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Spotlight

This roundtable series reviews options after progression on platinum-regimens for patients with mismatch repair–deficient recurrent or advanced endometrial cancer, as discussed by key opinion leaders and participants at virtual live events.

Therapeutic Choices in dMMR Recurrent or Advanced Endometrial Cancer

Please review the systemic therapy options for patients with metastatic dMMR/MSI-H (mismatch repair deficient/microsatellite instability-high) endometrial cancer.

What are your determining factors in selecting next-line therapy for a patient who relapsed less than 12 months after a complete response to frontline carboplatin/paclitaxel? What if the patient had a partial response?

: [Systemic therapy options include] chemotherapy rechallenge with the platinum doublet therapy. Hormonal therapy is our mainstay, that’s what’s been known for years as the only therapy. Immune checkpoint inhibitors [include use of] the single-agent therapy. We don’t use tyrosine kinase inhibitors such as lenvatinib [Lenvima] as a single agent, but that would [fall under the] pembrolizumab [Keytruda]/lenvatinib combination.

What’s determining our selection of the next line, and would it change if a patient’s prior response to the carboplatin/paclitaxel was a partial response rather than a complete response? Would you order repeat molecular testing for that patient?

From my standpoint, if the disease recurred [in less than 12 months means that] after multiple therapies, I want to give as much as I can, so immunotherapy plus lenvatinib would be my choice.

 I don’t think there are any wrong answers. The textbook answer would probably be single-agent immunotherapy. Anyone who has the ability to get immunotherapy should get it as early in their disease course is possible, because sometimes it takes time to work. I’ve seen it kick in even when I move on to the next therapy. [However], if single-agent immunotherapy is going to work, there’s no reason pembrolizumab plus lenvatinib wouldn’t work, and I think it’s a better regimen that might be synergistic. Even though that might not be the textbook answer, that’s what I would go to. I don’t know of any data where [adding] lenvatinib it would make it work less well in MSI-H disease. I’m curious to see what you think of that.

I think it’s a great point.… We will go in depth about KEYNOTE-775 [NCT03517449], which was the trial of pembrolizumab/lenvatinib vs provider’s choice of chemotherapy. Your point is well taken…does the combination of lenvatinib with pembrolizumab work better than pembrolizumab? We don’t know whether it works better, but what we know is for FDA approval and therapeutic benefit, you can certainly go with a single-agent checkpoint inhibitor. [The dMMR/MSI-H population is] what they are FDA approved for. We know that it works very well in that patient population.

But you bring up a point that is often lost in the results of KEYNOTE-775. We use [lenvatinib/pembrolizumab] for patients who have proficient MMR [pMMR] because it did show benefit and it’s [becoming] the standard of care for the pMMR patients. We also know it works better in the dMMR group [than the pMMR group]. Although that trial was not only trying to look at pMMR—about 20% of the patients had dMMR, and they did exponentially better than the pMMR patients.

You’re absolutely correct that if you want to use both, you can. [The concern is] more about the toxicity profile. We can all agree that single-agent immunotherapy is going to have a better toxicity profile than the combination of lenvatinib and pembrolizumab. I’m also happy to hear that some physicians aren’t afraid of lenvatinib due to the toxicity profile, because I do hear a lot of that. I hope to [assuage] that because it is a great doublet agent for the right patient.

I probably wouldn’t use a platinum doublet chemotherapy in a patient who has recurred after fewer than 12 months. We don’t talk about platinum-free interval too much in uterine [or endometrial] cancer, but it is still significant. When we have an active therapy with a better adverse event profile and less bone marrow toxicity, [it suggests that] something based on immunotherapy should be the next line of therapy.

As far as repeat molecular testing, if you already [determined] dMMR status, you would [only retest if you are] looking for some other targeted therapy. Whether you [test for] that now or at another time, you should be basing your therapy at this point on some sort of immunotherapy.

Then, if the patient had a partial response to previous carboplatin/paclitaxel, they probably would have moved on to another therapy a bit sooner and you probably would have included immunotherapy.

