Rationale for Treatment Strategies with Single Agent IO in Patients With dMMR/MSI-H Advanced or Recurrent Endometrial Cancer


Dr Matthew A. Powell details the rationale for using single-agent immunotherapy treatments for patients with advanced or recurrent endometrial cancer with reference to data updates from several key clinical trials.

Matthew A. Powell, MD: When we look at treatment strategies for the use of single-agent immunotherapy [IO] in patients with defective mismatch repair [dMMR] who either have advanced or recurrent endometrial cancer, we have some updates from key trials. Building on what we learned, [NRG]-GY018 and RUBY again, these were trials where it was combined with chemotherapy. What about immunotherapy alone?

As I mentioned, [let’s go] back to the [findings from the] KEYNOTE-158 study, which Dr [David M.] O’Malley, [MD], presented at ESMO [European Society for Medical Oncology] [Congress] in 2022 [in Paris, France]. This is where we see this near 50% response rate in this population. Similarly, with [NRG]-GY018 [findings] having very high response rates, nearly that same level for patients getting single-agent checkpoint who have defective mismatch repair tumors, we felt quite comfortable that not only is the response rate high but there’s very long durability and even cures in this population. Now that we have some of these patients 5, 6, 7 years out, we’re not seeing relapse. And it’s very exciting.

When we look at treatment and response and predictive biomarkers, there’s been a lot about this, and clearly, tumor mutational burden [TMB] seems important. It tends to overlap very highly with defective mismatch repair. PD-L1 is also interesting, and there is a slight trend toward the positive ones being more likely to respond. But there are a lot of PD-L1–negative tumors that respond to checkpoint. I would not use that as the biomarker driving your choice of using checkpoint. Use the mismatch repair status or the TMB to decide about checkpoint inhibition. And one of the key caveats [is] even if the primary tumor was mismatch repair proficient, consider biopsies in the recurrence about 7% to 11% of the time. Based on [findings from] a couple of different studies, you’ll see defective mismatch repair in that recurrent tumor where it wasn’t found or noted in the primary tumor. When we look at these real-world data, we’re seeing long durability of response, high response rates. The one other caveat is promoter methylation of MLH1 vs a somatic or germline mutation in one of the Lynch syndrome genes. It does seem like there may be a higher response rate in [findings from] some studies for those patients who have a somatic gene mutation or a Lynch-like cancer vs those who have promoter methylation. And you could imagine that promoter methylation could be lost over time. And one of the things we’re looking at there is dual immuno-oncology in the form of CTLA-4 plus PD-1, PD-L1. Is that a good strategy for some of those patients? [There’s] more to come in that area. We currently have a randomized trial through the NCI [National Cancer Institute] looking at that, the NRG-GY025 [trial].

Any time we have new therapies, we also want to see the cost of that therapy in terms of toxicity. As I just mentioned in [findings from] KEYNOTE-158, the overall response rate was nearly 50%; it was 48%. And when we look at the quality-of-life assessments, how are these patients doing? These data have been published; Dr O’Malley published this very nice analysis with multiple sensitive markers of quality of life. The majority of these patients completed these analyses. [It’s] one of the first times we see the scores improve and improve quite significantly. It’s always hard to interpret quality of life and some of the measures that we use. But we feel [that in] these patients, especially the patients who achieved a complete or partial response, there was dramatic improvement in their quality of life. We should all see that as clinicians. These patients on therapy have minimal adverse effects and have improvements.

When we look at the additional data, dostarlimab…held up as well. There are known toxicities of our checkpoint inhibitors, namely the PD-1 inhibitors, the dostarlimab and pembrolizumab, but these are somewhat predictable. We know how to manage them, and the adverse effect profile warrants additional follow-up and knowledge of these agents as we’re giving them. But the quality of life is compelling to think about [with] these agents for our patients with defective mismatch repair endometrial cancer.

Transcript is AI generated for clarity and readability.

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