Navigating the Evolving Landscape of Second-Line Endometrial Cancer Care

The treatment landscape for patients with metastatic or recurrent endometrial cancer has undergone significant transformations in recent years, particularly with the movement of immunotherapy into the first-line setting. This shift has created new challenges and decision-making points for clinicians managing disease progression in the second line.

During the 17th Annual International Symposium on Gynecologic Malignancies, Dana Chase, MD, a gynecologic oncologist and professor of Clinical Obstetrics and Gynecology in the Division of Gynecologic Oncology at the David Geffen School of Medicine at UCLA Health, outlined current strategies, the importance of biomarker testing, and the emerging role of antibody-drug conjugates (ADCs) in addressing unmet needs for this patient population.

CancerNetwork: What recent shifts have you observed in the second-line endometrial cancer treatment landscape?

Chase: In the last several years, we’ve started to incorporate immunotherapy into the first-line treatment of metastatic or recurrent endometrial cancer, which means many of our patients—not all of them, but potentially many of them—have been on platinum-based chemotherapy with immunotherapy in the form of either dostarlimab-gxly [Jemperli], pembrolizumab [Keytruda], or atezolizumab [Tecentriq]. Some patients are progressing on immunotherapy maintenance, and other patients are potentially progressing after immunotherapy maintenance. What that means is that a portion of our patients have seen immunotherapy and are now progressing on or after it.

The second group of patients are those who have potentially not seen immunotherapy and are progressing after platinum-based chemotherapy alone or with bevacizumab [Avastin]. The third type of patient is one who has seen HER2-targeted therapy. They’ve gotten platinum-based chemotherapy with, for example, trastuzumab [Herceptin] and progressed on trastuzumab or after trastuzumab maintenance. We have those groups of patients that we’re now seeing in the second-line setting. What the patient has been previously exposed to impacts what you’re going to give them for their second-line treatment.

If a patient has progressed on immunotherapy, you are thinking about whether you’re going to switch strategies altogether or perhaps add lenvatinib [Lenvima] to the immunotherapy maintenance that they’re on at the time of progression. Perhaps you’re going to totally jump ship, not use immunotherapy again, and go to single-agent chemotherapy—maybe platinum-based chemotherapy—or maybe you’re going to move to a HER2-targeted therapy if they have HER2 immunohistochemistry (IHC) 2+ or 3+. Maybe you’re going to do hormonal therapy. The other thing to consider in every situation is whether you have a clinical trial available for that patient.

If the patient has never seen immunotherapy before and they’re progressing after platinum-based chemotherapy with bevacizumab, perhaps you are going to give them an immunotherapy-based regimen such as lenvatinib with pembrolizumab, you’re going to give platinum-based chemotherapy with immunotherapy this time around, or you have the HER2-targeted therapy you could use in recurrence. Of course, you also have hormone therapy and clinical trials.

The third group of patients are those who have seen trastuzumab or HER2-directed therapy before; the question is whether they are eligible for HER2-targeted therapy again. Potentially, they are. You could use HER2-targeted therapy again. You could use immunotherapy if they haven’t received it before, like platinum-based chemotherapy with immunotherapy or lenvatinib with pembrolizumab. Then, there’s the option for clinical trials and hormone-type treatment, or perhaps traditional chemotherapy again.

How has the recent shift of immunotherapies into the first-line setting changed the approach in the second line for patients who progress?

We don’t have a ton of data in the gynecologic or endometrial setting of what immunotherapy after immunotherapy looks like. But what I’ve learned from my medical oncology colleagues who treat other cancer types is that immunotherapy after immunotherapy is not thought to be effective. If you’ve used it once and the patients progressed on it, it’s not indicated to use it again.

In general, I think it is frowned upon to use immunotherapy after immunotherapy unless they’ve had a long treatment-free interval since they’ve seen immunotherapy. Perhaps they’re still sensitive. In that situation, you could use platinum-based chemotherapy with immunotherapy or lenvatinib with pembrolizumab, which is a reasonable option.

There’s some indication based on small retrospective analyses in the gynecologic cancer space in endometrial cancer that in a patient progressing on pembrolizumab, you could add lenvatinib and perhaps get up to a response rate of 75% in patients with mismatch repair deficient (dMMR) disease. That could be an option to add lenvatinib to pembrolizumab for a patient who is progressing on pembrolizumab. We’ve seen that work in disease sites such as melanoma; they had a study that showed a good response rate when adding lenvatinib to pembrolizumab in patients progressing on pembrolizumab. But we don’t have prospective trials in the endometrial space that tell us for sure what we should do.

