Dr Westin on Development Strategies for B7-H4–Directed ADCs in Gynecologic Cancers

“I think this is a really big opportunity for potential combinations and really changing the standard of care again.”

Shannon N. Westin, MD, MPH, FACOG, a professor and clinical medical director in the Department of Gynecologic Oncology and Reproductive Medicine in the Division of Surgery, director of Early Drug Development in the Department of Gynecologic Oncology and Reproductive Medicine, and co-director of the Ovarian Cancer Moonshot Program at The University of Texas MD Anderson Cancer Center, discussed the development of B7-H4–directed antibody-drug conjugates (ADCs), such as mocertatug rezetecan (GSK5733584) and puxitatug samrotecan (AZD8205), in endometrial and ovarian cancers, including differing biomarker strategies and potential roles in earlier lines of therapy.

B7-H4 is expressed at fairly high levels across gynecologic malignancies, particularly endometrial and ovarian cancers, Westin said. Two development strategies have emerged, she explained: one in which an agent is given regardless of expression, with retrospective analyses of whether expression level matters, and another in which patients must exceed a predefined expression cut point to receive treatment.

In the phase 1 BEHOLD-1 study (NCT06431594), mocertatug rezetecan produced confirmed objective response rates of 62% (95% CI, 46.5%-76.2%) in platinum-resistant ovarian cancer at 5.8 mg/kg (n = 45) and 67% (95% CI, 35%-90%) in endometrial cancer at 4.8 mg/kg (n = 12), with responses observed across a range of B7-H4 expression levels. Puxitatug samrotecan is being evaluated in B7-H4–selected endometrial cancer in the phase 3 BLUESTAR-Endometrial01 trial (NCT07044336).

Efficacy has been similar across these approaches so far, Westin noted. She added that she favors biomarker-directed strategies but that when a target is highly expressed across a tumor type, testing may not be necessary.

According to Westin, these agents have produced high response rates that appear durable, and they may be more tolerable than ADCs directed at other targets, with lower rates of mucositis and fatigue, which can be troublesome with this drug class.

Beyond a potential role in the second-line setting, Westin highlighted opportunities to improve frontline therapy, such as using a B7-H4–directed ADC in place of a chemotherapy partner in regimens like the one evaluated in the phase 3 DUO-E trial (NCT04269200), or combining an ADC with immunotherapy. Most of these agents carry topoisomerase I inhibitor payloads, and emerging data suggest that topoisomerase I inhibition may help overcome PARP inhibitor resistance and may be synergistic with immunotherapy, she explained.