B7-H4–Targeted ADCs Signal a New Frontier for Platinum-Resistant Ovarian and Endometrial Cancer

Antibody-drug conjugates (ADCs) continue to reshape treatment for platinum-resistant ovarian cancer (PROC) and recurrent endometrial cancer, with the immune checkpoint molecules B7-H3 and B7-H4 emerging as the field’s newest targets.

“Those two molecules are known to be overexpressed in both ovarian and endometrial cancers and that makes them an ideal target,” Dana Chase, MD, said in an interview with OncLive®. “They also have potential potent immunosuppressive roles in the microenvironment. Those two characteristics make these ideal targets that [possess] unique immune regulatory characteristics.”

In an interview with OncLive®, Chase discussed the significance of the phase 1 BEHOLD-1 data (NCT06431594) for mocertatug rezetecan (Mo-Rez); the rationale for combining Mo-Rez with dostarlimab-gxly (Jemperli) in the phase 1/2 BEHOLD-2 trial (NCT06796907); early data for puxitatug samrotecan (PSAM; AZD8205) from the phase 1/2a BLUESTAR trial (NCT05123482); and how the field should think about sequencing B7-H4–targeted ADCs against existing agents such as mirvetuximab soravtansine-gynx (Elahere), fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu), and tisotumab vedotin (Tivdak).

Chase is a professor of clinical obstetrics and gynecology in the Division of Gynecologic Oncology at UCLA Health in Los Angeles, California.

OncLive: Why has B7-H4 emerged as an attractive ADC target in gynecologic cancers specifically, and what makes its expression profile different from targets that are already exploited like FRα or HER2?

Chase: There are multiple novel targets that the current ADC class of medications are targeting, and one of the novel targets includes these immune checkpoint molecules B7-H3 and B7-H4.

The BEHOLD-1 data for Mo-Rez presented at the 2026 SGO Annual Meeting drew a lot of attention. How do you interpret a confirmed objective response rate in the 60% range in PROC, and does it justify launching multiple pivotal phase 3 trials?

Yes, so that B7-H4 drug that’s part of the BEHOLD trial portfolio is otherwise known as Mo-Rez, and they presented results in the PROC setting, as well as in the recurrent endometrial cancer setting. In both disease sites saw response rates that were in the 60% range. If that pans out, that is on the better side of response rates that we’ve seen for both recurrent PROC and endometrial cancer. Other ADC medications are getting to 60% but being that Mo-Rez demonstrated response rates over 60% at least in the phase 1/2 setting is impressive, and I suspect that’s what led to launching several phase 3 trials after those results were presented.

With respect to BEHOLD-2, can you walk us through the rationale for combining Mo-Rez with dostarlimab in the endometrial cancer population, particularly in the pMMR, MSS population that part 1B is enrolling?

Patients with advanced or recurrent metastatic endometrial cancer that is mismatch repair proficient [pMMR] don’t have a robust response to immunotherapy alone in the maintenance setting, or immunotherapy with drugs like lenvatinib [Lenvima]. There’s a big unmet need in the population of patients with advanced recurrent pMMR disease who have completed first-line platinum-based chemotherapy with or without immunotherapy followed by immunotherapy maintenance. That patient population really needs more approaches to improve their outcomes, specifically their survival outcomes. It would be nice to see a lengthening in progression-free survival [PFS] as well. From the previous phase 3 trials using immunotherapy alone in maintenance, we really hope that we’ll start to see significant differences in overall survival [OS]. The idea is maybe if you combine the immunotherapy agent, the dostarlimab or pembrolizumab [Keytruda] with Mo-Rez, that that potentially in a maintenance setting could improve outcomes in that specific patient population.

How is BEHOLD-1 structured to inform the phase 3 program, especially BEHOLD-Endometrial02 trial (NCT07684599) in pMMR disease, and what have you learned about managing the overlapping toxicities when you layer a topoisomerase-I ADC on top of a checkpoint inhibitor?

