Frontline IO-Combos, Next-Generation ADCs: Evolutions in Endometrial Cancer

The treatment paradigm for endometrial cancer is undergoing a rapid transformation, shifting from a traditional chemotherapy-centric approach to one defined by molecular biomarkers and innovative combination strategies. As frontline standards evolve to incorporate immune checkpoint inhibitors alongside platinum-based backbone therapy, clinicians are now tasked with navigating complex sequencing decisions and managing the distinct toxicity profiles of these intensive regimens.

During a recent Satellite Session hosted by CancerNetwork®, a panel of experts gathered to discuss the endometrial cancer space. The discussion was led by Susana M. Campos, MD, MPH, clinical director in the Division of Gynecologic Oncology, director of Educational Initiatives in the Division of Gynecologic Oncology, institute physician at Dana-Farber Cancer Institute (DFCI), and assistant professor of medicine at Harvard Medical School.

She was joined by Tara Berman, MD, MS, medical oncologist at DFCI, and a member of faculty at Harvard Medical School; Sarah Paraghamian, MD, associate program director of the Gynecologic Oncology Fellowship and assistant professor at Tufts University School of Medicine; Sanggyu Bae, MD, an oncologist from DFCI; Lucy Yu, PharmD, BCPS, BCOP, clinical pharmacy specialist at DFCI; Wendy Young, MSN, ARNP, FNP-C, from Women’s & Infant’s Hospital in Rhode Island; Sudha Bolla, MD, a network physician at DFCI; Leslie S. Bradford, MD, at MaineHealth; and Paul A. DiSilvestro, MD, from Brown Health.

First-Line Treatment Options

According to the NCCN, preferred category 1 systemic treatment options for stage I to IV endometrial carcinoma include¹:

• Pembrolizumab (Keytruda) plus carboplatin/paclitaxel;
• Dostarlimab-gxly (Jemperli) plus carboplatin/paclitaxel;
• Durvalumab (Imfinzi) plus carboplatin/paclitaxel (for mismatch repair deficient tumors only);
• Trastuzumab (Herceptin) plus carboplatin/paclitaxel (for HER2-positive uterine serous carcinoma or carcinosarcoma);
• Carboplatin/paclitaxel for carcinosarcoma

The category 1 recommendation for biomarker-directed therapy after platinum-based therapy, including neoadjuvant treatment for mismatch repair proficient (pMMR) tumors, is lenvatinib [Lenvima] plus pembrolizumab.

The panel also highlighted results from the phase 3 KEYNOTE-868 trial (NCT03914612), the phase 3 RUBY trial (NCT03981796), and the phase 3 DUO-E trial (NCT04269200) (Table).^2-4

Second-Line Options

Campos: What is our perception of the 5-year data from the phase 3 KEYNOTE-775 trial [NCT03517449]?⁵ For a patient with pMMR disease progressing after a frontline immunotherapy [IO]/chemotherapy regimen, are these data sufficient to make pembrolizumab/lenvatinib your second choice, or are there other patients where you would like to use another choice first? Wendy, you’re in my clinic all the time; what do you think?

Young: You’d probably go to trastuzumab deruxtecan [T-DXd; Enhertu] first if they were HER2 positive.For other clinicians, it depends on the [adverse] effect profile. We’ve had good luck with [T-DXd] knowing that pembrolizumab/lenvatinib would still be available afterwards.

Bradford: I'm so conflicted about [lenvatinib/pembrolizumab] because I hate the [adverse] effect profile. Then, you look at that response rate, and it’s like, how are we not using this? Then, I think of my poor nurses answering all these phone calls about diarrhea. It is a discussion. It depends on the biomarkers. If they’re HER2 positive, [there are other] options for patients.

I do find myself having to remind myself of the objective data showing this incredible response rate and having to sometimes suck that up and put them on [lenvatinib/pembrolizumab] knowing that there are going to be a lot of phone calls about diarrhea.

Antibody Drug Conjugates

Campos: We all know that there are so many antibody drug conjugates [ADCs], some of which we can use in our clinic, some of which we can’t. The one that Wendy referenced was T-DXd, and this emanates from a very popular trial, the DESTINY-PanTumor02 trial [NCT04482309].⁶ This was, in essence, a simple trial that gained such amazing popularity because of its results. As we remember, this was not only in GYN cancer but multiple different disciplines. For the purposes of our discussion, it’s going to be GYN and endometrial [cancer]. These were patients who had had 2 prior lines of therapy. HER2/neu expression had to be either IHC 3+ or 2+.

