Significance of Dostarlimab Plus Chemotherapy Approval for Primary Advanced or Recurrent Endometrial Cancer

BJ Rimel, MD, Cedars-Sinai Medical Center, Los Angeles, California, shares insights on the recent approval for dostarlimab plus carboplatin and paclitaxel, followed by dostarlimab monotherapy, for patients with primary advanced or recurrent endometrial cancer. This approval was based on results from the phase 3 RUBY trial and expanded the previous indication for this regiment from only among patients with mismatch repair deficient (dMMR) or microsatellite instability high (MSI-H) to all primary advanced or recurrent endometrial cancer.

Dr Rimel concluded, “I'm really excited to see this approval add to our literature and start to ask questions of the people for whom immunotherapy did not add the same significant benefits.”

Transcript:

I am BJ Rimel. I'm a gynecologic oncologist in Los Angeles at Cedars-Sinai Medical Center.

What was the treatment landscape like for patients in this population?

Prior to the approval of dostarlimab, really, really prior, we had only chemotherapy for many, many years, about almost 15 years. We only had carboplatin-paclitaxel. Then we had an approval for the addition of pembrolizumab to carboplatin and paclitaxel. And now we have approval for dostarlimab in addition to carboplatin and paclitaxel for endometrial cancer.

How does this dostarlimab regimen fit into this treatment paradigm?

For someone with endometrial cancer, that's at least a stage 3 or 4m and stage 3 would be measurable stage 3, because that’s what was included in the RUBY trial. For folks with what we would consider later-stage endometrial cancer, that have not had prior treatment, or patients that have recurrent, metastatic endometrial cancer for which other treatments like surgery or radiation are not recommended, this approval changes what our options are for patients.

We know from the more recent data that a combination of immunotherapy with chemotherapy seems to provide us with an improvement in progression-free survival. And now some of the recent data says it may even give us some overall survival benefit, which is really exciting. The addition of dostarlimab to these options, is now we have a new immunotherapy, dostarlimab, that we can add to chemotherapy with carboplatin-paclitaxel.

What data led to this expanded indication in endometrial cancer?

The expanded indication for dostarlimab came from the RUBY trial. The RUBY trial was a large phase 3 study that looked at folks who had advanced or recurrent endometrial cancer and randomized them to carboplatin-paclitaxel alone, which was the standard of care, versus carboplatin-paclitaxel, and dostarlimab.

And they did some evaluation of those 2 populations looking at who might benefit the most, those: people with dMMR versus people with p53 mutations versus people that had no mutations, and tried to be sort of prepared for understanding who was going to benefit the most, not just the 2 populations in general.

It turns out that the ruby study demonstrated that the combination of carboplatin-paclitaxel and dostarlimab improved progression-free and overall survival for the group of people that got immunotherapy. But the people who benefited the most were the people in the dMMR group. And the expanded indication includes those dMMR folks.

There's also people who have p53 mutations who also benefited, and that's exciting data as but the numbers of folks in those smaller buckets were kind of lower. And so we don’t really know what that means, and more studies will be required.

What is the safety profile of dostarlimab plus carboplatin-paclitaxel?

Dostarlimab safety profile looks very similar to the safety profiles of other immune checkpoint inhibitors like pembrolizumab and nivolumab, things like that.

The main important side effects that we think about are obviously autoimmune side effects because those are the kinds of things that we see. The really dangerous ones tend to be things like colitis, which is not very common. There were no new safety signals seen, but it's still a serious side effect that has to be monitored, and sometimes the drug has to be stopped. Serious side effects like pneumonitis, very, very rare again, but known as part of the class.

And then we worry about some of the common, maybe less risky, but more common things like hyper- and hypothyroidism, skin changes, problems with other immune disorder, so there's some autoimmune diabetes that can happen, some autoimmune hypopituitarism, hypoadrenalism, so things like that can happen, and they really require a careful look-about to make sure that's not happening. I'm not able to even list all the types of things that can go wrong with these kinds of drugs, but thankfully they tend to be very rare and the common things, we can look for clearly.

