Level 1 Evidence Needed to Drive Optimal Sequencing Strategies in Endometrial Cancer

Brian M. Slomovitz, MD

Research efforts regarding optimal sequencing in endometrial cancer are needed as the armamentarium continues to expand, explained Brian M. Slomovitz, MD.

"We haven't focused on the role of sequencing in endometrial cancer much at all," explained Slomovitz. "In ovarian cancer, we are beginning to learn the optimal order of treatment. However, there are more treatment modalities available in endometrial cancer compared with ovarian cancer."

Although hysterectomy remains the standard frontline option, systemic therapy, targeted therapy, and hormonal therapies offer alternative options for patients who are not candidates for surgery.

Additionally, immunotherapy has become a key component of the paradigm. In May 2017, the FDA granted an accelerated approval to pembrolizumab (Keytruda) for the treatment of patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed after prior treatment and who have no suitable alternative treatment options.

Moreover, the combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima) received an accelerated approval from the FDA in September 2019 for the treatment of patients with advanced endometrial cancer that is not MSI-H or dMMR, and who have disease progression following prior systemic therapy but are ineligible for curative surgery or radiation.

In an interview with OncLive, Slomovitz, professor and chief of the Division of Gynecologic Oncology at Sylvester Comprehensive Cancer Center, University of Miami Health System, explained the need to determine optimal sequencing strategies in endometrial cancer.

OncLive: Could you shed light on the current treatment paradigm in endometrial cancer?

Slomovitz: Traditionally, we have used radiation, chemotherapy, or hormonal therapy. More recently, we have started to incorporate immunotherapy and other biologic therapies in the treatment of patients with endometrial cancer.

However, we don't know the right way to incorporate those treatments [into the paradigm]. We have to use the evidence we have to make some assumptions because we don't have head-to head clinical trials with different sequencing strategies.

Particularly for practicing clinicians, when given the choice of sometimes 5 different options, we need to start focusing on the right treatment to give up front to derive the best outcome in the first-line setting and improve outcomes in subsequent settings.

What sequencing strategies are currently being utilized?

Traditionally, the [standards of care] have always been chemotherapy and radiation therapy for patients with advanced or recurrent disease.

Recently, the results of the GOG-258 trial demonstrated that radiation therapy with chemotherapy does not [significantly improve] survival. Holding off on radiation therapy until salvage therapy is needed is one potentially effective option.

More recently, we learned that immunotherapies are active in endometrial cancer, depending on the patient's genetic makeup and the classification of the tumor. For example, pembrolizumab is approved for patients with MSI-H endometrial cancer. For patients who do not have MSI-H disease, the combination of pembrolizumab and lenvatinib [is approved].

We know those agents work in the second-line setting, but we need to think about whether we can get better results by giving immunotherapy earlier and following it up with chemotherapy.

Could you discuss the role of somatic testing in endometrial cancer? Should all patients undergo testing?

The data from The Cancer Genome Atlas project defined 4 subgroups of endometrial cancer. We are now learning that different outcomes and different treatment options are associated with those subgroups.

Patients who have a more mutated disease profile are more amenable and more likely to respond to immunotherapy.

Furthermore, regarding biologic therapies, I conducted a study looking at mTOR inhibitors in combination with hormonal therapy in endometrial cancer. Particularly in patients who were chemotherapy-naïve, we saw a very high response rate and a longer progression-free survival (PFS) [with that combination]. Perhaps we should be giving patients biologic therapies to take advantage of the high response rate and prolonged PFS and save chemotherapy for later on in a patient's disease course.

What is the role of surgery and radiation in this space?

In ovarian cancer, we are doing more neoadjuvant treatment, but that has not come into play as much in endometrial cancer. Traditionally, performing a hysterectomy to evaluate the extent of disease has been the first step in the management of patients with endometrial cancer. However, there are some patients who are not candidates for surgery or whose disease has spread too far prior to surgery that we need to start with a different approach.

While we traditionally do surgery first, we should explore whether we should give chemotherapy or another option as first-line systemic therapy.

What are the main factors that impact treatment decisions?

We have to look at the toxicity profiles of the different agents that we are proposing to give. Obviously, chemotherapy [has a lot] of toxicities associated with it, so moving away from chemotherapy would benefit patients.

Especially now, given the era of the novel coronavirus 2019 (COVID-19) and social distancing, we are looking to do whatever we can to keep patients out of the hospital. For example, oral therapies, including hormonal therapies, are very exciting. We need to consider that an otherwise healthy, elderly woman [is at an increased risk for COVID-19], and we should try to keep her out of the hospital.

Could you shed light on ongoing research efforts in this space that could have an impact on current sequencing strategies?

It is important that we use the current data we have to plan our future trials to look at how we can determine which sequencing strategy works best. Much of what we are doing currently is based on hypotheticals.

The LEAP-001 trial (ENGOT-en9/MK-7902-001; NCT03884101) is looking at the combination of pembrolizumab and lenvatinib versus chemotherapy as first-line treatment in endometrial cancer. That will be a telling, and perhaps a game-changing trial. We need to continue with the clinical trials we are doing. Whether we are in an academic- or community-based settings, it is important to participate in clinical trials as best as we can. Then we can use those data to determine the optimal treatment decisions for our patients.

The other option is combination therapy. We are running 2 trials. One is called the RUBY trial (NCT03981796) looking at the combination of chemotherapy with or without a checkpoint inhibitor dostarlimab (TSR-042). The other is the DUO-E trial (NCT04269200), which is evaluating chemotherapy in combination with durvalumab (Imfinzi) with or without the PARP inhibitor olaparib (Lynparza) [as maintenance therapy in advanced or recurrent disease].

It is an exciting time to participate in clinical trials. The GOG Foundation, particularly the GOG Partners [Program] is a way for academic- or community-based sites to participate in research. It is great to participate in conferences to learn what our next treatment options should be. Our goal is to offer these trials to our patients. I would encourage [my colleagues] to consider opening up clinical trials to their patients.