Investigating Immunotherapy and Chemotherapy in Endometrial Cancer Outcomes
Brian M. Slomovitz, MD, is the Director of Gynecologic Oncology and Co-Chair of the Cancer Research Committee at Mount Sinai Medical Center, as well as a Professor of Obstetrics and Gynecology at Florida International University. A specialist in clinical trial development, robotic surgery, sentinel lymph node evaluation, and immunotherapy, Dr. Slomovitz serves as the Uterine Cancer Lead for GOG Partners and sits on the Board of Directors for the GOG Foundation. He is a national and global principal investigator on multiple clinical trials and has authored over 100 peer-reviewed publications. Board-certified in both obstetrics and gynecology and gynecologic oncology, he completed his medical degree at Rutgers University – New Jersey Medical School, residency at New York Presbyterian – Cornell Medical Center, and fellowship at MD Anderson Cancer Center. Recognized as a Castle Connolly Top Doctor, Dr. Slomovitz continues to lead advancements in gynecologic cancer research and treatment. (Miami, FL)
Additional Resource:
Slomovitz BM, Cibula D, Lv W, et al. Pembrolizumab or placebo plus adjuvant chemotherapy with or without radiotherapy for newly diagnosed, high-risk endometrial cancer: results in mismatch repair-deficient tumors. J Clin Oncol. 2025;43(3):251-259. doi:10.1200/JCO-24-01887
TRANSCRIPTION
Consultant360: Your study highlights a clinically relevant improvement in disease-free survival with pembrolizumab in patients with dMMR endometrial cancer. How should this inform clinical decision-making for high-risk patients in the adjuvant setting?
Brian M. Slomovitz, MD: That's a great question. The purpose of the study was really to see if there's an adjuvant therapy that we could do to add to our current standard of care, which is carboplatin and palcotaxal, to improve patient outcomes. While in the entire patient population, we did not see the improvement, that's in the IITT population, in those patients with a DMMR or deficient mismatch repair on biomarker, there was a significant difference in outcomes with an improvement in disease-free survival.
The hazard ratio was 0 .3, so approximately 70% reduction in disease recurrence in those patients who were treated with pembrolizumab, which in itself is quite remarkable and will likely change practice patterns if it's available.
C360: The study emphasizes the unique biology of dMMR tumors, including high TMB and PD-L1 expression. How can clinicians effectively utilize these biomarkers in practice to identify patients who would benefit most from pembrolizumab?
Dr Slomovitz: Yeah, that's a great question. When we're talking about biomarker design therapies and endometrial cancer, we've really been fortunate to change the way we look at the diseases from the typical type one, type two, to breaking up endometrial cancer in one of the four molecular subclassifications. One of those classifications being microsatellite and stability or deficient mismatch repair, DMMR. We know those are what we call quote unquote hot tumors, very responsive to immunotherapy. They don't need as much of a tumor burden or what we call a neoantigen load in order to have an effect, and we're seeing that in the adjuvant setting.
So the pembrolizumab map works in the adjuvant setting in the DMMR tumors, but we didn't see the same effect in the PMMR or proficient mismatch repair proteins, possibly one reason being that there's not enough neoantigens to stimulate an immune response.
C360: Your data suggest a benefit in the dMMR subgroup, but not in the pMMR population. How might this discrepancy affect the broader applicability of pembrolizumab in endometrial cancer management?
Dr Slomovitz: Yeah, no, I think that we know that DMMRs respond well to immunotherapy, and we know that patients with proficient mismatch repair protein tumors, while they do have a benefit of immunotherapy, it may not be as abrupt or as pronounced as it is with the DMMRs. So they likely need the chemotherapy or a traditional kinase inhibitor like lenvatinib to help them work. Or they may not just work, as we've seen, it doesn't have an effect in the adjuvant setting. But that's why it's important to separate these tumors and treat tumors individually, not just to lump all the endometrial cancers together.
C360: Immune-related adverse events were more frequent in the pembrolizumab group. What should clinicians keep in mind regarding safety monitoring and managing these events when considering this treatment for their patients?
Dr Slomovitz: The nice thing is when in this study, you know, there was no new safety signals that came up with the use of pembrolizumab. So it's a well-used drug that we know the safety profile and there were no surprises. We do see some immune-related adverse events, but there I would say overall well-managed. So without the new safety signals, we have a lot of experience giving pembrolizumab with chemotherapy in the first line of recurrent You know, we're seeing that there's not many new safety signals in the adjuvant setting, and it should be perceived with caution, but not any new caution than we already have known.
C360: What emerging questions or gaps in knowledge would you prioritize for future research in dMMR endometrial cancer?
Dr Slomovitz: I think it's clear with DMMR and endometrial cancer, they're very responsive to immunotherapy. The ultimate goal, at least one of my goals in my career, is to get rid of chemotherapy. It would be really cool if we could figure out if immunotherapy by itself has the same response of immunotherapy with chemotherapy in this setting. There are some ongoing trials, some trials that have completed that haven't read out. One of them is a keynote C93 or GOG3064. There's a Domenica trial that's looking at these questions, eliminating chemotherapy. And I'm excited to see if we in fact can get rid of chemotherapy for patients with endometrial cancer, particularly those with deficient mismatch repair protein tumors.
I just say in the world of endometrial cancer, it's so exciting. There are constantly changes being made. There's newer drugs that we're investigating. I do believe that with the addition of immunotherapy and with the current and future use or evaluation of antibody drug conjugates in this setting, and with our expansive knowledge of CDK46 and other biomarker-driven/hormonal -driven therapies, we're getting so close to coming up with more and more cures of this disease, not just delays in disease progression. And ultimately, that's what we need, and that's what we want for our patients.