Looking Towards the Future: Moving Targeted Therapies for mEC Into the First-Line Setting

Experts discuss ongoing clinical trials focused on moving second-line and higher targeted therapies, including immunotherapy, into the frontline setting for mEC, and then comment on how these advances might impact treatment paradigms and patient outcomes.


Kathleen Moore, MD: The frontline studies are open and will probably be reporting out in 2023. Why don’t we go through the differences between RUBY Parts 1 and 2? We’ll probably hear Part 1 soon. and then DUO-E as compared with LEAP-001. Do you want to take us through that so that our listeners can anticipate what we should be hearing results for maybe 2023?

David O’Malley, MD: We’re looking at having these results close at hand. The basis of these trials are a backbone of carboplatin-paclitaxel plus or minus IO [immuno-oncology]. We have the AtTEnd trial, which is atezolizumab. We have RUBY Part 1, which is dostarlimab. We have NRG-GY018, which was plus or minus pembrolizumab. All of those have the carboplatin-paclitaxel backbone plus or minus IO. That’s different from LEAP-001 and KEYNOTE-C93, where we’re looking, we’re looking to replace chemotherapy in the first-line setting with immune-based therapy. LEAP-001 is pembrolizumab plus lenvatinib vs carboplatin-paclitaxel. If that trial is positive, we’ll be looking at a nonchemotherapy regimen to give before chemotherapy. The problem is, we’re going to have to cross-trial compare. We never do that, right Dr Moore? We never cross-trial compare.

Kathleen Moore, MD: No, never [smiling].

David O’Malley, MD: But we’re going to have to cross-trial compare with regard to these other 3 trials for advanced or recurrent disease, which is the carboplatin-paclitaxel plus IO. How do those look? Do we treat with pembrolizumab-lenvatinib, or do we treat with carboplatin-paclitaxel plus IO? We know that lenvatinib-pembrolizumab is indicated for that mismatch-repair-proficient patient. We know it works really well on a deficient patient because we know pembrolizumab by itself works well. How much does the lenvatinib add to that?

These are all decisions we’re going to have to make in the future. There’s a very high chance we’ll have IO in the first-line setting. Is it with the backbone of chemotherapy, or is it IO instead of chemotherapy? What’s your feeling? At least several of these are going to be positive, particularly for the deficient population, when we’re looking at the IO plus the backbone of carboplatin-paclitaxel. In the deficient population and the proficient population, LEAP-001 has a very good chance of outperforming chemotherapy.

Kathleen Moore, MD: I agree. In the mismatch-repair-deficient or MSI [microsatellite instability]–high population, it’s hard to imagine a scenario in which an IO–containing therapy is not going to be superior to a non–IO–containing therapy. I’d be utterly shocked, but I guess it could happen. I haven’t predicted well of late. I anticipate that being positive and likely moving into approval. The bigger question is whether it will make a difference in mismatch-repair-proficient [patients].

It’s going to come down to all the other small factors that predict for a response to immune checkpoint inhibitors that aren’t mismatch-repair deficient and how well populated they are in that microsatellite stable group and across the studies. You may see a little bit of a bump if you had tumor mutational burden high or another microenvironment marker that predisposes to benefit from IO, which otherwise isn’t mismatch repair deficient in 1 trial or another. I’m very interested in microsatellite stable [patients] to see what changes will happen.

The other part is that there are 2 studies that have added not only immune checkpoint inhibitors but PARP inhibitors to the maintenance space as well. RUBY Part 2 has dostarlimab and niraparib, and DUO-E has durvalumab plus olaparib vs durvalumab vs paclitaxel-carboplatin alone. Those 2 studies have thrown the PARP inhibitor question in there, which will also be interesting. It’s hard to even call. Of course, I’m biased about DUO-E because I’m a co–PI [principal investigator] with Shannon Westin. I’m fully expecting it to be positive. I don’t lead things that I don’t believe in, but we’ll see. We’re trying to change the trajectory in frontline metastatic or recurrent endometrial cancer. All these studies are going to have results that are very proximal to one another. It’s going to be a bit of an information overload. Hopefully good and fun.

David O’Malley, MD: It’s going to be fun [finding out] which groups will benefit from the PARP inhibitors. Thank you for adding to that. I didn’t talk about those arms in the reviews. Is it going to be the TP53 mutated? A lot of people ask me, “What about quality of life?” Some patients are on therapy for 2 years. My answer is always that most IO therapies are very well tolerated. But most important, if we keep the disease away, then patients feel better, hands down. If they recur, they don’t feel well. If we can cure more people, we can keep the disease away. The impact on quality of life is marked if we can control their disease, shrink their disease, and most important, keep it away.

Kathleen Moore, MD: I agree. Quality of life is improved when tumors are shrinking and gone, as long as the drug is not too toxic. We do have examples of significant toxicities with some of these therapies. Lenvatinib-pembrolizumab is 1 example—we can mitigate it in the recurrent setting quite well. We can use it to its best effect, but patients aren’t on it for as long as they might be in the front line. That’s going to be an interesting study to look at from a PRO [patient-reported outcome] standpoint.

It depends on the readouts of these studies. We just talked about 7 frontline studies that will be reading out with various combinations of things and a lot of biomarker work. We’re on the cusp of being able to look at a patient presenting to us, do the panel of biomarkers that hopefully will be validated, and those patients who are microsatellite instable get pembrolizumab alone—they don’t need any chemotherapy; hopefully they’re cured. For those who are mismatch repair deficient and more sporadic and not Lynch [syndrome]–like, maybe they do need chemotherapy plus IO, or maybe they do fine with IO alone. But we can make that determination.

Transcript edited for clarity.

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