In a patient like this, if I started on pembrolizumab and they started subtly progressing, given that they are dMMR, would you add on lenvatinib in that case?

 Great point. Yes, I do that commonly. If I start a patient on single-agent immunotherapy, and they’re having no toleration issues, and they start to progress on it, I will add lenvatinib and I have seen amazing responses. I’ve gotten complete responses off that combination when the [disease failed to respond to pembrolizumab, more than] just a slight progression. That’s an excellent point, and I definitely see the synergy when that happens in an optimal treatment regimen.

What factors influence your preferred immune checkpoint inhibitor for a patient such as this?

I have had physicians say they’ve gotten nivolumab [Opdivo] approved [by insurance], but nivolumab, durvalumab [Imfinzi], and avelumab [Bavencio] haven’t reached [FDA] approval yet for [endometrial cancer]. Dostarlimab [Jemperli] and pembrolizumab by far have the most data in uterine and endometrial cancer. I would use either one of those, and they’re equally effective.

I don’t have anything specific that influences me on either one. For me, it is the data for which the patient most fits into what I think would work. The prior trials for the single-agent therapies…the KEYNOTE-158 [NCT02628067] and GARNET [NCT02715284] trials looked at dostarlimab [and] pembrolizumab [respectively], and both had pretty equal efficacy.

 We’re not supposed to compare trials head-to-head [since they had] different patient populations, but when you look at the duration of response and rate of complete response, partial response, and stable disease, they’re all remarkably similar, even with slightly different patient populations, in the dMMR group. So for me, none of the [trial outcomes] factor into this.

The one factor would be with pembrolizumab, [the ability to use] every-6-week dosing. Some physicians have considered that, but there are less data on it currently. There are more coming out about every-6-weeks dosing in uterine cancer.

1. Makker V, Colombo N, Casado Herráez A, et al. Lenvatinib plus pembrolizumab for advanced endometrial cancer. 

. 2022;386(5):437-448. doi:10.1056/NEJMoa2108330

2. O’Malley DM, Bariani GM, Cassier PA, et al. Pembrolizumab in patients with microsatellite instability-high advanced endometrial cancer: results from the KEYNOTE-158 study. 

. 2022;40(7):752-761. doi:10.1200/JCO.21.01874

3. Oaknin A, Gilbert L, Tinker AV, et al. Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) or proficient/stable (MMRp/MSS) endometrial cancer: interim results from GARNET-a phase I, single-arm study. 

. 2022;10(1):e003777. doi:10.1136/jitc-2021-003777

During a Targeted Oncology™ Case-Based Roundtable™ event, Bradley Corr, MD, discussed the use of immune checkpoint inhibitors in patients with advanced endometrial cancer. This is the second of 2 articles based on this event. 

Factors Influencing Treatment Post-Chemo in dMMR Endometrial Cancer

Should every post-menopausal patient with signs and symptoms suggestive of endometrial cancer undergo molecular testing? ​

For which biomarkers do you test and why?​

What kind of testing do you use in practice? ​

Which biomarkers do you test for and why? When should you order testing? What kind of testing do you use in practice, and how are you applying test results?

In my practice for the very few patients I see [with endometrial cancer], I make sure they get MSI-H [microsatellite instability-high] and dMMR [mismatch repair deficiency] testing at diagnosis. At progression and recurrence, we do a next-generation sequencing [NGS] panel of common mutations.

 Is that consistent with everybody else? Is it mostly centered around dMMR or MSI-H?

: For localized disease, I would do just that. Once it’s recurrent and metastatic, then I start to send for the NGS testing.

 Is there anything else that anybody wants to test for?

 Yes, I do NGS initially when I see the patient including the 

 mutation, MSI status, and I also look for 

 mutations in these patients. The NGS includes [testing for] 

, and that also includes tumor mutational burden too.

I’m happy that no one said [they would test for expression of] PD-L1. It is sometimes misunderstood [when we are] categorizing PD-L1 and MMR or MSI as the same thing, and they’re not. Specific to endometrial cancer, PD-L1 testing has no correlative significance with response to immunotherapy.

