Immunotherapy Continues to Redefine Treamtent Considerations in Advanced/Recurrent Endometrial Cancer

The selection of systemic therapy for patients with advanced or recurrent endometrial cancer has evolved significantly with the integration of immunotherapy and antibody-drug conjugates (ADCs), according to Matthew Wagar, MD.

Recent advancements have expanded treatment options with pembrolizumab (Keytruda) and dostarlimab-gxly (Jemperli) incorporated into frontline chemotherapy regimens based on results from the phase 3 NRG-GY018 (NCT03914612) and RUBY (NCT03981796) trials, respectively. Wagar explained that these trials have redefined the standard of care for patients with metastatic or recurrent disease, emphasizing the importance of treatment sequencing, molecular profiling, and staging in clinical decision-making.

For patients with HER2-positive endometrial cancer, Wagar highlighted the role of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu), an ADC that has demonstrated efficacy in a basket trial across multiple solid tumors, leading to its application in endometrial, ovarian, and cervical cancers. He underscores the importance of early HER2 testing to inform treatment decisions and optimize patient outcomes.

In the interview with OncLive® following an OncLive State of the Science Summit (SOSS), Wagar discussed the integration of immunotherapy in frontline and recurrent settings, key considerations for treatment sequencing and staging, and the future role of clinical trials in refining therapeutic strategies. Wagar is a gynecologic oncology fellow at the University of Wisconsin School of Medicine and Public Health in Madison.

OncLive: How has the management of advanced and recurrent endometrial cancer evolved in recent years?

Wagar: In the last couple of years, the management of advanced/recurrent endometrial cancer has changed dramatically. We have seen an integration of immunotherapy with chemotherapy, as well as new ADCs that have found a home and have thrived for some of our patients with endometrial cancer.

During the SOSS, we reviewed 2 different cases. One centered on the integration of immunotherapy with chemotherapy, and then [the other] focused on the new ADC, trastuzumab deruxtecan, for endometrial cancer.

First, we reviewed a clinical situation where a patient presented with recurrent endometrial cancer who had never [received] chemotherapy before; we reviewed some of the inclusion criteria, exclusion criteria, and the data supporting the use of chemotherapy—specifically with carboplatin and paclitaxel.

Prior to the publication of the NRG-GY018 and RUBY trials, [carboplatin/paclitaxel] was the standard of care for those patients. Both of those trials introduced immunotherapy [in addition to chemotherapy] with pembrolizumab and dostarlimab, respectively, for patients with advanced disease at presentation or with metastatic/recurrent disease. We discussed some of the specific considerations about integrating those new [immunotherapies], monitoring specific adverse effects, and indications for using those therapies, either up-front or in the recurrent setting.

What key considerations should clinicians keep in mind when staging to optimize treatment selection in this setting?

From my perspective, the integration of immunotherapy into the adjuvant treatment realm drives home the importance of staging and having access to someone capable of performing these staging procedures for these patients. There are some mixed data for using immunotherapy in patients who have early-stage disease or disease that is not necessarily very high risk for recurrence; maybe that is not as efficacious as some of these more high-risk patients.

Having that information, particularly with sentinel lymph nodes, or if [clinicians decide] to go one step further and do a full lymphadenectomy, including pelvic lymph node dissection, can be helpful to help risk stratify some of these patients. We are seeing a dramatic effect with the integration of immunotherapy, particularly when these patients are adequately staged.

Besides staging, what additional factors should clinicians consider when selecting the most appropriate treatment options?

[Similarly] to what we would do for any other patient that we were considering for other types of therapy, [it is important to] understand their medical comorbidities and surgical comorbidities, and to make sure that you're working closely with a pathologist to have as much molecular data available to you as possible.

We have indications for using immunotherapy for many different types of patients, but we see a profound effect for patients that have mismatch repair deficiency; therefore, being able to have that information available to you, particularly in somebody who maybe isn't going to be a candidate for surgery, or that has advanced or recurrent disease. That's going to help stratify how we can expect someone to respond to these therapies and how we might push the envelope in terms of helping to get them through [treatment] vs trying something else.

What key factors are important for clinicians to consider when selecting trastuzumab deruxtecan as a treatment option for these patients?

[T-DXd] is an ADC that has gained approval and support in endometrial cancer [for patients with pretreated, HER2-positive advanced disease]. Because that [trial] involved a lot of different solid tumors, and there was this particularly noticeable benefit in the endometrial cancer cohort, a lot of people tend to think about it for patients with endometrial cancer, but there are also indications for patients with ovarian cancer and cervical cancer.

I would [advise colleagues in the space] to always think about requesting HER2 testing from the get-go for patients with endometrial cancer patients. If you're concerned someone has an aggressive phenotype and you're worried about their response to systemic therapy, having that information ahead of time in your back pocket to switch [allows us to better define] the trajectory [for treatment].

Another thing to consider is that the way that that study assigned HER2 positivity was based on data from stomach and gastric cancer, and that is different than how we assign HER2 positivity for somebody who has HER2-positive uterine cancer. At our institution, we work closely with our pathologists to make sure that we're spelling out the criteria by which they meet this HER2 positivity in order to know that we're not missing patients who could potentially be eligible for this ADC.

What key factors should clinicians consider when selecting between first-line treatment options for patients with advanced endometrial cancer?

We're still in period of management for endometrial cancer where there's a lot of different ways to approach [treating] endometrial cancer, particularly advanced endometrial cancer in the [frontline] setting. Having all of your molecular information, having a good radiographic understanding of where your disease [to understand] how it's responding, and understanding your patient's goals [is important].

We give people chemotherapy for 6 cycles or so. We continue their immunotherapy for anywhere from 2 to 3 years, depending on the protocol you're using, and there are benefits to it that we're seeing in our clinical practice settings. We need to make sure we have all of the information necessary and that [we’re] setting people up for what to expect [from treatment].

What key factors should clinicians consider when sequencing immunotherapies with other treatments?

The other thing to think about is that we're starting to wonder more about the sequence of some of these therapies when people are getting immunotherapy that was previously reserved for recurrent endometrial cancer in the upfront setting. What do we do when they progress? Do we switch their immunotherapy? Do we add in something like lenvatinib [Lenvima] to help augment how their immunotherapy works, and in what treatment setting or for what patients, is that going to be particularly beneficial?

[We are still exploring] that to some degree, and I think that the jury's still out. That's one of the double-edged swords of endometrial cancer: you can kind [use] different [treatment mechanisms], and you're always going to be backed up by some study somewhere, but we're still sort of wading through that [data] to figure out what the best sequence of [treatment] is going to be, particularly while we integrate immunotherapy into the frontline [setting].