Robert L. Coleman, MD, FACOG, FACS

 The relationship of the molecular biology of endometrial cancer and the opportunities based on available compounds, which continues to grow every day, is very optimistic and exciting. We have several trials that are focused largely on the combination or addition of immune checkpoint inhibitors to a mostly chemotherapy backbone for patients who have either recurrent or primarily metastatic disease.

One of these trials, LEAP-001, is trying to take on combination paclitaxel-carboplatin in that line of therapy for patients with advanced-stage or first recurrent endometrial cancer. Pembrolizumab and lenvatinib are being compared with paclitaxel and carboplatin. In the patients with deficient MMR [mismatch repair], we’re looking at single-agent pembrolizumab against chemotherapy as well. We’re using or leveraging the biology to move the field along.

One of the other new and exciting targets in endometrial cancer has been to address the frequent 

 mutation that we see in our copy number high or uterine serous type tumors. We’re focused on looking at compounds that can address that genetic finding. The SIENDO trial is looking at a nuclear export inhibitor to assess whether we can add to chemotherapy as a maintenance strategy for this cohort of patients. We’re excited to see this alternative to the immune checkpoint space.

There are a number of exciting targets in endometrial cancer. It’s been one of the most explosive new areas of evaluation in gynecology because of the frequency of alterations, particularly in the PI3 kinase and MAP kinase signaling pathways, as well as the integrin pathways, that has now opened up a large number of new trials and concepts to try to provide new therapies for our patients with this disease.

A question I get frequently is whether the PARP drug class works in endometrial cancer. It’s a good question. Many of you who treat gynecological cancers know that PARP inhibitors have basically revolutionized our approach to ovarian cancer, with the drugs now approved in recurrent treatment, recurrent maintenance after platinum, and in the front line as maintenance treatment after index therapy. It’s completely painted across the landscape of ovarian cancer.

Because of the similarities that we’re seeing with copy number high endometrial cancer, the question was raised on whether this would apply as a potential treatment alternative in women with endometrial cancer. There has been interest in looking at this, and certainly in TCGA [The Cancer Genome Atlas program] data, we know that these tumors are found, although infrequently, with mutations in many of the genes that govern homologous recombination, including 

. We’ve seen these cases appear in our endometrial cancer landscape, so it makes sense to consider it. The relationships directly between these mutations, which are overall infrequent, and the loss of heterozygosity, which we also use in ovarian cancer, isn’t so cleanly differentiated. Nevertheless, we have seen several trials that are evaluating the role of PARP inhibitors either alone or in combination in patients with recurrent metastatic disease across multiple different histologies.

We’ve seen some signal of activity, and there’s at least 1 trial trying to combine the PARP inhibitor with immune checkpoint inhibitors as a maintenance strategy for patients who have responded to chemotherapy. This is part of an ongoing clinical trial. We’re excited to see this potential opportunity to evaluate another class of drug in patients with this particular disease, and hopefully we’ll rewrite the treatment landscape for our patients.

Case:  A 64-Year-Old Woman With Endometrial Cancer

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Future opportunities being explored in clinical trials that show promise in treating advanced endometrial cancer.

Advanced Endometrial Carcinoma: Treatment Pipeline

 Prognosis is something that’s regularly updated. When we started this case, this patient was diagnosed as having a grade 2, stage IB endometrioid microsatellite-stable endometrial cancer. She had surgery and evidence of no metastatic disease by the assessment and was treated with vaginal cuff brachytherapy. Our estimation of her prognosis at that stage was quite good. We would have expected that her potential for recurrence was probably on the order of 20% or 25%, and unfortunately, she fell into that category. Her prognosis then would be reevaluated at the first recurrence. At that point, she had relatively limited disease, but it was definitely present.

At first recurrence, the prognosis drops. We know that depending on the disease volume, if those patients aren’t candidates for surgery, then we’re essentially looking at chemotherapy. And while we have high relative response rates in that setting, the long-term cures reduce by as much as 50%. Her prognosis has definitely decreased because she recurred. She did respond to treatment, but then she recurred again. In that situation, she has a much worse prognosis than we started with, because she’s now recurred twice and demonstrated the biology of this disease.

Fortunately, she’s getting a good treatment that’s associated with a progression-free survival of about 7 months, which is good on the median. Her overall survival would be around a year and a half, which is better than with the alternatives. But long-term outcomes are still going to be under 50% with respect to survivorship, meaning over 2 years. Prognosis is a moving target in this situation. You can see how prognosis was affected by the previous histories that preceded when we make that estimation of prognosis.

What patients can expect in terms of prognosis when receiving systemic therapy for advanced endometrial cancer.

