Endometrial Cancer Treatment Options: What are the Experts Using?

Among the many conversations floating around the recurrent endometrial cancer space are considerations regarding long-term data, biomarkers, and emerging targets. For second- and later-line treatments, there are several options available. Lenvatinib (Lenvima) plus pembrolizumab (Keytruda) is one of the hotly debated regimens, particularly when compared with carboplatin plus paclitaxel in specific patient groups.

As part of a Satellite Session hosted by CancerNetwork®, a panel of experts discussed the treatment landscape for patients with recurrent endometrial cancer. The panel was led by Ritu Salani, MD, a gynecologic oncologist and the director of Gynecologic Oncology at University of California, Los Angeles (UCLA) Health. She was joined by Shirin Khorashadi, PharmD, BCOP, a research pharmacist at UCLA; Dana M. Chase, MD, a professor of Clinical Obstetrics and Gynecology in the Division of Gynecologic Oncology at UCLA Health; Isabel Lazo, MD, a gynecologic oncologist at Olive View UCLA Medical Center; Jessica Walchonski, PA-C, a physician’s assistant at UCLA Health; Carolyn E. Haunschild, MD, a gynecologic oncologist at UCLA Health; Annie A. Yessaian, MD, a clinical assistant professor of Obstetrics and Gynecology at Keck Medicine of University of Southern California (USC); and Richard L. Friedman, MD, a gynecologic oncologist at Keck Medicine of USC.

The panel discussed the most recent data from the phase 3 LEAP-001 trial (NCT03884101), which evaluated lenvatinib plus pembrolizumab vs paclitaxel and carboplatin in patients with advanced recurrent endometrial carcinoma.¹ Discussion points also included hypothetical paradigm shifts and their respective repercussions, as well as specific clinical cases.

Genetic Testing

Salani: How does molecular testing guide your treatment in advanced cases?

Yessaian: It has become the standard of care. Fortunately, even at endometrial biopsy, referring physicians are at least doing the mismatch repair immunohistochemistry, so I see that more often, even from community referrals. Whatever wasn’t done at the original [endometrial biopsy] gets fully done at the hysterectomy. We’re fortunate; we send everything for next-generation sequencing.

Salani: Do you [perform] that at the time of primary diagnosis for all advanced cases?

Yessaian: Yes.

Friedman: We do, too.

Lazo: Unfortunately, being at a county hospital, we have some funding limitations sometimes, so even though we would want to do POLE testing, that’s not an option. We do have mismatch repair protein reports on everybody. We are able to do TP53 testing, so we have that. Next-generation sequencing is not standard, and it is not part of our expected practices unless it’s in very specific cases. But for some high-grade histologies, we do have HER2 testing.

Friedman: Would you do next-generation sequencing for an advanced case? Is there any advanced case where you wouldn’t do it?

Salani: I don’t do it.

Data from LEAP-001

Salani: In LEAP-001, at 48 months, you had 41% [of patients] who were still alive vs 27% to 28% in [the phase 3 KEYNOTE-775 trial (NCT03517449)].² This was in a recurrent setting, so it’s a little bit of a different population. You can see that there is a survival benefit for patients who received lenvatinib and pembrolizumab vs single-agent paclitaxel or single-agent doxorubicin. It argues that lenvatinib and pembrolizumab really should be chosen for second-line therapy after carboplatin and paclitaxel alone.

The overall survival continues to show that same trend. When you look at the mismatch repair proficient (pMMR) population, specifically, you can see that those trends actually held. You’d expect in mismatch repair deficient (dMMR) populations that you would see that continued benefit. But here, you do see that continued benefit, both in the LEAP-001 population and in KEYNOTE-775.

In patients who’ve received prior neoadjuvant chemotherapy, are these data meaningful or not?

Haunschild: I’ve come across these data before, and truthfully, the platinum paradigm is ingrained in us. We revert back to that, thinking that maybe it saves us a line [of treatment].

