Bhavana Pothuri, MD

The real unmet need in endometrial cancer is the high-risk histologic subtypes. A recent study noted that endometrial cancer mortality is increasing. It’s nearing that of ovarian cancer, and it’s soon to surpass the mortality of ovarian cancer. Clearly, we need to do better with this disease. The reason for this is 2-fold: 1, we’re seeing the increasing obesity epidemic, and 2, we’re seeing a higher proportion of high-risk histologic subtypes. Those are mostly in racially and ethnically diverse patients. Black patients have a very high preponderance of uterine serous cancers, which have a much poorer prognosis. We have treatments for front line and second line that are effective. After chemotherapy in the front line, we have lenvatinib and pembrolizumab for the MMR [mismatch repair]–proficient patients. For dMMR [MMR deficient], we have both dostarlimab and pembrolizumab. These treatments have very good efficacy, so the critical unmet needs at this point are therapies beyond this.

The idea is to identify effective therapies in the later-line setting and move them into the front line, so we can try to effect more cure. Once the disease has relapsed, we rarely can cure patients. The strategy is to move these agents into the frontline setting. LEAP-001 is looking at the combination of pembrolizumab and lenvatinib in the first-line setting to replace chemotherapy. The RUBY trial is evaluating paclitaxel-carboplatin with dostarlimab vs paclitaxel and carboplatin alone. We’ll have to await the results, which should be coming at any time. I would love to see these move into the frontline setting.

What are we going to do after? What other promising treatments am I excited about? There are CDK4/6 inhibitors with hormonal agents that are exciting for our hormonally driven or copy number low tumors. We’ve also heard about selinexor, which inhibits XPO1, and it has been shown to have efficacy in 

 wild-type patients. In addition to that, there are some exciting antibody-drug conjugates on the horizon. There are agents such as STRO-002, mirvetuximab, and MORAb-202. There are also HER2 [human epidermal growth factor receptor 2]–directed therapies that are very exciting and small-molecule inhibitors, such as tucatinib. HER2 antibody-drug conjugates recently have had exciting data and approvals in breast cancer. Finally, the WEE1 inhibitors are an exciting target in uterine serous cancers. As I stated earlier, the uterine serous cancers are noted in Black patients and are a true unmet need. I’m hoping we have some of these therapies available to use in our patients going forward.

I’m most excited about awaiting the data from RUBY, LEAP-001, and GY018, but that’s going to come a little later because that’s still enrolling. These are trials that may be practice changing and may change the way we approach the frontline treatment of endometrial cancer, so I’m looking forward to those data.

Videos

Closing out her discussion on the management of recurrent metastatic endometrial cancer, Bhavana Pothuri, MD, highlights ongoing clinical trials and novel treatment modalities. 

Metastatic Endometrial Cancer: Future Directions in Care 

That’s a really important question about the differences in adverse events [AEs] that are related to immunotherapy vs chemotherapy. I talked a little about the timing of those events. One thing that’s important with immunotherapy is that unlike chemotherapy, adverse events during chemotherapy usually end with the treatment. Though patients may need several months to recover and regain their strength, the actual adverse event usually is during the treatment time.

Immunotherapy varies because even after stopping immunotherapy, you can develop an immune-related adverse event. That can even be 3 to 6 months after you stop the treatment. Having this threshold of suspicion for these adverse events, even after you stop, is important. The other thing that’s really important about these immune-related adverse events is that some of these can be fatal. Although they occur in a small percentage of patients—the serious adverse events were about 5%—if they’re not identified early and treated or the dose is held, these can be fatal. You have to be very vigilant when treating patients on immunotherapy.

When you’re dealing with colitis, you need to pay attention the patient’s baseline and then know how many stools above the baseline they’re getting. If they develop a grade 3, you have to make sure they get on high-dose steroids and that they’re improving. If you’re not hospitalizing those patients, there needs to be very close follow-up as an outpatient. If they’re not improving in 24 to 48 hours, they should be hospitalized. If they’re not improving with the high-dose steroids at 1 to 1.5 mg/kg, then you need to consider other therapies, such as infliximab. It’s also important to get GI [gastrointestinal] consultants involved in the care of these patients. That’s 1 example.

The other example is pneumonitis. If patients have a severe pneumonitis, it’s important to identify it, stop the treatment, and start high-dose steroids. The other thing about the steroids is that you need to continue steroids even if the symptoms get better. They should not be weaned off quickly. They should be weaned off over a long period of time. I don’t wean off steroids in less than 6 to 12 weeks. Keep that in mind. They shouldn’t be weaned until the adverse event is down to a grade 1.