Are all your patients getting molecular testing?

Yes. At UCLA, we are testing people in the first line so that we have those results by second-line [treatment]. It’s very much part of the workflow at UCLA to test people in the first line to do potentially full next-generation sequencing panels. There is a suggestion that it’s reasonable to retest a patient at recurrence. For example, HER2 status can change maybe 30% to 40% of the time. If I can rebiopsy the patient and check HER2 status again, I will do that and potentially look for other biomarkers as well at the time of recurrence.

What patients with second-line disease are you treating with ADCs? Are you concerned about cumulative toxicities like ocular events or interstitial lung disease (ILD)?

For sure. If my patient has ILD and/or ocular disease on an ADC and I know that the next ADC has the potential to cause ILD or ocular toxicity, I’m going to be nervous about it. In general, we like to say a patient has to resolve to a grade 1 [toxicity] before you start a new therapy that could cause similar toxicity. But with ILD, I would want it to be gone completely if I were going to put the patient on an ADC again. We’re going to have to think about that in the future. I worry that a patient could lose their opportunity to get another ADC if they had one of those toxicities already.

What are your overall thoughts on ADCs in the second-line metastatic endometrial cancer landscape?

There are 2 things to talk about here. First, are we going to see ADCs for which you don’t need to have the biomarker to use? For example, you don’t have to be HER2 2+ or 3+; you could be in an all-comer patient population and have access to the ADC. It would be nice to have ADCs we can use in patients who don’t have the traditional biomarkers, for example, fam-trastuzumab deruxtecan-nkxi [Enhertu].

The other thing is, are we going to see ADCs that have an improved response rate, progression-free survival (PFS), and a potential overall survival (OS) advantage in the second line? Currently, we have one phase 3 trial that we’re basing treatment upon, which is lenvatinib and pembrolizumab. It was one of the only recent phase 3 trials in second-line endometrial cancer where patients were randomly assigned to standard-of-care single-agent physician’s choice of chemotherapy. Can we, in a phase 3 trial, improve upon the KEYNOTE-775 trial [NCT03517449] results? It would be nice to see an improvement on PFS and OS; can we now make patients survive 2 years instead of 18 months? Can we make their PFS 8 months, 9 months, or 12 months instead of 6 months?

Third, it would be nice to see ADCs that potentially have a different payload, meaning not a topoisomerase I payload, but something different than trastuzumab deruxtecan. Whether or not that matters, I’m not entirely certain, but it’s been suggested that perhaps an ADC with the same payload might not be as effective if you’ve already seen an ADC with that same type of payload. But that is more theoretical than proven in the endometrial space.

If we can have a little more heterogeneity in terms of payload in our ADCs that we’re using in endometrial cancer, that would be great. For example, a microtubule inhibitor type payload in an ADC indicated for endometrial cancer would be nice just for variety.

Perhaps [something] more important is an ADC with a different target, linker technology, and drug-to-antibody ratio. The mechanism of action of the payload is also something that would be nice to see change in the future.

What is the most prevalent unmet need in the current state of second-line endometrial cancer care?

I would like to see us have a better handle on toxicities. In the second-line [setting] where [patients are] not going to be cured and we’re potentially offering them, in the current situation, 1 to 2 years of survival, it would be nice to be able to control toxicity a little bit better.

Hormone therapy is usually an oral therapy, meaning not a long infusion. You don’t have to go to the infusion center for it, and it has very good tolerance and a low adverse effect profile. We could improve on the efficacy of hormone therapy. It would be nice to see response rates over 40% with hormone therapy considering that it’s so well tolerated. It would be nice to have therapies that are as well tolerated as hormone therapy and have improvement in outcomes at the same time.

Are there any specific clinical trials that you’re watching and waiting to report?

I’m eager to see the results of selinexor (Xpovio). That’s [being evaluated in] a metastatic or recurrent endometrial cancer maintenance study. I also think we’re going to see the endometrial cancer TROP2 ADC results in the next year or 2. There are multiple other ADC second-line trials that are going to [read out] in the next couple of years as well.