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FAQs: Adv EC
Answers to Frequently Asked Questions on the Rapidly Evolving Landscape in the Management of Patients With Advanced Endometrial Cancer

Released: June 12, 2024

Expiration: June 11, 2025

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Key Takeaways
  • For patients with early endometrial cancer or for whom p53 status is needed quickly, testing via protein assays such as immunohistochemistry work best; for patients with advanced-stage and/or recurrent disease, a full NGS panel is recommended. 
  • Pending FDA approval, addition of PARP inhibitor maintenance in advanced/recurrent pMMR endometrial cancer is being considered.
  • To date, there have been no reports of increased risk of AML or MDS with the addition of PARP inhibitor maintenance in patients who are receiving platinum-based chemotherapy plus immunotherapy in the DUO-E and RUBY part 2 phase III clinical trials.

The field of endometrial cancer care is rapidly evolving, with a growing need for oncology healthcare professionals (HCPs) to remain up to date on the individualized treatment of patients with advanced and recurrent endometrial cancer, as well as exciting new options on the horizon. In this commentary, we provide answers to questions posed by a live audience of oncology HCPs during a webinar on gynecologic cancers following the 2024 Society of Gynecologic Oncology (SGO) Annual Meeting.

What are your thoughts about the efficacy of adding immunotherapy to first-line platinum-based chemotherapy in the subgroup of patients with NSMP (no specific molecular profile) endometrial cancer?   

Ramez N. Eskander, MD:
At SGO 2024, Dr Manzoor Mirza presented a subgroup analysis from part 2 of the phase III RUBY trial evaluating dostarlimab plus chemotherapy followed by dostarlimab plus niraparib maintenance in primary advanced or recurrent endometrial cancer. In that report, subgroup analyses showed a correlation with TP53-mutated status and lower progression-free survival (PFS) benefit, albeit in small numbers, in the NSMP population. I will just say that we have to be cautious about interpreting those data because that was a subset analysis and was not controlled for other variables that could affect these data. I also will mention that the main difference in PFS was due to the control arm doing much worse in the TP53-mutated population. We see a substantial drop for that group at about 8 months. Thus, for me it is somewhat informative, but I would not use it to guide my treatment decisions.

If, after FDA regulatory review for the phase III DUO-E trial, the quadruplet combination of durvalumab immunotherapy plus carboplatin/paclitaxel followed by maintenance durvalumab plus olaparib in patients with mismatch repair deficient (dMMR) and mismatch repair proficient (pMMR) status obtains approval in a population of patients similar to the DUO-E trial, in the pMMR population I am going to use that opportunity to pursue the DUO-E regimen in my practice.

Shannon N. Westin, MD, MPH, FASCO:
I agree. We will learn which population benefits the most. To your point, if DUO-E receives approval across broad-based molecular subtypes such as pMMR, as a start we may begin to use that for everybody. But if we can determine which patients benefit the most, of course we will focus on that approach. My question has always been, is there a way to measure homologous recombination deficiency (HRD) in endometrial cancer? This potentially would be a strong indicator for the use of a PARP inhibitor for that population. For DUO-E, we did a broad-based study because at the time we did not know how to even test for HRD in endometrial cancer. Now, however, we can use the study results to look back and say, “Okay, this is a population that appears to be HRD+, and it appears to benefit the most from the addition of a PARP inhibitor.” So, I am eager to look at the translational data in the hope that it will help us understand more about what it all means. Again, at this time, this is all hypothesis generating, but potentially it can help us target the appropriate clinical use and inform future trial development. 

What is the best way to pursue TP53 status testing in patients with advanced/recurrent endometrial cancer?

Shannon N. Westin, MD, MPH, FASCO:
We have seen data presented for immunohistochemistry (IHC) compared with next-generation sequencing (NGS)  that show a strong correlation between the 2 approaches for the assessment of TP53 status. However, in resource-limited settings, or if you want to get results much faster, using IHC or p53 protein testing is a good choice. Clearly, if you are doing the POLE mutation testing, then NGS is your best choice because of testing a panel. But again, if you are going to pursue TP53 gene testing via NGS anyway, but that is going to take too long, I think it is reasonable to make decisions and utilize information based on p53 from that preliminary IHC protein testing. 