If you look purely at the data, they’re very similar. But practically, when you utilize these drugs, I find that patients tolerate dostarlimab well. They have less reflux than some of the patients on pembrolizumab. That said, both are great drugs, and I’ve utilized both. It’s a nuanced finding because I’ve taken care of a lot of patients. But when you look at the actual data, there’s no difference.

The key to management is extensive counseling, breaking down the symptoms related to the adverse events so patients know what to look for, and training your entire team because they’re the ones who are going to be taking the phone calls when these patients are calling. You don’t want someone saying, “It’s just diarrhea. Take Imodium [loperamide].” If it’s diarrhea, then I want to know what grade it is. If it’s a high grade, then they need to come in and be seen. They need to be started on steroids. Having a thorough counseling before they start and engaging the patients to be their own advocates—writing down their adverse effects, reporting AEs early—is the key.

Bhavana Pothuri, MD provides a perspective on the management of immune-related adverse events that can be seen in patients treated for recurrent metastatic endometrial cancer, as well as a focused discussion on the conversations she has with her patients.

Recurrent Metastatic EC: Common Immune-Related Adverse Events And Patient Discussions

Obviously, chemotherapy is the standard first-line treatment. For a dMMR [mismatch repair deficient] patient, immunotherapy is the standard of care. With response rates as high as 44%, and with that long duration of response, it’s safe to say that it’s the standard of care. With that, you have 2 choices that are FDA approved. Both are good choices, but my personal preference is dostarlimab. I find it very well tolerated with patients, and I have had a lot of experience with it, putting many patients on clinical trials with it. That’s my choice of therapy, but both are great choices.

In terms of the 2 drugs, there are not a lot of differentiators. Their efficacy, AE [adverse event] profile, discontinuation rate, and all that are quite similar. There aren’t any specific clinical factors. But 1 factor is you have to make sure of is if the patient a good candidate for immunotherapy. If they have severe underlying autoimmune diseases or are on steroids at very high doses, they may not be the best candidates for this. However, there are some clinical trials looking at patients who have these autoimmune diseases and treating them with immunotherapy. Once we have that data, we may be shifting the pendulum on utilization in those patients. But for now, it’s safe to say that those are some of the patients who I don’t necessarily treat without putting them on a clinical trial.

The typical response rates are similar to what’s been reported. I see long, durable responses as they have been reported in the trials KEYNOTE-158 as well as GARNET. In terms of the goal for these patients, everyone wants to get a CR [complete response], but CRs occur in about 10% of patients, even in the recurrent setting. There’s so much value in getting even a partial response with improvement in symptoms, or stable disease in patients who don’t have symptoms, and those are acceptable goals in recurrent metastatic disease.

It’s some of the things that we alluded to before: patients with more significant underlying comorbidities may have more adverse effects. Make sure you monitor those patients [because] they may not be able to tolerate the regimens as well, and their performance status may not be as good either. You have to take all that into account. As you’re treating these patients, you need to be very mindful of all that.

Focusing on patients with recurrent metastatic endometrial cancer, an expert oncologist identifies factors that help inform the selection of second-line targeted therapy.

Considerations for Second-Line Treatment Selection for Patients With Metastatic EC

The GARNET trial enrolled patients with recurrent endometrial cancer, and they were patients who had progressed on a prior platinum-based chemotherapy. These patients either had recurrent or advanced disease that was measurable. They were enrolled into 2 parallel cohorts. Cohort A1 was the dMMR [mismatch repair deficient] endometrial cancer cohort, and then cohort A2 was the mismatch repair proficient endometrial cancer. In terms of the primary and secondary efficacy outcome, let's start with cohort A, which was the dMMR or MSI-high [microsatellite instability-high]. The objective response rate was 43.4%, there was a 10% CR [complete response] rate and the disease control rate [DCR] was 55.7%. In the mismatch repair proficient cohort, the objective response rate was 11.5% and a DCR of 35.2%. I think the thing that's really notable is that the duration of response is really long with the treatment. That is really one of the biggest advantages with immunotherapy.

