Emi-Le ADC Shows Early Promise Across B7-H4–Expressing Tumors

Emiltatug ledadotin (Emi-Le; XMT-1660), a novel B7-H4–targeted antibody-drug conjugate (ADC), demonstrated early antitumor activity across multiple tumor types, including triple-negative breast cancer, endometrial cancer, and adenoid cystic carcinoma, in a phase 1 dose-escalation study (NCT05377996), with a manageable safety profile.

In an interview with Targeted Oncology, Erika Hamilton, MD, director of breast cancer research at the Sarah Cannon Research Institute, discussed the rationale behind targeting B7-H4, the unique features of the Emi-Le construct, and what makes this agent a promising candidate in the evolving ADC landscape. She also shared insights on early safety signals, tumor types of interest, and next steps in clinical development.

Targeted Oncology: Can you discuss the mechanism of action of Emi-Le?

Erika Hamilton, MD: Emi-Le is a B7-H4[–targeting] antibody-drug conjugate. What is unique about this drug is it is a novel payload. It is an auristatin payload, and it is not an auristatin that you are familiar with. It is not an MMAE, it's not an MMAF; [it is] a new, novel auristatin payload. Then B7-H4 is also a new target for us. In the land of ADC resistance, we have seen some resistance of topo-1 ADCs after another topo-1 ADC, but I think it is important to file this away as both a novel target as well as a novel payload.

What were some of the key safety and tolerability signals from this phase 1, dose-escalation study?

B7-H4 is highly expressed across a lot of different tumor types. In this particular trial, we enrolled [patients with] breast cancer, both triple-negative breast cancer as well as [estrogen receptor (ER)]-positive, some of the gynecologic cancers such as ovarian cancer and endometrial cancer, and a cancer that's a little bit more rare—adenoid cystic carcinoma—as they have very high B7-H4 expression on tumor as well.

What we saw in the way our trial was designed was really a standard dose escalation. We kind of grouped these into subclinical doses, an intermediate dose, and a high dose. And a lot of the data we presented was around this intermediate dose. What we saw was, in the intermediate dose range, the objective response rate was 31% if we select specifically for the patients with triple-negative breast cancer.

I think this was encouraging…because 93% of the patients with triple-negative breast cancer here had already seen at least topo[isomerase]-1 ADC. And in fact, a quarter of them had already seen 2—essentially both sacituzumab govitecan [Trodelvy] and trastuzumab deruxtecan [T-DXd; Enhertu].

We saw an objective response rate of 23% in endometrial. We saw a response rate of 50%. And then very encouraging—in the small number, 9 patients with adenoid cystic carcinoma—we saw a response rate of over 55%, and 5 of the 9 patients are still ongoing on treatment.

What were the most common adverse events observed?

Our most common adverse events were [aspartate aminotransferase (AST)]/[alanine aminotransferase (ALT)] increase. This is transient and then reversible. And luckily, needing to dose only every 4 weeks, we haven’t encountered too much issue with that. We also can see fatigue and nausea. All of these are predominantly low grade.

We are also following proteinuria, and this is not a proteinuria like a bevacizumab [Avastin] that you think about, but it actually comes from leaky podocytes. We have recognized that stopping the drug is completely reversible. We are able to be a little bit more liberal with a little bit of the protein now that we know that this is not a concerning type of proteinuria.

Based on these initial findings, what tumor types do you think this is most promising for?

Currently, we are still enrolling in this trial in the triple-negative breast cancer expansion. We are selecting for patients that have had 1 to 4 prior [lines of therapy], because we saw particularly that progression-free survival was lengthened if we did not get above that fifth line of therapy—not surprising. We continue to enroll patients there. But I think that the data in adenoid cystic [carcinoma] looked very encouraging. I could see us looking at this drug in several other tumor types as well.

What are the next steps that you anticipate or recommend for development?

We are continuing to enroll into the triple-negative breast cancer expansion cohort, and we are looking at 2 different doses: the 67 mg/m² every 4 weeks, and then also a different dose level that is in the 40s, essentially given day 1, day 8, and then a little bit higher every 4 weeks after that—just once every 4 weeks at 80 mg/m². A little bit more of refining the dose, more information around those triple-negative breast cancer patients that have already seen topo-1 ADCs. And then I anticipate we're going to be looking at other tumor types as well.

Are there any other trials that are evaluating the B7-H4 expression?

There are other B7-H4 ADCs out there. I think this one is unique because of the auristatin payload. I think we are recognizing that resistance to ADC comes from both the target as well as the payload. A lot of our ADCs in development right now are topo-1 ADCs, which tends to be where we already have a rich option of drugs in the breast cancer setting. I am particularly interested in these ADCs that bring in a novel payload.

REFERENCE:

Hamilton EP, Han HS, Kalinsky K, et al. Initial phase 1 dose escalation data for emiltatug ledadotin (Emi-Le), a novel B7-H4-directed dolasynthen antibody-drug conjugate. J Clin Oncol. 2025;43(suppl_16):3009. doi:10.1200/JCO.2025.43.16_suppl.3009