Brian M. Slomovitz, MD

 The future is bright for the treatment of endometrial cancer. We’re going to move toward biomarker-driven therapies for all patients. What do I mean by that? We’re going to be doing studies in newly diagnosed patients, eliminating chemotherapy and giving immunotherapies—or hormonal therapies, for that matter—based on biomarker-driven profile. In a world of immunotherapies, we’ve done a great job with lenvatinib in combination with pembrolizumab, but there are other ongoing studies looking at newer combinations of biomarker-driven therapies with immunotherapy to better the response rates and cure this disease.

One trial being done is a collaboration between the Alliance Foundation and Genentech, which is looking at immunotherapy atezolizumab in combination with a biomarker-driven therapy based on the biological makeup of the tumor. Hormonal therapy for ER [estrogen receptor]–positive cancers is going to continue to progress with research. We have tamoxifen, aromatase inhibitors, and Progestin, but there’s a new class of drugs called SERDs [selective ER degraders], which will be looked at to better manage this disease with hormonal manipulation. Biomarker-driven therapies—for example, CDK4/6 inhibitors and others—are going to continue to evolve and work to eradicate the deaths from this disease, but [they will also] help women get treated without chemotherapy, which has its own set of adverse effects.

As far as where we are now with endometrial cancer and how I treat my patients, I encourage testing for mismatch repair [MMR] proteins at the time of diagnosis. We’re using immunohistochemical screening, which tests for MLH1, MSH2, MSH6, and PMS2 to determine if there’s a loss of expression. If there’s a loss of expression, these tumors are deemed deficient in MMR proteins and are more amenable to single-agent immunotherapy in treatment. In initial diagnosis, we’re also doing estrogen and progesterone receptor testing to determine if hormonal therapy would eventually work or if we need it for treatment.

By doing this type of screening, we can better identify which treatments work best for individual patients. Carboplatin and paclitaxel work well for some patients, but we can do better. The way we’re going to do better is by taking advantage of the science that we have and to incorporate new treatment strategies. This will be based on matching the findings from that science with the patient’s individual tumor. It’s the ultimate in personalized medicine.

Videos

Reflections on the future management of endometrial cancer and practical advice for practicing oncologists. 

Looking Toward the Future of Endometrial Cancer Management

 The landscape for endometrial cancer is very exciting. We have 5 first-line global trials evaluating immunotherapy pushed into the first line. Four of these trials are looking at chemotherapy plus or minus immunotherapy, and the fifth is looking at lenvatinib-pembrolizumab vs chemotherapy carboplatin-paclitaxel in the first-line setting. There’s no doubt that if any trials are positive, the treatment paradigm will change and will move I/O [immuno-oncology] to the first-line setting.

There are also great areas of research being done in the second line to determine better treatment options for those patients, which represents a complete unmet need. The first thing we’re looking at is immunotherapy after immunotherapy. Meaning that in patients who fail immunotherapy, is there a role for additional immunotherapy? Another area has been biomarker-driven research. PTEN or PI3-kinase pathway mutations are very common in endometrial cancer.

Looking at the biomarker inhibitors that work in this disease, we found that mTOR inhibitors have good efficacy compared with traditional hormonal therapies. A study I did, GOG-3007, compared everolimus and letrozole vs Megace and tamoxifen. In this study, although we had comparable response rates, the progression-free survival with the combination of everolimus and letrozole, an mTOR and an aromatase inhibitor, was improved compared with Megace and tamoxifen. In addition, in the subset analysis, we looked at patients who are naïve to chemotherapy. In those patients, we had similar response rates to chemotherapy alone and longer progression-free survival in a cross-trial comparison, 21 months vs 14 months. At 1 recent meeting, there were data presented for a newer mTOR inhibitor with hormonal therapy, and it continued to demonstrate the benefit of this combination.

In addition, CDK4/6 inhibitors are being investigated in combination with hormonal therapy for the treatment of this disease. My close colleague in Denmark, Dr Mansoor [Raza] Mirza, presented a paleo study looking at the combination of CDK4/6 inhibitor plus letrozole vs letrozole alone. In this trial, he found a significant improvement in progression-free survival in the CDK4/6 plus letrozole vs letrozole. Finally, in another subset, uterine serous cancers, we’re looking at WI-1 inhibitors. Based on some great work at Dana-Farber [Cancer Institute], they demonstrated activity in this subset of endometrial cancers. There are more ongoing trials being done to evaluate this pathway in pretreatment of uterine serous cancers.

Brian Slomovitz, MD, MS, FACOG, shares excitement for novel and combination therapies being investigated in the endometrial cancer landscape. 

Novel Strategies Being Investigated in Endometrial Cancer

 Pembrolizumab and lenvatinib changed the world. Their implementation into the treatment of endometrial cancer was game changing. FDA indications allow pembrolizumab and lenvatinib for patients who fail prior systemic therapy. It doesn’t require a full regimen of chemotherapy. It doesn’t even require chemotherapy. Patients can fail hormonal therapy. But it’s a second-line trial, so those patients can be included.