The BEHOLD-1 data told us told us that overall, the toxicities from Mo-Rez are tolerable. There are some cytopenias and some nausea or gastrointestinal toxicity, but very few grade 3 or 4 events that would make us concerned for things such as ocular toxicity or interstitial lung disease. If that pans out in a phase 3 setting, it really doesn’t look like there’s going to be much overlapping toxicity with Mo-Rez on top of a checkpoint inhibitor. Checkpoint inhibitors do not traditionally do not cause cytopenias, nor do they cause severe nausea or vomiting, so combining Mo-Rez, which potentially could cause cytopenia or nausea, with a checkpoint inhibitor, I don’t suspect that that overlapping toxicity would be too detrimental to the patient, but time will tell. We’ll have to see how this pans out in the phase 3 setting.

Puxitatug samrotecan is furthest along in endometrial cancer. What stands out about the BLUESTAR results, particularly in patients who've already progressed on platinum and a checkpoint inhibitor?

PSAM is another B7-H4-targeting ADC, and in the recurrent endometrial patient population, we saw response rates in the mid-40% range, and then 60% in patients specifically with prior platinum and immunotherapy. It would be exciting if we could use PSAM in a patient with recurrent endometrial cancer who has gotten prior immunotherapy and prior platinum. If we could get response rates of 60% or higher with impactful end points like PFS or OS, that would be awesome. It would be great to be able to see that in our patients with recurrent endometrial cancer.

Do we need a B7-H4 IHC assay to use these drugs or is activity agnostic of expression level?

It seems like B7-H4 is widely expressed in both ovary and endometrial cancer, so most of my patients will have the biomarker. Because of that, the biomarker profile of the patient isn’t really going to matter because most patients are going to have the biomarker, but we need to learn more about that. I’m not sure I can say with great confidence that patients will not need to be tested, and I don’t know if there’s going to be a range of biomarker-positive patients. But, from what I understand, most patients with endometrial or ovarian cancer express high levels of B7-H4.

The payload chemistry differs across these ADCs. Pfizer discontinued the vedotin-based felmetatug vedotin, while the topoisomerase-I agents are advancing. What does that tell us about payload choice, and how should community oncologists manage the toxicities they’ll see?

We’re really seeing a lot of ADCs with a topoisomerase-I inhibiting payload. We don’t know much about whether prior exposure in patients who’ve already had a topoisomerase-I type payload ADC drug is going to impact future exposure. We still don’t completely understand whether the same payload is going to be as effective in a patient who has previously received a drug with a similar payload and whether that’s a good strategy in gynecologic cancers. Why most ADCs are [being developed with] a topoisomerase-I payload I don’t have a good answer for, but these days we have a lot of experience with drugs at this point that have a topoisomerase-I payload, such as T-DXd. At this point, we [have a good] understanding of their toxicity [profiles], and hopefully these new ADCs like PSAM or Mo-Rez are not going to have more toxicities that we don’t already understand.

Looking at the crowded gynecologic ADC landscape with mirvetuximab soravtansine, T-DXd, tisotumab vedotin, and now B7-H4 agents, how do you see these fitting together in sequence, and is ADC-after-ADC a viable strategy given overlapping payloads and toxicities?

Ideally, if we’re moving these ADCs into the first line, the hope is that maybe more patients will be cured and not need an ADC in the recurrence setting. But I’m guessing the reality is still there’s going to be a portion of patients that have not been cured and are going to need second-line therapy. I am not super confident yet that if you have a drug with the same payload that it is going to be as effective in the recurrence setting. We do have some data, single-institution or retrospective data that in gynecologic cancers tell us that using drugs previously that have a similar mechanism of action, although not in an ADC type of mechanism, that an ADC with a similar payload can be effective. But it’s a little premature to be able to say for sure that we can use an ADC after an ADC when the payloads are the same.