I'll start with the second question, what are the strategies that I use to mitigate and manage the side effects, and then I’ll get into the side effects. So, I think that these agents, the PD-1 inhibitors, are immunotherapy agents. So, while they work to kill the tumor cells, they can also affect essentially any part of your body. Educating your team as well as your patients is really important. I am a big believer in the team-based approach. My nurses, my nurse practitioners, and my clinical research team all are educated about the adverse events [AE] with immunotherapy. The most common side effects of dostarlimab are actually very manageable, such as nausea and fatigue. But the more important and severe side effects that one needs to be cautioned and concerned about are the immune related [IR] adverse events. Although they only occur in the grade 3 or greater, or only occur in about 5%, I think it's really important because early identification is key. So the early adverse events are usually things like rash and colitis. The later side effects [are] endocrine, so disorders of your thyroid and other endocrine AEs start at about 10 weeks or so and then can occur throughout the treatment. Then you have pneumonitis, which typically occurs between 12 and 20 weeks, and usually the liver adverse events occur late.



I think it's not just understanding that they can affect all these parts of your body, but really understanding the symptoms that are associated with this, and making sure your clinical team understands it, and your patient before they start the therapy understands it. I tell them to keep a log of their side effects and bring them in. I say pay close attention to some of the IR adverse events. So if you're having diarrhea then the nature of that diarrhea is important. If it is more bloody and mucusy, then it's more likely related to a colitis type picture. Pay attention to shortness of breath or cough, which can be a sign of pneumonitis. In addition, there are more rare ones where you can get an immune related pericarditis. We've all seen the kidneys being affected with nephritis and then commonly are thyroid, either hyper- or hypo-thyroidism. So it's really important to monitor your TFTs [thyroid function tests] during immunotherapy on a regular basis.

Centering discussion on safety and efficacy data from the GARNET trial, Bhavana Pothuri, MD, reflects on the role of dostarlimab therapy in patients with recurrent metastatic endometrial cancer.

Dostarlimab Therapy in Recurrent Metastatic Endometrial Cancer: The GARNET Trial

In terms of, “would I have added on brachytherapy to external beam,” I probably would've included vaginal brachytherapy as well. Something else that I would've considered is if this was a endometrial cancer that was confined to the endometrium without any myoinvasion, I would actually consider hormonal therapy in someone who was refusing surgical treatment.

At the present time, I think the standard of care still remains paclitaxel and carboplatin. This is what I would start with. The one thing I would consider is adding immunotherapy after a few cycles, given that her tumor is dMMR [mismatch repair deficient]. Hopefully we will have data from the ongoing studies, RUBY, DUO-E, and NRG-GY018, which will help us move immunotherapy into an earlier line of treatment.

There are currently 2 that are approved for this indication of dMMR endometrial cancer, pembrolizumab as well as dostarlimab. Both are PD-1 [programmed cell death protein 1] inhibitors that bind to PD-1 and block PD-1 and PD-L1 [programmed death-ligand] or PD-L2, and essentially restore the cytotoxic activity of T-cells and the immune system to fight cancer. There are other PD-1 inhibitors as well as PD-L1 inhibitors that have been studied in trials, but these are the 2 that are currently FDA approved and available for use as treatment in our patients.

Comprehensive insight to the systemic treatment armamentarium available to patients with metastatic EC.

Systemic Therapy Options for Patients With Metastatic Endometrial Cancer 

The typical patient that we see with endometrial cancer is obese, hypertensive, and usually has a well differentiated or grade 1 endometrioid histology. Since I'm in New York City, I also see a very racially and ethnically diverse patient population and many of these patients unfortunately present with more advanced-stage disease and more of the higher risk histologic subtypes, such as uterine serous cancer.

Typically about a quarter to a third of patients have mismatch repair deficiency. I recommend all patients with endometrial cancer have mismatch repair testing. In my practice, our pathologists routinely test for mismatch repair deficiency by immunohistochemistry [IHC] for 

 is absent on immunohistochemistry, they reflexively get tested for 

 hypermethylation. In terms of other molecular testing, if your mismatch repair IHC is intact you can consider MSI [microsatellite instability] testing for completeness sake and so that you don't miss any patients.

Expert perspective on the presentation of endometrial cancer, followed by advice on providing optimal workup and diagnosis.

Bhavana Pothuri, MD | Authors

Articles

Metastatic Endometrial Cancer: Future Directions in Care

Recurrent Metastatic EC: Common Immune-Related Adverse Events And Patient Discussions

Considerations for Second-Line Treatment Selection for Patients With Metastatic EC

Dostarlimab Therapy in Recurrent Metastatic Endometrial Cancer: The GARNET Trial

Systemic Therapy Options for Patients With Metastatic Endometrial Cancer

Endometrial Cancer: Patient Presentation and Initial Workup