Lazo: I would consider it…. I don’t think with endometrial cancer that we’ve followed that same routine of platinum until it’s exhausted. In other situations, if you did the surgery first then treated with [carboplatin plus paclitaxel], and someone with pMMR [disease] recurred, you would consider doing lenvatinib and pembrolizumab. This is that situation. I do think that this subgroup analysis could be meaningful if we’ve already challenged them with the carboplatin plus paclitaxel. That’s not to say I’m 100% going to follow it, but it’s something to consider, especially for [a patient] who had a lot of adverse effects with their chemotherapy.

Salani: That’s my point. I feel the same way. If you had asked me what my biggest issue with KEYNOTE-775 was, it’s that I don’t like the control arms. They are not that standard. Yes, we use weekly paclitaxel and, yes, we use doxorubicin, but I’m often rechallenging my patients with a platinum-based regimen. This subgroup helped me address that. If the patient hasn’t received immunotherapy, I think lenvatinib plus pembrolizumab is the choice I’m going to go with.

This helped elucidate that for me, but I do think there are nuances to it. Patient tolerability is something [to consider]. Dana, you mentioned that patients are most able to tolerate therapies earlier on, and that’s important. It’s not that we want to give them our harshest [options], but we want to make sure we’re getting them the most effective therapy when they can tolerate it.

Chase: They’ll like that when you give them lenvatinib plus pembrolizumab. They’re not going to lose their hair, and they’re not going to have neuropathy or [anything] even worse than neuropathy. They’re going to like to go on lenvatinib plus pembrolizumab vs carboplatin plus paclitaxel [and pembrolizumab] or [carboplatin plus paclitaxel and dostarlimab-gxly (Jemperli)] if they hadn’t gotten immunotherapy before. But they’d be happy not to lose their hair.

Haunschild: It’s hard because…of their adverse effects and experience. I have had some patients [experience issues on lenvatinib plus pembrolizumab]. If they had previously been on [carboplatin plus paclitaxel], and have been okay, that’s probably when I [would consider it]. I’m not a purist in this.

Paradigm Shifts

Salani: Let’s say we live in a world where [therapy targeting] HER2 becomes the frontline [choice] for patients with IHC 2 to 3+. Now, what becomes your second-line [therapy]? Is it chemotherapy? Is it chemoimmunotherapy? Is it lenvatinib plus pembrolizumab?

Chase: Assuming they’re pMMR and have never gotten chemotherapy before, I would do chemoimmunotherapy. But we could do lenvatinib plus pembrolizumab too.

Salani: Probably chemotherapy. [Then], do you save lenvatinib plus pembrolizumab as a third-line option? The only thing is, like selinexor (Xpovio), HER2 therapy is probably going to be 2 different strategies because the [patient] has TP53 mutations, which are HER2 expressers. We’re going to start seeing differences. If you have carboplatin, paclitaxel, and selinexor, your second-line [therapy] might be very different than if you had trastuzumab deruxtecan [T-DXd; Enhertu]. We’re going to have this divergence of therapy.

Chase: In the HER2 frontline [setting], they’re going to get T-DXd for 12 cycles, or something like that. After that, they’re going to be pretty tired, and you probably don’t want to go for chemotherapy at that point. Maybe lenvatinib plus pembrolizumab would be there.

Salani: I’m going to pick on you 2 right now. From your standpoint, you probably see a lot of the dose reductions and are helping to manage some of the adverse effects. What do you see most commonly with T-DXd?

Khorashadi: Our clinic doesn’t do it very often.

Walchonski: Honestly, I feel like it’s tolerated well in a lot of our patients. I do think that we have to closely monitor the blood counts because we do see those dropping, maybe [with] a little bit of fatigue and nausea, but I think they will do really well.