For “up-front” early-stage disease, we are testing everyone using protein assays––IHC. And then if we see an aberrant p53 result, we often will send for NGS to see if that TP53 gene aberration is driven by POLE. That said, that patient is not necessarily as high risk as we might think. For advanced and recurrent disease, however, we are getting NGS for all patients because we believe there is a much higher chance that we are going to need to make future decisions based on knowing what the molecular status is for that patient. Dr Eskander, what approach are you using in your practice?

Ramez N. Eskander, MD:
Our approach is very similar. We are pursuing IHC p53 protein testing as much as we can, as you alluded to, but also mismatch repair, HER2, and estrogen receptor/progesterone receptor testing. In speaking to our pathologists, it can be challenging to “carve out” all these molecular categories of advanced endometrial cancer based on the initial IHC assessments alone. For us as well, any patient with advanced-stage and/or recurrent endometrial cancer is recommended for full NGS analysis. 

Do you have any concerns in relation to increased risk of acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and other such malignancies with the addition of PARP inhibitor maintenance to those patients who are receiving platinum-based chemotherapy plus immunotherapy, such as in the DUO-E and RUBY part 2 trials?

Shannon N. Westin, MD, MPH, FASCO:
I can speak about our experience with the DUO-E trial. To date, with approximately 21 months of follow-up, we have not yet seen any cases of AML or MDS in the treated population. This is obviously not as long as we need to assess for this, but certainly early data are encouraging. And perhaps, like in ovarian cancer, when patients receive PARP inhibitors earlier during the course of treatment, maybe the rates of MDS and AML are a bit lower.

For a patient with recurrent disease and dMMR status, after previous chemotherapy and pembrolizumab previously achieving complete response, would you recommend a different chemotherapy partner with pembrolizumab, or would you consider pembrolizumab and lenvatinib? In addition, do you have any thoughts about the utility of lenvatinib plus pembrolizumab in relapsed patients with dMMR endometrial cancer? 

Ramez N. Eskander, MD:
This is the question that we are all presently struggling with. For me, it depends on a few things—first, if the patient’s disease has a dMMR status, and then the patient received platinum-based chemotherapy plus immunotherapy and progressed while receiving an immune checkpoint inhibitor. A report by Dr Peter Rose and colleagues looked at a retrospective Institutional Review Board–approved series of 8 patients with dMMR status who experienced failure or progression while receiving immune checkpoint inhibitor (pembrolizumab) monotherapy who then went on to receive treatment with lenvatinib plus pembrolizumab. In total, 6 of the 8 patients had reduction in their tumor size (1 complete response and 5 partial responses), and 2 patients achieved stable disease per Response Evaluation Criteria in Solid Tumors criteria. I will say that all of them had some reduction in tumor volume, and for me that is a signal. I cannot say that I know the definitive answer here, but we do have some choices, and clinical trials are often an option. Some may say, “If I gave one checkpoint inhibitor in the first-line setting, then I can try to give a different checkpoint inhibitor for subsequent therapy.” I am not very confident about that approach––switching to the same class of drug to try to elicit a response. For me, I would check for molecular biomarkers in that patient, and although they are not frequent in the dMMR population, I have seen a subset with HER2-positive status. Other than that, we have the traditional chemotherapy options we have used in the past. Dr Westin, what are your thoughts?

Shannon N. Westin, MD, MPH, FASCO:
I agree. I do not know if there is a perfect answer at this point for what to do in the recurrent setting after patients have received chemotherapy plus immunotherapy in the first-line setting. This is a clear unmet need for clinical research to address moving forward. Now that trastuzumab deruxtecan is an option in previously treated patients with HER2-positive solid tumors, we can check the HER2 status for our patients with gynecologic cancer. As a reminder, for our readers, trastuzumab deruxtecan is a HER2-directed antibody–drug conjugate, now approved for use in patients with solid tumors, including advanced endometrial cancer, who have a HER2 IHC score of 3+ and no other satisfactory alternative treatment options available, based on data from the phase II DESTINY-PanTumor02 trial. 

Ramez N. Eskander, MD:
Yes, and I do hope we get those answers. Lastly, in the population with microsatellite instability–high or copy number–low disease, it was unclear what the benefit of adjuvant therapy might be as far as chemotherapy was concerned. That remains to be assessed in a larger nonexploratory subgroup setting. 

Your Thoughts?
What are your thoughts or questions on the rapidly evolving treatment landscape for patients with advanced endometrial cancer? Answer the polling question and join the conversation by leaving a comment. Also, feel free to visit the overall program page to view the on-demand webcast from the live event and access downloadable slides on this topic.

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