Matthew A. Powell, MD, shares an overview of the systemic treatment options for patients with relapsed or metastatic endometrial cancer and the factors he considers when selecting an appropriate frontline therapy.
Matthew A. Powell, MD: For patients who [experience] relapse after frontline therapy, we have several different options and thankfully more options than ever before. Traditionally, [for] our patients who receive frontline chemotherapy with carboplatin/paclitaxel, at recurrence, they were typically treated with single-agent cytotoxic therapy with either doxorubicin or paclitaxel. Obviously, if radiation is an option, if it’s limited disease or surgery is an option, those should be performed. And we’ve made a lot of progress evaluating antiangiogenic agents and now combination antiangiogenic agents with immune checkpoint inhibitors. And as many of you know, the combination of lenvatinib plus pembrolizumab—lenvatinib being a multitargeted tyrosine kinase inhibitor [and] pembrolizumab [being] a PD-1 inhibitor—has become our standard choice for patients requiring second- or third-line therapy. And again, this was the KEYNOTE-775 study that…was a large, randomized trial comparing that lenvatinib/pembrolizumab combination to a choice of either doxorubicin or paclitaxel. There was a doubling of the survival at 3 years, some from 15% to 32%, which I think drove a lot of enthusiasm when we see these longer-term survivors, a doubling of the response rate and very impressive improvement in progression-free survival. All were statistically, significantly different from chemotherapy, driving this to be a standard of care for second-line therapy.
When we look at factors for determining what to do [in the] front line, should you use carboplatin/paclitaxel with checkpoint, or should the patient consider carboplatin/paclitaxel followed by lenvatinib/pembrolizumab? That is a tricky question. Right now, what we have approved is for the defective mismatch repair population [MMR]: the use of a triple therapy of carboplatin/paclitaxel. For the patients [with] proficient MMR, we’re still subject to debate. It may be…carboplatin/paclitaxel followed by lenvatinib and then pembrolizumab at progression or relapse. Given the current data, we are going to learn more in the next few months about the molecular subtypes that were involved in both the RUBY and [NRG]-GY018 studies, and [they] may provide increased precision as we make the decisions on what is the best first-line therapy.
When we look at patients with endometrial cancer who [experience] relapse after first-line treatment, hopefully this is changing dramatically as we have better first-line therapy. It looks like from [findings from] these recent trials of [NRG]-GY018 and RUBY that we’re perhaps curing more patients with this. The defective mismatch repair–type tumors and the duration of response to first-line therapy can be quite long lasting. And you recall the maintenance period on [NRG]-GY018 was 2 years of pembrolizumab therapy. And then the RUBY trial was 3 years of dostarlimab. So these patients often are many years out from their cytotoxic chemotherapy if they do [experience recurrence].
When we think about recurrence, we would have to think, “Well, should we rechallenge them with a cytotoxic again, with carboplatin/paclitaxel, or should we switch to a new regimen?” Whether they had checkpoint up front or not, we’ll help drive that decision. There is interest in carboplatin/paclitaxel with bevacizumab, and that was evaluated in [the] GOG-86P [study] and seems to be explicitly active in the population[with] P53 [mutations]. We’ll be learning more about that in subsequent trials as we try to figure out how to integrate antivascular therapy with checkpoint inhibition and chemotherapy in the frontline setting. [Findings from the] LEAP-001 study will be presented soon at the ESMO [European Society for Medical Oncology] meeting, which is looking at lenvatinib/pembrolizumab in the frontline setting, comparing that directly with carboplatin/paclitaxel. That’s going to help us sort out what we should be starting with [in the] front line. [There are] a lot of exciting things in endometrial cancer, but I would try to make this simple and say check for defective mismatch repair if it’s present. Thinking about checkpoint inhibition, if the patient can be cured with radiation or surgery at their relapse, those things should be considered strongly before doing systemic therapies. But the combination of lenvatinib and pembrolizumab should trump a single-agent set of toxic therapy with either doxorubicin or paclitaxel, [because] we would expect only about a 15% response rate from those drugs in the second- or third-line setting, with a short durability of response.
[With] regard to the ECHO study, which was a retrospective study of 124 eligible patients who initiated second-line chemotherapy plus or minus bevacizumab or immunotherapy, these patients were evaluated, and most patients—92 of them—received pembrolizumab. And among those patients, the overall progression-free and overall survival was 29 and 30 months, respectively. So pointing [out] that…real-world evidence suggests that pembrolizumab monotherapy provides considerable benefits for patients with mismatch repair–deficient endometrial cancer who are candidates for curative surgery or radiotherapy.
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