When do you consider HER2/neu testing in your [patients with] endometrial cancer? At what point in the treatment journey are you routinely retesting HER2/neu status at recurrence? How are you currently using the HER2/neu testing results to guide therapy in recurrent disease?

Young: Yes. 100% of the time. Then, we’ll rebiopsy them as well if they are HER2-0 or 1+.

Campos: There are several clinical trials that are even looking at HER2/neu 1+. It’s quite important to get some testing done. How does HER2/neu status, IHC 2+ vs 3+ influence your decisions? We’re all very familiar with the fact that the FDA approved T-DXd for solid tumors that are 3+.⁷ The NCCN guidelines, given the data of the DESTINY-PanTumor02 trial, expanded that to both 2+ and 3+. Does this influence your treatment decisions? Does it matter if they’re IHC 2+ or 3+?

Paraghamian: It doesn’t make a huge difference to me, but my experience has definitely been very remarkable with the 3+ patients, and I’ve still been impressed with responses in the 2+ patients. I have a 3+ patient who’s now over 1.5 years with no evidence of disease, and she’s been tolerating T-DXd well. I haven’t seen that with the 2+ [population]. With a 3+ patient, I’m very excited to be able to offer that to them, and I’m inclined to use it right away. With a 2+ patient, if there was a potential clinical trial option, I might favor that. I don’t know that I would be excited about just throwing lenvatinib/pembrolizumab at them. I would still use T-DXd in a 2+ patient, certainly.

Campos: We could go on and on about ADCs for endometrial cancer, but there is a group of them that are coming up that are incredibly interesting. One of them is rinatabart sesutecan [Rina-S] in ovarian cancer; the RAINFOL-01 trial in ovarian cancer closed in a heartbeat based on a particular cohort: the B2 cohort.⁸

Where do you think Rina-S might fit into the treatment paradigm, if approved? We have chemotherapy plus IO, we have pembrolizumab/lenvatinib, and we have T-DXd. Where does Rina-S fit into our treatment paradigm?

Paraghamian: I imagine using this in second-line setting. Hopefully, it’ll be approved and available for patients who don’t have another biomarker-directed therapy. I would be using it early.

Bradford: I’ll admit my bias. I’ve been excited about Rina-S in a variety of disease sites. It is going to be an option for those patients who don’t have other biomarker options and where we don’t have a marker necessarily, and the efficacy data are great. The question is, and I don’t know if we have the data yet with some of these ADCs, is also balancing that toxicity earlier on as we move it further along in treatment. The hematologic toxicity is severe with a lot of these [ADCs]. If you’re doing that up front, are we going to [harm] their bone marrow? Are they going to tolerate subsequent lines? I don't think we know that yet. It’s always been in the back of my mind, but I’m excited about it.

Campos: How are you thinking about the emerging ADC data in this space? Are there any agents that you’re particularly excited about?

DiSilvestro: The folate receptor drugs have been trying to work their way into the endometrial space for a while now. Rina-S is an exciting option. Hopefully, we’ll see the phase 3 RAINFOL-3 trial [NCT07166094] give us a nice positive result.

Key Takeaways

Berman: It’s important to consider sequencing. I thought the data that you shared with the platinum-free interval, specifically in endometrial cancer, is something that we don’t often discuss. That was interesting to consider and to learn about our colleagues' practice and how we extrapolate platinum sensitivity and resistance in the endometrial cancer setting. If there’s a longer interval, I would re-challenge, and if there was a shorter one, I wouldn't. I’m also considering patient comorbidities, but that’s one of the takeaways. Most of us use IO, but then considering that there was no residual disease for patients with pMMR [status], would we maybe consider holding IO and using it in a later setting? Just a disclaimer for the dostarlimab: in the frontline setting, I still don’t know if I would use it, even though it’s a different mechanism than lenvatinib/pembrolizumab because of the 3-year maintenance paradigm setting.