Advanced Endometrial Carcinoma: Systemic Therapy & Patient Prognosis

 Adverse events are very important to consider when choosing a regimen. Every counseling session that I go through with a patient, when we’re going to start a new therapy or are already on therapy, we review those adverse events so that they’re clear and known to the patient for their expectations. One of the most important reasons to do this, other than to provide a thorough counseling for the patient, is that it allows us to navigate through events that might discontinue treatment. As you could imagine, patients who are off therapy aren’t likely to benefit. We try to provide the expectation for these so that it can be navigated in an effort to keep patients on treatment.

Most of us are very familiar with chemotherapy. Paclitaxel-carboplatin as a chemotherapy regimen is a day in and day out therapy, and the others that we’ve used, like doxorubicin, have been around for decades. Our experience with those drugs with respect to the hematologic and nonhematologic toxicities are very front of mind. For clinicians who haven’t treated a lot of patients with endometrial cancer with combination chemotherapy, there are some additional considerations. In general, these patients are older and more frail. They may also have comorbidities, which may make the routine administration of these drugs more challenging. Those need to be taken into consideration.

Also, many of our patients with endometrial cancer have pelvic radiation. This patient received cuff radiation, which doesn’t impact the marrow much. However, pelvic radiation, and pelvic radiation with paraaortic radiation, can provide a very large barrier to the administration of intended doses and the tolerance of chemotherapy over time. This is one of those areas where breaks, dose reductions, and modifications may be necessary with chemotherapy.

With respect to the other options, lenvatinib and pembrolizumab both have a long track record within the clinical community. Pembrolizumab is approved in a number of different tumors and generally has a very predictable adverse effect profile. When combined with lenvatinib, especially at the doses that we use—20 mg of lenvatinib and 200 mg of pembrolizumab—we see some toxicities that are factors that wouldn’t be in our normal evaluation of women who are on endometrial cancer recurrence therapies because we don’t use a lot of bevacizumab here.

Lenvatinib can cause hypertension, which can be difficult treat at times. It’s something that we can identify early and is one of the factors that we’d want to educate the patient on and intervene early so that we can maintain the combination. This is an adverse effect that needs attention. And although it’s not uncommon to do a dose reduction in the presence of this, if we have trouble getting control, fortunately the frequency of patients discontinuing therapy for hypertension is relatively modest. Our strategies for dose interruption and dose reduction have been effective in maintaining persistence of this.

The combination of the 2 drugs leads to a higher rate of overall toxicities, but fortunately we didn’t necessarily see an overlap. But the 2 drugs given at their recommended doses definitely have these particular features, and we see general effects that we see with therapy, like fatigue, nausea, vomiting, and diarrhea, and also immune adverse effects, such as hyperthyroidism, stomatitis, and rash. These types of features aren’t uncommonly seen with the drug and were seen in the regimens as a combination as well.

Recommendations on how to best prepare patients for chemotherapy, lenvatinib plus pembrolizumab, and other therapies used to treat advanced endometrial cancer.

Treating Advanced Endometrial Carcinoma: Counseling on Safety Profiles

 This patient fell into the typical algorithm. She was treated with adjuvant radiation for her high risk for local recurrence. She had a distant recurrence. She was treated with combination chemotherapy, paclitaxel and carboplatin, and then recurred again after a relatively short time. She was given lenvatinib and pembrolizumab, which aligns very well with the treatment algorithm for patients who have microsatellite-stable tumors. This would have been right along the lines of what we would have hoped for. Fortunately, because of the accelerated approval mechanism, we had access to this drug well before its regular approval in July. But this patient did fall in line with the treatment algorithm that we would have ordinarily undertaken with the availability of that combination.

Most of us who take care of gynecologic patients are pretty familiar with what platinum-free interval is. Most of this has been focused in ovarian cancer, where we use this as a way to discriminate these large terms, such as platinum-sensitive, platinum-resistant, and platinum-refractory, as descriptions of patient cohorts. The same isn’t as clear in endometrial cancer. We have noticed that patients who have a “longer” platinum-free interval may have a higher likelihood to respond, but there’s no guarantee that that’s the case.

The performance of platinum in endometrioid and the other histologies of endometrial cancer can be quite variable. Based on the fact that if we know the genetic landscape of endometrial cancer can be all over the place with respect to copy number high and copy number low type tumors, those that carry microsatellite stability or 

 mutation, and those that have a serous or clear-cell phenotype, you can imagine that the linkage between time off of platinum and re-response to platinum might not be as crisp as we see with ovarian cancer.