Patient Case 1

• A 62-year-old woman with endometrial cancer
  • Stage IIIC1 endometrial carcinoma at diagnosis
  • pMMR
  • HER2-negative
  • Estrogen receptor (ER) positive
• Treated with:
  • Carboplatin/paclitaxel plus pembrolizumab followed by maintenance pembrolizumab
    • Achieved a partial response and remained on pembrolizumab for 15 months before disease progression
• Imaging:
  • Enlarging retroperitoneal lymph nodes
  • New bilateral pulmonary nodes
• Status:
  • ECOG performance status of 1
  • Controlled hypertension
  • No history of significant immune-related adverse events

Salani: Taking clinical trials off the table, what treatment would you use for this patient?

Yessaian: I’ll check the ER receptor on that lung biopsy again. I’ll consider hormonal treatment—letrozole [Femara].

Haunschild: Was the patient still on maintenance?

Salani: She was on pembrolizumab while she progressed.

Yessaian: Hypothetically, you can always add lenvatinib to the pembrolizumab.

Haunschild: Yeah, that’s probably what I would do.

Lazo: If they were already on pembrolizumab, then I might consider adding lenvatinib.

Salani: Do the time on maintenance immunotherapy and the disease progression influence you?

Lazo: No. I’d still try it.

Salani: Let’s say this patient did what most of [you thought about] doing. We started lenvatinib in addition to pembrolizumab, and she has a partial response—a 60% reduction in her target lesions. We talked a little bit about this if you’re platinum-free. Are there any other thoughts about when you do a chemotherapy challenge vs adding lenvatinib? We’ve already talked about the toxicities—hypertension, thyroid disease, fatigue—is there anything else? Has anybody had bad experiences with diarrhea?

Haunschild: Not as much as I was told I would.

Yessaian: My patient was on lenvatinib plus pembrolizumab, so I didn’t exactly know what to blame, whether it was immune colitis or the lenvatinib.

Chase: I had [a patient with] bad diarrhea, but it was [due to] the pembrolizumab. She had presented for her infusion of lenvatinib plus pembrolizumab with diarrhea, and I made the mistake of assuming it was the lenvatinib and gave her the pembrolizumab. It turned out to be a bio-related colitis.

Patient Case 2

• A 69-year-old woman diagnosed with stage IVB uterine serous carcinoma
  • pMMR
  • HER2 immunohistochemistry 2+
  • ER negative
• Initial treatment:
  • Carboplatin/paclitaxel plus trastuzumab (Herceptin) followed by maintenance trastuzumab
  • Achieved a partial response and remained progression-free for 14 months before developing radiographic progression
• Imaging:
  • New hepatic metastases
  • Progressive peritoneal disease
• Clinical Status:
  • ECOG performance status of 0
  • Mild residual grade 1 neuropathy
  • No underlying pulmonary disease

Salani: What would you select for this patient?

Chase: T-DXd.

Khorashadi: T-DXd.

Yessaian: It might be anecdotal, but my experience is that the duration of the response is quite long with T-DXd and the antibody-drug conjugates.

Lazo: In a serous patient, if she was just on maintenance trastuzumab, I would consider chemotherapy again for her.

Haunschild: I would do lenvatinib plus pembrolizumab, then T-DXd.

Chase: Yeah, I would do lenvatinib plus pembrolizumab, too.

Salani: I would do lenvatinib plus pembrolizumab, too. But I don’t think any of the answers are better than another, so I think that they’re all very reasonable strategies. After T-DXd, what would you choose?

Yessaian: I’ll take a look at the adverse effect profile. Lenvatinib plus pembrolizumab is always there, and if I have a good stretch, chemotherapy is an option. But lenvatinib plus pembrolizumab would probably be my next [choice].

References

1. Marth C, Moore RG, Bidziński M, et al. First-line lenvatinib plus pembrolizumab versus chemotherapy for advanced endometrial cancer: a randomized, open-label, phase III trial. J Clin Oncol. 2025;43(9):1083-1100. doi:10.1200/JCO-24-01326.
2. Makker V, Colombo N, Herráez AC, et al. Lenvatinib plus pembrolizumab for advanced endometrial cancer. N Engl J Med. 2022;386(5):437-448. doi:10.1056/NEJMoa2108330