity in patients with recurrent mismatch repair–proficient (pMMR) or microsatellite stable FRα-positive serous endometrial cancer, according to Rebecca Porter, MD, PhD, who noted that next steps include the identification of biomarkers for this patient population.

Data from a phase 2 study (NCT03835819) presented by Porter at the 2024 AACR Annual Meeting demonstrated that, at a median follow-up of 4.7 months, 37.5% of patients (n = 6/16) treated with mirvetuximab soravtansine plus pembrolizumab achieved an objective response; responses were comprised of 1 complete response (CR) and 5 partial responses (PRs), 3 of which were confirmed. Five patients experienced stable disease, 4 experienced progressive disease, and 1 patient was not evaluable.

“The response rate [with mirvetuximab soravtansine plus pembrolizumab] was favorable in a difficult-to-treat population who has a high unmet need. It underscores the rationale for combining antibody-drug conjugates [ADCs] with immunotherapy,” Porter said. “However, it also highlights that we need to have better biomarkers and predictors of who would have durable responses to these combinations. That is a difficult question to answer in these studies [because] it requires tissue biopsies which this study did not have. But in the future, that has to be part of our studies when we are able to do it.”

In an interview with OncLive®, Porter, detailed data from the phase 2 study and highlighted the potential of ADCs in endometrial cancer. Porter is a medical oncologist and an active translational and clinical researcher in the Gynecologic Oncology Program in Dana-Farber Cancer Institute’s Susan F. Smith Center for Women's Cancers in Boston, Massachusetts.

OncLive: What was the rationale for exploring mirvetuximab soravtansine plus pembrolizumab in patients with pMMR FRα+ serous endometrial cancer?

Porter: FRα is overexpressed on many cancers including endometrial cancer—approximately 60% overexpress it—which was the rationale for looking at [mirvetuximab soravtansine] in endometrial cancer. A phase 1 trial [NCT01609556] showed that the monotherapy activity of [mirvetuximab soravtansine] wasn’t great and there is a lot of preclinical data to support the rationale for combining ADCs with immunotherapy.

The phase 1 study enrolled all patients and found that the highest expression of FRα tended to be in the serous endometrial cancer population [which] is also a population with high unmet need [as] patients [tend to have a] poor prognosis. We wanted to look specifically within that population. Most patients with serous endometrial cancer have pMMR [disease], but we also know that patients with mismatch repair–deficient disease [dMMR] have the opportunity to receive immunotherapy as a single agent. That led us to focus on [patients with] pMMR tumors that express FRα.

What were the key findings from the study presented during the 2024 AACR Annual Meeting?

A total of 16 patients were enrolled in the trial and treated, 15 of which had evaluable scans on treatment. The response rate was 37.5% with 1 confirmed CR, and 3 confirmed and 2 unconfirmed PRs, which was very encouraging for this patient population. Within that, there were 2 patients who had exceptional responses—1 patient had a CR for more than 18 months and 1 patient had a PR for approximately 12 months.

Reassuringly, there were no new safety signals identified. [Toxicities seen] were in line with the monotherapy safety profiles that we know for each agent. There was one case of grade 3 adrenal insufficiency and one case of grade 3 acute kidney injury which was in line with the pembrolizumab data. With mirvetuximab soravtansine we [pay close attention to] the ocular toxicities, and those were all low grade in this study as we see with mirvetuximab soravtansine monotherapy. There were no grade 3 or 4 ocular toxicity events.

What are the next steps for further investigating this regimen?

The combination met the prespecified end point to be worthy of further study. We want to understand the duration of response [better because] those 2 patients had a prolonged duration of response, but other patients tended to progress more quickly after they initially responded. Trying to understand biomarkers to predict who within this population of patients would be most likely to have a durable response [is key along with] other mechanisms of acquired resistance that can mediate that progression after the initial response. Right now, we’re focusing on correlative studies to understand that and that will help guide where we want to move this combination in the future.

What potential do ADCs have in the endometrial cancer field?

The potential is huge. Recent data looking at immunotherapy added to upfront chemotherapy for endometrial cancer [showed] that it’s improving outcomes especially in the dMMR population; it’s [FDA] approved now and also the NCCN guidelines added immunotherapy in the first line [recommendations]. That potentially brings ADCs into the second line or even earlier if we’re thinking of combinations. There are multiple targets in development and the questions are going to be how to sequence these therapies in patients who have tumors that express multiple targets—understanding which targets to choose first and how to sequence [agents] in terms of the toxicity profiles and mechanisms of cross resistance [is important].

I enjoyed the science presented [at the 2024 AACR Annual Meeting that was] trying to understand the interplay between the innate immune response and the adaptive immune response, looking at crosstalk between myeloid cells and T cells. That will be informative when we try to understand [data such as those seen in] this study combining ADCs and immunotherapy.

Reference

Porter RL, Xiong N, Tayob N, et al. A phase 2, two-stage study of mirvetuximab soravtansine (IMGN853) in combination with pembrolizumab in patients with microsatellite stable (MSS) recurrent or persistent endometrial cancer.Presented at: 2024 AACR Annual Meeting; April 5-10, 2024; San Diego, CA. Abstract CT008.