One issue with pembrolizumab and lenvatinib has been toxicities, leading to dose delay and dose discontinuation. The normal starting dosage of lenvatinib is 20 mg daily. We’ve found that several of those patients have required dose reductions in order to get an acceptable dose in. The starting dose is 20 mg. Some patients would likely benefit from starting at a lower dose. We’re performing studies to determine if that would yield the same efficacy as starting as 20 mg. As we know, some patients do well with a lower dose. If we started at a lower dose, we wouldn’t be sure we’re getting an adequate dose in to those patients who wouldn’t normally require a dose reduction. As far as discontinuations go, it does happen with this drug. We’re looking for mitigation strategies to limit that from happening.

The No. 1 adverse effect of pembrolizumab and lenvatinib that I’ve seen is hypertension. Lenvatinib can cause an elevation of blood pressure. When I prescribe pembrolizumab-lenvatinib, I look to manage the high blood pressure, or manage the blood pressure. In patients who are on antihypertensives, I encourage them to reach out to their primary care provider or the cardiologist who’s prescribing those drugs. This is to prepare them for lenvatinib, which may increase their blood pressure. For those who aren’t on antihypertensives, we monitor their levels closely and ensure that if they do develop a hypertension, we start them on an antihypertensive that will help manage symptoms.

Another common adverse effect we see is diarrhea. It’s sometimes difficult to determine which of the 2 drugs, pembrolizumab or lenvatinib, causes diarrhea. In my patients who developed diarrhea while on this regimen, my strategy has been to hold the lenvatinib to see if the diarrhea resolves. If the diarrhea stops, it’s most likely from lenvatinib. If it doesn’t resolve, then it’s most likely from pembrolizumab. Then we implement different strategies to limit the diarrhea based on the drug that caused it.

Practical perspectives on the optimal use of combination lenvatinib-pembrolizumab in endometrial cancer. 

Lenvatinib + Pembrolizumab in Endometrial Cancer: Practical Considerations

 Some of the biomarker-driven therapies, or even immunotherapies, for endometrial cancer are tyrosine kinase inhibitors, immunotherapy options, or checkpoint inhibitors. Tyrosine kinase inhibitors go after specific proteins that are overexpressed or have driven the pathogenesis within a cell. I refer to it almost as a weed killer, or a poison to the entire tumor, while tyrosine kinase inhibitors or other biomarker-driven therapies are like putting a stick in the spoke of the wheel. They’re not as damaging to the cells, but they go after a specific pathway.

In tumors that overexpress dysregulated proteins often found on the surface of the cell, tyrosine kinase inhibitors help limit their growth and proliferation. Immunotherapies work by stimulating the body’s immune system to recognize, kill, or stop proliferation of cancer cells. For example, a subset of endometrial cancers have microsatellite instability [MSI], or something called deficient mismatch repair [MMR] proteins. In those patients, those are recognized by the body as nonself, or something that shouldn’t be there. Adding a checkpoint inhibitor stimulates the body’s immune system to get rid of those cells.

When we talk about immunotherapy in endometrial cancer, the initial studies looked at treating women who had microsatellite instability with single-agent pembrolizumab, which was very effective. Also, the original studies looked at women who were biomarker negative, who did not have deficient mismatch repair, or MSI. Single-agent pembrolizumab did not work as well. KEYNOTE-146 was a combination study of pembrolizumab and lenvatinib in those women with biomarker negative, meaning microsatellite stable, or proficient MMR. In that study, there was good activity of this combination, even in those tumors that weren’t originally amenable to immunotherapy. By adding lenvatinib to the pembrolizumab, we got an acceptable response rate, which led to an accelerated FDA approval to use immunotherapy in combination with tyrosine kinase inhibitors [in biomarker-negative endometrial cancers].

After the initial accelerated approval, the confirmatory study for the combination of pembrolizumab and lenvatinib was KEYNOTE-775. In this second-line trial, the investigators, led by Vicky Makker at [Memorial] Sloan Kettering [Cancer Center], evaluated the pembrolizumab-lenvatinib combination vs chemotherapy. The 2 options were the 2 best options in second-line setting: doxorubicin or weekly paclitaxel. They found significant improvement in both progression-free survival and overall survival in women treated with pembrolizumab-lenvatinib and not chemotherapy.

This study included both dMMR [deficient MMR] and pMMR [proficient MMR], or both biomarker-positive and negative patients. Subset analyses of these data had been done. One subset analysis looked primarily at the dMMR patients, which also showed a benefit of the combination of pembrolizumab-lenvatinib when compared with the chemotherapy. One obvious question is do those patients need lenvatinib, or would pembrolizumab alone be enough? Another subgroup analysis looked at different histological subtypes, and it was interesting to find that pembrolizumab-lenvatinib worked across histological subtypes. Initially, we thought that endometrial cancer should be split and not clumped and treated by their histological subtype. However, in this subanalysis we found that all comers, not just in a particular histology, responded.