 A lot of times we’ll get [PD-L1 testing] because when we order our FoundationOne or Caris testing [or] whichever platform you’re using for NGS, you get to check off the box if you want PD-L1 testing, but it’s important to recognize that for endometrial cancer, there is no correlation with response to that. It is solely [based] on MMR or MSI. That’s important to recognize.

. Depending on the pathology from where the patient came from, 

 [testing] is routinely being done by a lot of institutions, but not by all. I think 

 is an important biomarker at this point. There are going to be a lot more data coming out over the next couple of years, but we already have good data to show that 

 mutations, whether by NGS or immunohistochemistry, is more responsive to chemotherapy.

 These are patients who, if you’re unsure about therapy decisions, [could receive] radiation therapy or chemotherapy; chemotherapy should be a mainstay of treatment with 

 mutations. This is why it’s important to get testing at diagnosis.

The other reason [for testing at diagnosis] is because we’re centered around dMMR, and we still pick up patients who have Lynch syndrome.… It’s not uncommon that I’ll get a patient who has undiagnosed Lynch syndrome with diagnosis of endometrial cancer, and [oncologists should understand] the downfall cascade of what that entails for not only them but family members [at risk]. I also think it’s important to recognize that not all dMMR is Lynch syndrome. The most common is hypermethylation of 

 like [Dr Mushtaq] was mentioning. [There could be a] discussion about response to immunotherapy with hypermethylation. We know that they respond better than the MMR proficient patients, but they’re not quite as good as the patients with dMMR as if it was a patient with 

 mutation [associated with Lynch syndrome].

 mutations or hypermutations typically have a better prognosis.

 I would say we’re not quite at the point of completely deescalating therapy, but I would predict that in the not-too-distant future, patients with 

 mutations will instill no further therapy. But the important part that I want instill is early testing, and testing by whatever means is most efficient for you and the patients, whether that’s talking to your pathologists to do immunohistochemistry staining, or doing the NGS testing that most of you are doing.

1. Cao W, Ma X, Fischer JV, Sun C, Kong B, Zhang Q. Immunotherapy in endometrial cancer: rationale, practice and perspectives. 

. 2021;9(1):49. doi:10.1186/s40364-021-00301-z

2. Corr B, Cosgrove C, Spinosa D, Guntupalli S. Endometrial cancer: molecular classification and future treatments. 

. 2022;1(1):e000152. doi:10.1136/bmjmed-2022-000152

3. Toboni MD, Wu S, Farrell A, et al. Differential outcomes and immune checkpoint inhibitor response among endometrial cancer patients with MLH1 hypermethylation versus MLH1 “Lynch-like” mismatch repair gene mutation. 

. 2023;177:132-141. doi:10.1016/j.ygyno.2023.08.015

During a Targeted Oncology™ Case-Based Roundtable™ event, Bradley Corr, MD, discussed the importance of mismatch repair deficiency testing and the value of next-generation sequencing in patients with advanced endometrial cancer. 

Considerations for Ordering Biomarker Testing in Endometrial Cancer

In August 2021, a 64-year-old postmenopausal woman presented with abnormal uterine bleeding lasting 4 months. ​She underwent menopause at 55 years of age. She is a widow, has no children, and lives alone​. She had a medical history of arthritis, obesity (body mass index = 40), and hypertension well controlled with medication​. Her ECOG performance status was 1. She was counseled on surgical options, then scheduled for surgery.​ She had stage IA; grade 1 endometrial cancer​. Immunohistochemistry/molecular testing results showed a mismatch repair deficiency (dMMR)​ and microsatellite instability-high status (MSI-H), ​3+ estrogen receptor–positive​.

In August 2022, she reported intermittent pelvic pain over prior 4 weeks​. CT scan of the chest, abdomen, and pelvis suggested relapsed/metastatic disease with involvement of 1 right external iliac lymph node. Carboplatin/paclitaxel (6 cycles every 4 weeks) was administered, chemotherapy was well tolerated, and a complete response was recorded at the end of the regimen​.

