ADCs are rapidly emerging in the treatment landscape for endometrial cancer, offering promising efficacy in biomarker-selected patient populations. Several presentations at the 2026 ASCO Annual Meeting shared data that build on this research.

Following these presentations, featured expert Charles A. Leath 3rd, MD, MSPH, FACS, FACOG, was interviewed by Conference Reporter Medical Director Noreen Iftikhar, MD. Clinical perspectives from Dr Leath on these findings are presented here.

Over the past 5 years, what we have seen in gynecologic cancer is a rapid and persistent interest in ADCs. As we know, ADCs have been approved by the US Food and Drug Administration (FDA) for both ovarian and cervical cancers. Just as with other gynecologic cancers, we used to lump all patients with endometrial cancer together. So, this should be a cautionary tale: if we treat all these tumor types the same, we may miss potential benefits for certain patient populations.

I think most would agree that the DESTINY-PanTumor02 study, which looked at trastuzumab deruxtecan and its use in HER2 overexpressors, was a game changer for endometrial cancer. This study ultimately led to an FDA approval for patients with immunohistochemistry 3+ solid tumors. DESTINY-PanTumor02 was a relatively small study (approximately 40 patients per cohort), and, although it was not designed to compare results between malignancies (eg, gynecologic vs gastrointestinal), the observations suggested that gynecologic cancers did very well on this treatment—perhaps better than some other tumor types. And interestingly, even though the ultimate FDA approval was limited to HER2+ immunohistochemistry 3+ tumors, some patients with limited expression, who perhaps still had activity, still had a response, suggesting the potential more inclusive treatment as well as bystander effects of ADCs.

At ASCO 2026, during a session chaired by David M. O’Malley, MD, a presentation by Funda Meric-Bernstam, MD, FASCO, looked at how we can use ADCs in patients with endometrial cancer. During her presentation, Dr Meric-Bernstam provided a very nice summary on some of the proposed mechanisms of resistance. The exact mechanisms of resistance to ADCs are yet to be fully understood. Are we losing a target? Is posttherapy downregulation occurring in a patient who initially had overexpression? Are we seeing changes in some processes (eg, the agent is being pumped out of the cells or degraded)? I think that Dr Meric-Bernstam’s discussion was very informative. Ultimately, determining the mechanisms of resistance is going to be necessary to design therapies that can take advantage of that resistance. And, again, like many things in gynecologic cancer, because our cancers are relatively uncommon, we often extrapolate some of our understanding from other tumor types, specifically breast cancer.

Another challenge in gynecologic cancer is trying to get pathologists to agree on evaluation metrics because HER2 scoring is tumor-type specific. There is not really an HER2 status for ovarian, cervical, or endometrial cancer, so we have had to adopt the gastric HER2 scoring algorithm that was used in the DESTINY-PanTumor02 trial. Ultimately, this is important to identify patients who are eligible for trastuzumab deruxtecan treatment in clinical practice.

Despite some of these challenges, as my colleagues Floor Jenniskens Backes, MD, MBA (abstract TPS5645), Noelle Cloven, MD (abstract TPS5646), and Stephanie Gaillard, MD, PhD (abstract TPS5647), discussed in their trials-in-progress poster presentations at ASCO 2026, early clinical trial cohorts have shown promising activity for investigational ADCs for endometrial cancer in dose escalation schemas. So, once the maximum-tolerated or recommended phase 2 dose is used in clinical practice, it is possible that we will see greater-than-expected response rates. And, as we are seeing these ADC cohorts being reported out, it seems like the response rates and activity are better than what we would expect with traditional second, third, and greater lines of chemotherapy.

However, while the activity of many of these agents is better than what we have seen with traditional cytotoxic chemotherapy, there have been substantial toxicities reported. From DESTINY-PanTumor02, we know that the incidence of severe and potentially fatal interstitial lung disease is something that we cannot overlook. As we continue to use ADCs, I think we need to make sure that we are using and monitoring them appropriately. We may learn about toxicity management from trials in other tumor types, along with, perhaps, ways to minimize toxicities and improve surveillance for these toxicities.