Key Advancements in Immunotherapy for Endometrial Cancer

A guest expert discusses groundbreaking research on pembrolizumab in adjuvant treatment for endometrial cancer, highlighting the significant impact on reducing recurrence risk in patients with deficient mismatch repair and the need for further molecular subclassification in future studies.

Brian Slomovitz, MD, MS: My name is Dr Brian Slomovitz. I'm a gynecologic oncologist and the director of gynecologic oncology at Mount Sinai Medical Center in Miami Beach. In addition, I serve on the board of directors for the Gynecologic Oncology Group (GOG) Foundation. I'm also the Uterine Cancer Lead for our clinical trials within GOG partners, which is the GOG's industry-sponsored arm. I'm a clinician and a clinical trialist. I love doing research and changing the standard of care to make patients’ lives better. 

Please share a brief overview of the research investigating the use of pembrolizumab in patients with mismatched repair-deficient endometrial cancer.

Dr Slomovitz: We've learned over the last several years that immunotherapy has a role in the management of patients with endometrial cancer. Just as with any new drug discovery, we started with recurrent patients. For patients with recurrent disease, we learned that all of them respond to immunotherapy. There's a certain subset called the deficient mismatch repair (dMMR) in tumors that respond to immunotherapy alone. There's also the proficient MMR (pMMR) [tumors], which in the recurrent setting responds to immunotherapy with a drug called lenvatinib. Pembrolizumab is a checkpoint inhibitor with lenvatinib.

After the second-line activity, we focused on the first-line activity. We found that the addition of immunotherapy to traditional chemotherapy helped improve both progression-free survival and, in some studies, overall survival based on some survival data and follow-up data. With that information, knowing that immunotherapy works in the second-line recurrent and the first-line [setting], the next step in our rationale was to see if it works in the adjuvant setting and in patients who have aggressive tumors that haven't spread yet but we know that they're high at risk for recurrence. 

Traditionally, adjuvant therapy has been chemotherapy with or without radiotherapy. We did a trial to see if combining pembrolizumab and chemotherapy can improve patient outcomes. Deficient mismatch repair protein tumors were included as part of a subset of a larger trial—a trial that I am the lead for the United States for the GOG, led by our European Network of Gynaecological Oncological Trial (ENGOT) groups. We found that when all patients with dMMR and pMMR [tumors] were treated with pembrolizumab with the intent to treat on a population level, it didn't work. But what we're super excited about is that in the dMMR patients—those with dMMR who we know respond to immunotherapy by itself in the second-line setting—had the best responses in addition to therapy in the first-line. What we looked at separately in this study is the response to dMMR in the adjuvant setting and the results are very, very promising.

Please share an overview of some of those key findings. What was surprising? Was there anything unexpected? 

Dr Slomovitz: This was a large study of over 1100 patients, and it is quite remarkable to have a study that large in the adjuvant setting. It's probably the largest study that was ever done, and it may be the largest study that we'll ever do. We found that dMMR occurred in 281 patients. The basis of this sub-study was to look at those 281 patients to see how they would respond to pembrolizumab. The entire group had a hazard ratio, or the risk of improvement, of 1.02—or not statistically significant—when ending pembrolizumab. However, when we looked at the dMMR group, the hazard ratio was 0.31, representing a 69% recurrence risk reduction. The disease-free survival hazard ratio is 0.31, which was statistically significant and, in my view, game-changing in how we manage patients who are at high risk with the dMMR mutation. 

Taking a deeper dive into the data, we looked at some of the other characteristics that we include, such as race, lymph node status, and whether they received radiation at the discretion of the clinician. All of these factors didn't change the results. The improvement in the dMMR subgroup held regardless of the subgroups that we looked at.

It was a large study and although the dMMR subgroup wasn't a pre-specified endpoint, hindsight is 20/20. Now, we would design the trial for more statistical power. Maybe then, regulatory authorities would more readily approve. It is still definitely clinically meaningful. In my practice, I can add pembrolizumab to the chemotherapy for patients who qualify, assuming they get insurance approval. These data help secure insurance approval for our patients. The side effect profile of pembrolizumab in the adjuvant setting showed no additional signals or safety concerns outside of the things we would normally see. Sometimes we see diarrhea or similar immune-type reactions or effects on blood count, but there were no differences with pembrolizumab than we've seen in other studies. 

How does this research impact current treatment options and strategies for patients with endometrial cancer, and what further research or follow-up studies are needed to further confirm and build upon these findings? 

Dr Slomovitz: Great question. Number 1, this was a large trial. I think in the future, we're going to need to break down endometrial cancer by its molecular subclassifications and not do all of them the same. This isn’t a “one-size-fits-all” situation. Future studies in the adjuvant setting looking at immunotherapies should probably limit those to those patients that respond better—the dMMRs. In other types of trials that aren't related to immunotherapy, maybe they should include pMMRs instead of dMMRs. Moving forward, I think dividing by molecular subclassifications will be important. 

There is also a whole new class of drugs that we're looking at called antibody-drug conjugates in treating endometrial cancer, and they may further benefit patients. Perhaps antibody-drug conjugates could even be in combination with immunotherapy, we're not sure yet. 

In general, I always believe that participating in clinical research offers the best outcomes for our patients. It allows patients to get drugs that they can normally not access. Particularly in endometrial cancer—where the risk of death for the first time is higher than the risk of death from ovarian cancer—we need to come up with better treatment options. Our most valuable asset and resource is patients. I want to encourage our patients to allow us to continue clinical research and participate in our trials.