Sequencing B7-H4–Targeted ADCs and Optimizing Toxicity Management in Gynecologic Cancers

Welcome to OncLive On Air®! I’m your host today, Caroline Seymour.

OncLive On Air is a podcast from OncLive®, which provides oncology professionals with the resources and information they need to provide the best patient care. In both digital and print formats, OncLive covers every angle of oncology practice, from new technology to treatment advances to important regulatory decisions.

In today’s episode, we spoke with Angeles Alvarez Secord, MD, MHSc. Dr Secord is a professor of obstetrics and gynecology and a member of Duke Cancer Institute in Durham, North Carolina.

In our exclusive interview, Dr Secord discussed the emergence of B7-H4 as an attractive antibody-drug conjugate (ADC) target in gynecologic cancers, noting that expression rates of 80% to 90% or higher across endometrial and ovarian cancers distinguish it favorably from other targets such as folate receptor α and HER2, where high expression thresholds are often required for meaningful benefit. She also highlighted a mechanistic distinction: unlike FRα- or HER2-directed ADCs, which target proteins involved in growth signaling, B7-H4 is more deeply embedded in immune regulation, making it a potentially powerful tool for converting immunologically cold tumors into ones that can respond to checkpoint inhibition.

She reflected on the phase 1 BEHOLD-1 trial (NCT06431594) data presented at the 2026 SGO Annual Meeting on Women’s Cancer, describing the confirmed overall response rate of over 60% in platinum-resistant ovarian cancer as remarkable in a disease where traditional chemotherapy achieves response rates of 15% or less. Dr Secord expressed strong support for the decision to advance this agent into five pivotal phase 3 trials, noting that data of this magnitude clearly justifies further development.

As principal investigator at Duke for the phase 1/2 BEHOLD-2 trial (NCT06796907), Dr Secord walked through the rationale for combining mocertatug rezetecan with dostarlimab-gxly (Jemperli) in endometrial and ovarian cancer. She explained that by suppressing B7-H4’s immunosuppressive effect in the tumor microenvironment, the ADC paradoxically increases immune stimulation and generates neoantigens through cell kill, creating a primed setting for dostarlimab to deliver a synergistic second hit. She also highlighted the BLUESTAR study (NCT05123482) results for puxitatug samrotecan, noting that response rates exceeding 60% in patients previously treated with both platinum and immunotherapy address a critical gap in the current treatment landscape.

On toxicity management, Dr Secord described a proactive approach to the topoisomerase 1 payload class, emphasizing aggressive antiemetic prophylaxis, liberal use of growth factor support, early intervention for diarrhea with anti-motility agents and dietary modification, and close laboratory monitoring in the first cycles of treatment. She noted that distinguishing between drug-specific toxicities such as stomatitis, interstitial lung disease, and neuropathy across the ADC class is essential for maintaining dose intensity and quality of life.

Finally, Dr Secord addressed the evolving questions of ADC sequencing and B7-H4 biomarker testing. She described herself as a biomarker enthusiast and noted that while current data do not yet show a clear association between B7-H4 expression level and antitumor activity, phase 3 trials represent an important opportunity to conduct robust biomarker collection and assess whether expression magnitude predicts differential benefit. On sequencing, she acknowledged that most phase 3 trials currently exclude patients with prior topoisomerase 1 payload ADC exposure, making clinical trial enrollment essential for generating the cross-ADC sequencing data the field urgently needs.

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