Novel Targets Facilitate Treatment Advances and Spur Further Questions in Endometrial Cancer

Delineating targeted therapies for subgroups of patients with mismatch repair–proficient (pMMR), MMR-deficient (dMMR), and/or TP53 wild-type endometrial cancer represents the next frontier in the management of this disease, where immunotherapy has already made substantial yet less targeted strides, according to Ritu Salani, MD.

In an interview with OncLive^®, Salani discussed antibody-drug conjugates (ADCs) in development for patients with TROP2- and HER2-expressing endometrial cancer, the potential role of selinexor (Xpovio) in patients with TP53 wild-type advanced or recurrent disease, and remaining questions regarding the utility of PARP inhibitors across endometrial cancer subsets.

Salani, the director of Gynecologic Oncology at the University of California Los Angeles, shared updates in ovarian and cervical cancer management in another article.

OncLive: What have been some of the biggest advances in endometrial cancer management so far in 2024?

Salani: The data are always still evolving. Although we’ve had some confirmed new standards of care [SOCs], they still lend themselves to more questions. The role of immunotherapy is clear in dMMR endometrial cancers, but the door is open in pMMR cancers.

The other big challenge is: What do we do after a patient recurs and they’ve had prior immunotherapy exposure? We don’t have data yet on [rechallenging with] immunotherapy after immunotherapy. Next on the horizon [are innovations with] selinexor maintenance therapy in the TP53 wild-type population, [which includes] pMMR and dMMR patients.

TROP2-directed ADCs are coming out. Folate receptor alpha–targeted ADCs are being used in endometrial cancer. A lot of treatments still on the horizon will evolve the paradigm and hopefully will help us take better care of these patients.

What novel ADCs may change practice for subsets of patients with endometrial cancer?

[The ADC target] I’m most excited about is TROP2. TROP2 is widely expressed in endometrial cancer, so it is a logical target for treatment. We’re still exploring the adverse effect [AE] profile [of TROP2-directed agents]. Some phase 2 datasets of TROP2-directed agents in endometrial cancer show good response rates in patients who have been heavily pretreated with multiple prior lines of therapy.

[We need to] understand the exact role of TROP2 and how expression correlates with [response]. Do patients who have high expression respond better? Do patients who have low expression respond the same [as those with high expression], or is it less of a response, but still a response? These are some of the questions that trials that are being developed or are now enrolling are hopefully going to answer.

Regarding fam-trastuzumab deruxtecan-nxki [T-DXd; Enhertu], we have some phase 2 data [in endometrial cancer] from the [phase 2 DESTINY-PanTumor02] basket trial [NCT04482309], which are exciting findings based on a limited number of patients. For patients who have HER2 expression, it’s an exciting option, but one challenge may be: How do we sequence [therapy in] these patients? T-DXd and the TROP2-directed ADCs both use a topoisomerase backbone as their payload, so some of the AEs, and maybe even the target efficacy, may be lost in sequencing those therapies. Being strategic about which therapies should be used in what sequence or which we should prioritize if we can’t sequence them will be important questions to answer.

How has the accelerated FDA approval of T-DXd for patients with HER2 3+ solid tumors affected your patient care?

There are a couple ways that the new accelerated approval is affecting us. One, we’re starting to look for HER2 expression more consistently across gynecologic cancers, which is not something we were doing outside of mostly uterine cancer [prior to this approval]. That understanding has helped us screen [for HER2 expression].

Additionally, in [DESTINY-PanTumor02], patients had multiple prior lines of therapy or had not responded to SOC regimens. Having another weapon in the armamentarium [for these patients] is key, and it is a nice option for patients who have HER2 expression. Using it earlier, we might even see more pronounced responses, although that’s just anecdotal. [Moreover, we need to] learn the AEs associated with this therapy and make sure we’re treating our patients safely, monitoring them cautiously, managing the dosing, and holding the dosing when necessary.

What might the future look like for the treatment of the pMMR endometrial cancer population?

There’s a lot of excitement about immunotherapy, but I’m personally not satisfied for the pMMR population. Even if we’re seeing a signal, it’s not enough. These patients are still recurring. We’re not curing most of them. We’re seeing [these outcomes] because we’re not seeing a statistically significant overall survival benefit [with current agents]. There may be some clinical trends, but we need to do better.

For the pMMR group, we can’t rest on immunotherapy in the front line. I’m excited about selinexor for the TP53 wild-type population, particularly patients with pMMR disease, because we don’t have a maintenance strategy for that group. [The phase 3 XPORT-EC-042 trial (NCT05611931) is] enrolling. We need to understand: How can we exploit the immunotherapy process better? Can we make these tumors hot? Is there a subgroup of pMMR patients, such as those with TP53 mutations, that maybe have a better response [with immunotherapy]? We need to understand [which patients should receive] immunotherapy and [which should receive another therapy]. Additionally, where do bevacizumab [Avastin] and other therapies potentially fall into this schema?

What is the rationale for the XPORT-EC-042 trial, which is evaluating frontline selinexor maintenance therapy in patients with TP53 wild-type advanced or recurrent endometrial cancer?

This trial is enrolling slowly because immunotherapy has helped create some challenges for the study. However, it’s important to evaluate patients who are TP53 wild type and target that mutation. Immunotherapy for all patients isn’t specific, and there is a role for immunotherapy in all patients with endometrial cancer in some form, whether it’s [for] primary or recurrent [disease], but we need to do better in the front line. If we can prevent patients from having cancer recurrence at the time of initial diagnosis and treatment, that’s where our success will be. The bar has been set, but we shouldn’t be complacent, and we should continue to look at other opportunities to capitalize on better cure rates.

What questions do the data that have been reported from part 2 of the phase 3 RUBY trial (NCT03981796)raise about the potential role of PARP inhibitors in endometrial cancer?

RUBY has changed the paradigm. The role for PARP inhibitors [based on the data] that we saw in RUBY part 2 is unclear, and we need to do further evaluation. [The niraparib (Zejula)-based regimen is not] ready for prime time, and we need to understand the contributory portion of the PARP inhibitors in that setting.

I’m not sure there’s any role [for PARP inhibitors] in the dMMR population because immunotherapy has made such a strong impact. We need to understand which pMMR patients would benefit from it, if any, and the study shows signals [of benefit in certain subgroups], which is exciting. We’ve seen some other prospective data in different settings, but they have not been consistent. Our understanding of the contribution of the PARP inhibitor vs the immunotherapy [agent] needs to be cleaner. These therapies add toxicities to patients’ [lives], and they’re financially expensive, so we need to be thoughtful about moving forward with these combinations or maintenance strategies in the absence of clear, concrete success.