Standard options to treat primary advanced or recurrent endometrial cancer after failure of platinum-based chemotherapy have been limited. The emergence of immunotherapy and targeted therapies in this space has been encouraging, and researchers are aiming to build on these initial successes.

Advanced and recurrent endometrial cancer is very difficult to treat. First, endometrial cancer tends to be more chemotherapy resistant than ovarian cancer. Second, there are few chemotherapeutic agents beyond carboplatin, paclitaxel, and doxorubicin for advanced and recurrent endometrial cancer. These are the most active chemotherapy agents, and, once you have used them, you really have little else to use.

In the second-line setting, the KEYNOTE-775 trial evaluated the combination of pembrolizumab with the multitargeted tyrosine kinase inhibitor lenvatinib in advanced endometrial cancer in all-comers. KEYNOTE-775 met both progression-free and overall survival end points, so the combination of pembrolizumab and lenvatinib is now US Food and Drug Administration approved for recurrent and advanced endometrial cancer, especially for patients with cancer that is mismatch repair proficient.

Patients who have mismatch repair–proficient or microsatellite-stable tumors are not expected to benefit from single-agent immunotherapy, and that is the rationale for adding lenvatinib in KEYNOTE-775. In the mismatch repair–proficient group of patients, the pembrolizumab-plus-lenvatinib combination did fairly well, with a response rate of 30%, and the responses were durable. In the mismatch repair–deficient group, the response rate was 40%. Pembrolizumab plus lenvatinib is not an easy regimen to give because lenvatinib can cause significant hypertension that is difficult to control. Nonetheless, this combination is very active, and we use it a lot.

When we face patients who have recurrent or advanced endometrial cancer, the first inclination is often to look for clinical trials for them. And, honestly speaking, that is the best scenario because the “standard-of-care” options are limited, and the aim of clinical trials is to improve upon what is currently available.

Immunotherapy is exciting for advanced and recurrent endometrial cancer because we have seen significant improvements in response rates and duration of response. Our main biomarkers for sensitivity to immunotherapy are microsatellite instability and mismatch repair deficiency because PD-L1 staining is not as useful of a marker in endometrial cancer as it is in other cancers.

Patients with endometrial cancer whose tumors have microsatellite instability or mismatch repair deficiency are likely to benefit from monotherapy with a PD-1 inhibitor such as pembrolizumab or dostarlimab. For patients who are microsatellite stable or mismatch repair proficient, we have fortunately found that the addition of the multitargeted tyrosine kinase VEGFR inhibitor lenvatinib improves responses. Lenvatinib is a multitargeted tyrosine kinase that acts on VEGF receptors.

Another new area of research in the treatment of advanced or recurrent endometrial cancer is in HER2-directed therapies. Amplification of the HER2 gene has been seen in some advanced serous carcinomas and other TP53-aberrant endometrial carcinomas, highlighting the future possibility of using HER2-targeted therapies in these variants. Although this is thought to be a relatively small group of patients, there could be a significant advantage to adding trastuzumab or another HER2-targeted agent to our traditional chemotherapy regimen of carboplatin and paclitaxel.

There is definitely more information available to fuel the general movement toward biomarker-driven care or using molecular classification to identify the best treatment for patients. Most trials are looking for not only a winning combination but also factors that can predict which patients will respond to a given treatment.

For example, in patients with mismatch repair deficiency, immunotherapy alone or in combinations might be the right treatment. Chemotherapy may fit better into the copy-number-high or TP53-mutated endometrial cancer space. Other patients may have hormone receptor–positive tumors, so perhaps targeted therapy, plus or minus hormonal therapy, may be more relevant in that space.

Now that we have data on molecular classification, we are better positioned to individualize therapies to a patient’s tumor profile rather than simply basing it on histology. Ongoing research into novel therapies is trying to identify which patients will benefit from a particular therapy. For patients with HER2-positive uterine serous and carcinosarcomas, prospective studies have shown that the addition of trastuzumab to carboplatin and paclitaxel followed by trastuzumab maintenance improves survival. This is currently a standard-of-care treatment. Other studies have looked at newer-generation drugs targeting HER2. The DESTINY-PanTumor02 trial, for example, showed efficacy of trastuzumab deruxtecan (commonly referred to as T-DXd) in multiple cancer types, including endometrial cancer.

Studies are also exploring CDK4/6 inhibitors in patients with estrogen receptor– and/or progesterone receptor–positive cancers, similar to studies in breast cancer. Combination therapy with the CDK4/6 inhibitor abemaciclib with the aromatase inhibitor letrozole has shown fairly promising results. A trial looking at everolimus and letrozole with or without the CDK4/6 inhibitor ribociclib is nearing completion of accrual (NCT03008408).