Bae: First, the platinum-refractory [population]: that concept was so vague to me all this time, but it was very helpful to know. Even [among] GYN experts, it’s not very clearly defined. That was helpful to know. I didn’t know that with T-DXd, you can use it for 2+ [populations] until now. For a solid tumor, I thought it was only 3+, so it was very helpful. I was always curious what to do when a patient has disease progression while on IO maintenance. Now, I think I have a better idea what to do with this. It was a very helpful session today for me.

Paraghamian: Some of the things that I always like when seeing and reflecting on the data are the data on lenvatinib/pembrolizumab.

Yu: Something that was interesting to me is thinking about whether sequencing IO after IO can be affected by switching the IO drug. Tara, you mentioned that some of our colleagues give dostarlimab in the front line so that they can use pembrolizumab and lenvatinib in the subsequent line. What about durvalumab? It’s a PD-L1 inhibitor instead of PD-1. Would that matter? I don’t know the answers to any of these questions, but it’s interesting to think about going forward, maybe in a retrospective context.

Young: It was a very helpful conversation for sure. I learned about sequencing and thinking more about quality of life, too. Thinking about 3 years of maintenance, it’s a long time for a lot of patients to commit to. T-DXd is one of our favorite drugs right now, for sure. For some patients, we’ve had people who have so much difficulty, not even with the [adverse] effects of taking the pills, but just remembering to take the pills, taking them wrong, and the cost of them because it’s run through a different program on their insurance. Thinking about all the options, it’s a much more exciting time, option-wise, for these patients than it was 20 to 25 years ago when I started.

Bradford: I agree with everybody. I think the sequencing of IO after IO is a topic of current clinical trials. It needs to be studied. As much as I love a prospective randomized control trial, I have a suspicion that might be a question we answer more with real-world evidence, given some of the smaller series of people adding in lenvatinib to pembrolizumab, which is OK if we can get robust, observational data to show that's effective. For those of you who are doing it in practice, please combine it. Pull your data so that we can maybe have something.

DiSilvestro: I was surprised by the lenvatinib/pembrolizumab data as they relate to the prior platinum-free interval presented. That’s compelling. I don’t know if it takes me away from my position of doing everything I can not to use it, but it’s certainly compelling. With the new ADCs in endometrial cancer, it’s exciting. It’s going to be interesting to see the RAINFOL-3 trial and how that turns out over time. The upfront data for Rina-S are compelling, and the toxicity data are good, which will be presented at the 2026 Society of Gynecologic Oncology Meeting.

Bolla: After listening to this, I maybe have to start thinking more of dostarlimab. That way, I can sequence with pembrolizumab/lenvatinib for the future lines.

References

1. NCCN clinical practice guidelines in oncology. Uterine Neoplasms, version 2.2026. Accessed March 27, 2026. https://tinyurl.com/4x22yxy2
2. Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer. N Engl J Med. 2023;388(23):2159-2170. doi:10.1056/NEJMoa2302312
3. Powell MA, Bjørge L, Willmott L, et al. Overall survival in patients with endometrial cancer treated with dostarlimab plus carboplatin-paclitaxel in the randomized ENGOT-EN6/GOG-3031/RUBY trial. Ann Oncol. 2024;35(8):728-738. doi:10.1016/j.annonc.2024.05.546
4. Westin SN, Moore K, Chon HS, et al. durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab with or without olaparib as first-line treatment for advanced endometrial cancer: the phase III DUO-E trial. J Clin Oncol. 2024;42(3):283-299. doi:10.1200/JCO.23.02132
5. Makker V, Colombo N, Casado A, et al. Lenvatinib plus pembrolizumab in previously treated advanced endometrial cancer: 5-year outcomes from the randomized, phase 3 Study 309/KEYNOTE-775. J Immunother Cancer. 2026;14(2):e013713. doi:10.1136/jitc-2025-013713
6. Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: primary results from the DESTINY-PanTumor02 phase II trial. J Clin Oncol. 2024;42(1):47-58. doi:10.1200/JCO.23.02005.
7. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. News release. FDA. April 5, 2024. Accessed March 30, 2026. https://tinyurl.com/mtm9fbte
8. Genmab announces new data demonstrating investigational rinatabart sesutecan (Rina-S®) achieved anti-tumor activity in heavily pretreated patients with advanced endometrial cancer. News release. Genmab A/S. October 18, 2025. Accessed March 30, 2026. https://tinyurl.com/ymsjkftk