Having said all that, we generally follow similar guidelines. If a patient has responded to previous platinum and has been away from platinum for a period—usually 6 months; not because there’s something magical about 6 months, but that generally aligns with at least 1 assessment after completion of therapy where there was no increase in disease or recurrence—it tells us that the response that was seen in the face of the previous chemotherapy has at least been durable for that period. It’s nothing magical, and we don’t have the precision from our testing algorithms to be able to determine who’s platinum-sensitive or platinum-resistant, but we’ve used those clinical parameters to at least consider the reintroduction of therapy.

For patients who have progressed within that timeframe, based on what I just mentioned, those patients either didn’t have a durable response or had progression of disease in a very short time after completing chemotherapy, which means that it was probably growing while they were on therapy. In that situation, many of my colleagues and I would choose something alternative, like we saw in the KEYNOTE-775 trial, those particular other alternatives for management.

If this patient had had an MSI [microsatellite instability]-high or deficient MMR [mismatch repair] tumor at the very beginning, we would have noted that. I don’t think it would have changed our treatment today, but this patient would have fallen into a category of a high-intermediate risk type of situation. There are trials being developed right now that are looking at the potential to provide lasting treatment effect or even cure with the use of immune checkpoint inhibitors as an adjuvant for patients who are getting treatment for this high or intermediate risk state. That’s moving this concept of immune-based therapy all the way into the adjuvant setting. That’s not available right now outside of the clinical research environment.

However, if you think about the activity of single-agent pembrolizumab in patients who have microsatellite-high tumors or are deficient in MMR, it’s sufficiently high enough to challenge chemotherapy. This drug does have FDA approval for use in this particular setting. And so while we haven’t been able to clearly document that we can replace combination chemotherapy in that first-line setting, it’s the focus of ongoing research. But in the patients who have gone through chemotherapy and are no longer candidates for curative intervention, pembrolizumab and dostarlimab are the immune checkpoint inhibitors that are approved for use as a single agent for treatment, which would be balanced against chemotherapy. We’re excited that we have these options for those patients. That’s why it’s important that we document the status of that tumor so that we can potentially leverage these exciting new therapies.

Variables that impact choice of therapy for patients with advanced endometrial cancer.

Advanced Endometrial Carcinoma Treatment Selection

 While this patient had a lot of very favorable prognostic features and we hoped she would have been cured with her surgery and adjuvant local brachytherapy, she had a recurrence in a relatively short period, just 14 months after completing her therapy. In this particular situation, we have a number of options. Most of the time, the presence of metastatic disease wants us to pursue the use of chemotherapy because it’s systemically administered, and we have studied chemotherapy in this disease for decades. Paclitaxel-carboplatin is where we are right now as a backbone.

There are cases in which we might consider some alternatives, though. I’ve seen several patients like this case who present with ER [estrogen receptor]-positive, progesterone receptor-positive endometrial cancer who have low-grade tumors and may be a candidate for hormonal therapy. We’ve studied hormonal therapy mostly in the metastatic recurrent setting, but we have data for the use of hormones for endocrine-based therapy, or endocrine-based therapy with other targeted therapy, such as a PI3 kinase pathway inhibitor or mTOR inhibitors, where we might be able to offer an alternative for patients who may be at high risk of chemotherapy complications or who decline chemotherapy. But in general, chemotherapy, paclitaxel-carboplatin, is the backbone by which we have based most of our treatment algorithm pathways for patients with metastatic recurrent disease.

The treatment options for patients who have MSI [microsatellite instability]-high tumors or deficient MMR [mismatch repair] has worked an algorithm through that has demonstrated that pembrolizumab as a single agent has activity. This led to an accelerated approval for that compound 4 years ago.

As we’ve looked at the treatment landscape for patients who have tumors that are microsatellite-instable or deficient MMR, the use of immunotherapy, such as pembrolizumab and dostarlimab, have demonstrated their efficacy as single agents in that setting. But for the vast majority of the patients who have proficient MMR tumors, or who are microsatellite-stable, we have focused on the use of chemotherapy. However, there’s been interest in patients who have previously progressed on chemotherapy for the combination of 2 drugs, one of which I just mentioned and a second drug, a multitargeted tyrosine kinase inhibitor called lenvatinib, which has single-agent activity in patients who have recurrent endometrial cancer.

We were very excited to see those very early preliminary data in patients who have proficient tumors, given the response of this particular combination. The first study to demonstrate that efficacy was KEYNOTE-146, which looked at the combination of lenvatinib and pembrolizumab in women who had recurrent and measurable endometrial cancer. What was exciting about this particular trial is that we had seen a response rate of about 40% in this population. This wasn’t broken down specifically by limiting eligibility to whether you’re MSI-high or PD-L1 status, but we saw activity across the spectrum. But what was most notable and interesting for most of us was that we saw activity in patients who had microsatellite-stable tumors. That response rate was very encouraging and was the foundation for the conduct of KEYNOTE-775.