In April 2023, disease relapse was documented on routine follow up​. CT scan of chest, abdomen, and pelvis showed heterogeneously enhancing mass in right suprarenal space, multiple bilateral pulmonary nodules, and a new right internal iliac lymph node (in addition to the previously observed positive lymph node)​. Fine-needle aspirate of the suprarenal mass confirmed metastatic endometrioid adenocarcinoma. The patient was counseled about systemic therapy options, during which she repeatedly expressed concerns about adverse events. ​

What are the systemic therapy options for a patient with dMMR/MSI-H disease?

How do you determine which next-line therapy to choose?

 Let’s talk about the systemic therapy options for patients with metastatic endometrial cancer where you have MSI-high/dMMR—chemotherapy, hormonal therapy, immune checkpoint inhibitors [ICIs], tyrosine kinase inhibitors, and anti-angiogenesis. How do you choose?

 [For] patients with MSI-H/dMMR, we have excellent data on ICIs as single agents either with pembrolizumab [Keytruda] or dostarlimab [Jemperli].

 Would anybody switch to hormonal therapy in this case, or do you always go to ICIs?

 This patient has recurrence within 12 months. This is her second recurrence since her diagnosis. For somebody with slow-growing cancer, I think I have used that in the past, but this patient has recurred quite quickly even after chemotherapy.

 Do you have any data comparing carboplatin/paclitaxel vs pembrolizumab for MSI-high endometrial cancer? Because for other solid tumors, an ICI is more effective, less toxic, and even provides survival benefit, so why would you choose carboplatin/paclitaxel first?

 That’s a great question. Let me ask, what if she had a partial response to paclitaxel/carboplatin, would that change anything? It sounds like everybody would go straight to ICIs at this point so it might not change.

 I certainly would not go back on platinum-based chemotherapy, and she may not have a second chance. As Dr Konala alluded to, it’s an aggressive recurrence so she needs the best therapy and a quicker response, too. For that reason, endocrine therapy is out and repeat carboplatin is out from my standpoint.

 [If] you had initial molecular testing, would you repeat it?

 Would you send new next-generation sequencing?

 I would repeat to make sure the blueprint for this particular recurrence is the same or different where we’re at. Because she needs the best targeted therapy with reasonable lower toxicity and highest response as much as possible.

Through shared decision making, ICI monotherapy was planned.​ The patient started on dostarlimab with instructions to continue follow up every 3 months.

How do you choose dostarlimab vs pembrolizumab?

 I don’t think there’s a right or wrong answer, both of these drugs have data. We have more experience with pembrolizumab so it is more [based on] experience…rather than preference. Either one would work well.

 I don’t have any experience with dostarlimab. I have a lot of experience with pembrolizumab [but] I didn’t choose pembrolizumab this time. I wanted to try a new agent, dostarlimab. I don’t know from comparison which one is better. It depends what you feel comfortable with.

What factors influence your ICI preference for a patient like this, such as efficacy, safety, comorbidities, logistics, and sites of metastases?

So far it sounds like familiarity has been the key. How do you choose which checkpoint inhibitor you’re going to use?

 I have never used dostarlimab in the past. I would go with pembrolizumab.

 I’d echo what everyone said. Obviously, most of us have a lot of familiarity with pembrolizumab. If that patient came across my clinic, I’d be interested to use dostarlimab. I think there was overall survival benefit demonstrated with dostarlimab [but not with] pembrolizumab.

 It may just be trial characteristics, but I think there’s enough there maybe to make me want to try it.

 Does anybody see any differences in efficacy, safety, tolerability, comorbidities?

During a Targeted Oncology™ Case-Based Roundtable™ event, Jubilee Brown, MD, discussed the treatment options for a patient with endometrial cancer who relapsed following resection and again following a complete response to chemotherapy. This is the first of 2 articles based on this event. 