And so, obviously bringing people back regularly for examinations for check-ups and also really communicating with your physician about any symptoms that are persistent or worrisome, so they can do the appropriate investigation.

Do you think that this approval will have an immediate impact in real-world practice?

The immediate impact of the dostarlimab approval provides choice where previously there was none. I think what's really interesting about this is whenever you have 2 options in the same space, like we do now for endometrial cancer, I wonder, as person who is interested in the economics of medicine, what that will do to pricing and options for patients. And if it will actually increase access options for patients for these drugs, which are fairly expensive. And so I look forward to seeing those kinds of things happen.

What advice do you have for practicing oncologists that are interested in using this dostarlimab regimen for their patients with advanced/recurrent endometrial cancer?

The most important thing that I have noticed in patients using immunotherapy is to really listen into the subtle but persistent symptoms that my patients experience on immunotherapy. This whispering fatigue that transcends just what you'd expect that's from chemotherapy. Stuff that doesn't clear up at the end of the chemo cycle but is really persistent, watching for changes in ADLs, asking people if they're having dry eyes, dry nose, dry mouth, looking for some of those sort of more subtle rheumatologic type symptoms that, at least as a GYN oncologist, I really didn't pay attention to, prior to using these kinds of drugs.

I have a much longer list of questions for patients that are on immunotherapy than I used to have. And my goal is trying to listen in for the things that are coming or subtle but annoying so that I'm ready to make adjustments or modifications or strategies to try and alleviate some of those symptoms.

Can you talk about the shift toward PD-1 inhibitors for endometrial cancer?

I can't say there's a specific shift because the approvals are what they are. But the question that you're raising of, why do we see only this one kind of inhibitor when there are 2 that really mechanistically we think act the same, right? A PD-1 inhibitor is binding one target on one kind of cell, and the PD-L1 is binding the ligand. It really should mess up the same process. The PD-1 and PD-L1 shouldn’t be able to get together. But we’re seeing a trend, in our approvals and our efficacy, and I’m very curious to see where this goes.

I do not know, I don’t pretend to know, but it’s exciting and I think this observation bears looking into as time passes.

Is there anything else pertaining to this approval or the study findings that you would like to add?

I'm really excited to see this approval add to our literature and start to ask questions of the people for whom immunotherapy did not add the same significant benefits. For example, our group of patients that are pMMR or have no significant molecular phenotype, those NSMP patients that don't have a p53 mutation. What will be the role in the future of immunotherapy for those patients? Are there other drugs that need to be added? Would an anti-angiogenesis inhibitor be helpful? Would a PARP inhibitor be helpful, right? We don't really know. We have really exciting data to think about with DUO-E, but we just don't really understand what the magnitude of benefit is in each of the populations. And I think that data is coming, and I'm excited to see that.

Are there any other trials upcoming that you're excited about in the endometrial space?

So many trials that are coming that I'm excited about. I'm excited to hear more about the TROP [antibody drug conjugates] ADCs. I'm excited to hear more about some of the folate receptor ADCs that may be available for certain types of endometrial cancer.

I'm super excited about trastuzumab deruxtecan and the DESTINY-PanTumor study, and I'm interested to hear more about that, and what the options are for considering combining. Or even in HER2-low endometrial tumors, is there a role for some of these agents because of how well they work. I mean, those are some of the areas where I'm pretty excited.

And then, of course, to toot my own horn, GY-012 is a platform trial that is looking at a lot of different combinations, including immunotherapy combinations. And I and my co-investigators are hoping for a readout of that study in 2025, so, fingers crossed.

Source:

Powell MA, Biorge L, Willmott L, et al. Overall survival in patients with endometrial cancer treated with dostarlimab plus carboplatin–paclitaxel in the randomized ENGOT-EN6/GOG-3031/RUBY trial. Ann Oncol. Published online: June 9, 2024. doi: 10.1016/j.annonc.2024.05.546

FDA expands endometrial cancer indication for dostarlimab-gxly with chemotherapy.Published online: August 1, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-expands-endometrial-cancer-indication-dostarlimab-gxly-chemotherapy