Based on the KEYNOTE-146 data, it became important to assess how active it is. We knew it was active, but how active was it relative to what would be considered standard of care chemotherapy? KEYNOTE-775 was conducted to directly address that question. It was a large trial that was made up of both proficient and deficient MMR tumors. These patients were given the combination with respect to what was considered physician choice chemotherapy in this setting. The 2 active agents in this setting would have been paclitaxel or doxorubicin, and both were allowed as physician choice alternatives for the standard of care arm.

This trial was randomized 1:1 and basically confirmed what we had already seen and our suspicions that this was an active regimen. This particular trial was very well done, well conducted, and very thoughtful with respect to its end points. It demonstrated efficacy from the point of view of progression-free survival, essentially almost doubling it, with hazard ratios of 0.55 to 0.6 across the different subgroups that were evaluated. But for the all-comer population—anybody walking in the door who essentially met the eligibility criteria—there was a profound effect, with a hazard ratio of 0.56. This also amounted to an improvement in overall survival with almost the same hazard ratio of 0.62. These 2 factors landed this particular initial accelerated approval into a regular approval, which was granted on July 21, 2021. We’re very excited to have this combination available for our patients, but it begs the question, how far can we take it?

The rationale for using systemic therapy to treat patients with advanced endometrial cancer.

Systemic Therapy for Advanced Endometrial Carcinoma

 The risk factors for endometrial cancer aren’t completely elucidated. One of the features that we recognized early was a connection between an estrogenic environment and the development of growth inside the uterus, ultimately turning into cancer. We noticed this because postmenopausal hormonal replacement was being utilized without a compensatory balance of progestin—this was unopposed estrogen therapy—and this was associated with an increase in the incidence of endometrial cancer back in the mid-1970s.

We knew that there was a connection between this tissue on the inside of the uterus that’s normally responsive to hormones and was part of the menstrual cycle, and the development of the genetic mistakes that could lead to cancer. But the exact mechanism for how and why it happens in patients who don’t have these characteristics is still unknown. We know that if you look at the disease from a molecular standpoint, there are a number of abnormalities. One of the more interesting and critical ones now that we have drugs available is the representation of the tumor cell to have this inability to fix these small mismatches in the DNA. This mismatch repair process is critical for normal cell survival, and when it’s mutated, altered, or disabled in any form, that leads to a higher probability for cancer development.

We know that endometrial cancer is one of the index cancers associated with Lynch syndrome, which is also associated with colon cancer and others. Early on, we learned that endometrial cancer can run in families associated with this syndrome. And now we know that this syndrome is associated with the imperfect productivity of the mismatch repair proteins and genes that regulate the expression of those proteins. Mismatch repair deficiency is a very important part of the evaluation of patients with endometrial cancer.

In this case, this patient had molecular testing, which isn’t clear in terms of exactly what was done. But what’s most frequently done is looking at the expression of the proteins in the tissue that are oftentimes associated with mismatch repair. Those are MLH1, MSH2, MSH6, and PMS2. This is now part of a routine evaluation of endometrial cancers, in particular endometrioid endometrial cancers, to evaluate for the potential of up to 30% of our endometrial cancers that might have an abnormality.

This is important because about 6% of patients with endometrial cancer who have this will have a germline mutation, which would be important to rule out. As I mentioned, this could be associated with Lynch syndrome. We test for that if we find the absence of these proteins by checking for promoter methylation of MLH1, and if we rule that out, then this would be a case that would at least need further evaluation for a germline mutation that would associate with Lynch syndrome. But the vast majority of these patients just have an alteration in these proteins, and they can also be assessed by the microsatellite loci by a number of tests.

With this patient, we described both tests. We usually do one or the other unless there’s concern that we’re missing the small fraction of patients who might have a positive hit on one vs the other. The last thing I’ll mention is that this patient had HER2 testing. We look for amplification. We see this in mostly our nonendometrioid tumors, particularly the serous subtype. But this patient had a shotgun approach of all these molecular tests, which may not have been done routinely for a grade 1, or in this case a grade 2 locally contained endometrioid endometrial cancer.

A discussion on risk factors associated with endometrial cancer and the role of molecular testing to help evaluate for mismatch repair abnormality.

Robert L. Coleman, MD, FACOG, FACS | Authors

Articles

Advanced Endometrial Carcinoma: Treatment Pipeline

Advanced Endometrial Carcinoma: Systemic Therapy & Patient Prognosis

Treating Advanced Endometrial Carcinoma: Counseling on Safety Profiles

Advanced Endometrial Carcinoma Treatment Selection

Systemic Therapy for Advanced Endometrial Carcinoma

Mismatch Repair Defects and Endometrial Carcinoma