Insight on the combination of lenvatinib and pembrolizumab in endometrial cancer, investigated between the KEYNOTE-146 and KEYNOTE-775 trials.

Combination of I/O and TKI Therapy in Endometrial Cancer

 When we talk about endometrial cancers that relapse, it’s important to note that there are different subsets, or different types of endometrial cancer. The relapse rate is based on the histological subtype. Women who have endometroid fall under the type 1 endometrial cancers, which are those that are hormonally driven. Their chance of treatment alone with a hysterectomy is 80% to 90%. Occasionally, we give adjuvant therapy, or immediate therapy after surgery, which may include radiation or chemotherapy. In total, 10% to 15% may recur from their disease and may require more systemic therapy. The more aggressive histological subtypes are primarily uterine serous cancers, carcinosarcomas, and clear-cell carcinomas. They make up a minority, about 10% of endometrial disease, but count for 50% to 60% of recurrences due to this disease. It’s much more common for those patients to require systemic therapy. It’s also important to note that the rates of endometrial cancer are rising in this country, and a lot of that is because environmental factors like obesity. Obesity drives the pathogenesis of endometrial cancer.

When we’re treating a patient with endometrial cancer over her lifetime, there are a lot of good treatment options. The first is often chemotherapy. It may take 6 months to a year for patients to have a good response and a long disease-free interval after completion of chemotherapy. If they do unfortunately recur, then 1 good treatment option would be to re-treat them with chemotherapy. If they have a disease-free interval of 6 to 12 months, treating with chemotherapy is a reasonable option if they recur again. Another option would be to continue the change to hormonal therapy, a biomarker-driven therapy, or immunotherapy, and then go back to chemotherapy at a later time.

Brian Slomovitz, MD, MS, FACOG, provides a brief review of endometrial cancer relapse and corresponding therapeutic approaches. 

Treating a Patient at Endometrial Cancer Relapse

 Endometrial cancer is the most common gynecologic malignancy. Fortunately, most women who are diagnosed with endometrial cancer are treated with surgery alone. Sometimes, there may be a hysterectomy, radiation, orchemotherapy. There’s a subset of women who recur with widespread metastases or who present with metastases at the time of diagnosis. There are several treatment options for these patients, and we’re getting better and more advanced at the options that we offer.

The first option is chemotherapy. The standard of care is carboplatin and paclitaxel for metastatic endometrial cancer. Other options include hormonal therapies. Similar to breast cancer, endometrial cancers have estrogen and progesterone receptor positivity and are amenable. It’s a good disease to be treated with hormonal manipulation. The standard of care is Megace, or progestin, and occasionally we give it with alternating demoxepam. In addition, immunotherapy has recently been in the spotlight for treating women with endometrial cancer.

Although it’s not in the first line yet, we’re treating women who have microsatellite instability, which is a biomarker-driven therapy with single-agent checkpoint inhibitors. Two of them have FDA indications, pembrolizumab and dostarlimab. In patients who don’t have microsatellite instability, we’re using pembrolizumab in combination with a tyrosine kinase inhibitor, lenvatinib. Finally, we’re also doing biomarker-driven therapies for women with systemic disease. The 2 that I would say have been best evaluated are looking at mTOR inhibitors in combination with aromatase inhibitors. That’s 1 of my areas of research. In addition, there are sufficient data looking at CDK4/6 inhibitors with letrozole for women with systemic disease presented at the European meeting last year. The bottom line is that there are a lot of options. It’s always good to have a lot of options, and we’re working to hopefully eradicate death from this horrible disease.

When we’re deciding which treatments to offer our patients with endometrial cancer, there are a lot of factors that we take into consideration. Obviously, age is important. Are they living by themselves? Are they doing daily activities if they’re living on their own? Are they bedridden most of the time? In addition, we look at sites of recurrence for where the disease is. We look at how long it took from their initial diagnosis for them to recur. In addition, we look at pathological factors: type of histology, lymph node involvement, or grade of the tumor. Finally, we’re dividing into 1 of 4 molecular subtypes. This is based on if it’s what we call hot or amenable to immunotherapy, or a cold tumor that’s not amenable to chemotherapy. We’re determining that based on next-generation high-throughput sequencing.

Expert perspectives on the endometrial cancer treatment landscape in light of approved therapies and drug classes.

Brian M. Slomovitz, MD | Authors

Articles

Looking Toward the Future of Endometrial Cancer Management

Novel Strategies Being Investigated in Endometrial Cancer

Lenvatinib + Pembrolizumab in Endometrial Cancer: Practical Considerations

Combination of I/O and TKI Therapy in Endometrial Cancer

Treating a Patient at Endometrial Cancer Relapse

An Overview of Endometrial Cancer and Treatment Options