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Responses to mocertatug rezetecan (Mo-Rez) occurred across a range of B7-H4 expression levels in patients with platinum-resistant ovarian cancer (PROC), nearly all of whom had B7-H4–positive tumors, according to an exploratory biomarker analysis of the phase 1 BEHOLD-1 trial (NCT06431594) presented at the
Among patients with evaluable baseline tumor samples across all dose levels (n = 111), 96% had B7-H4–positive tumors, defined as membrane staining at any intensity (1+ or higher) in at least 1% of tumor cells by immunohistochemistry (IHC). The proportion of tumor cells with membrane positivity was 1% to 24% in 33% of cases (95% CI, 25%-43%), 25% to 49% in 22% (95% CI, 15%-32%), 50% to 74% in 22% (95% CI, 15%-31%), and 75% or higher in 19% (95% CI, 12%-28%). Among patients treated at 5.8 mg/kg who had baseline and at least 1 post-baseline tumor assessment (n = 34), partial responses (PRs) occurred in all 4 expression categories, and the 2 complete responses (CRs) occurred in tumors with 25% to 49% and 1% to 24% membrane positivity.
In whole-transcriptome sequencing (WTS) of samples from all dose levels, responders (CR or PR; n = 34) had higher expression of cathepsin B (CTSB), the enzyme that cleaves the linker to release the payload, than nonresponders (stable disease, progressive disease, or not evaluable; n = 35; P = .02). Expression of TOP1, which is involved in payload sensitivity, tended to be higher in responders (P = .094), and a matrix remodeling signature, which enables antibody-drug conjugate (ADC) penetration into the tumor, was elevated in responders (P = .00065). All P values were nominal.
“Development of predictive biomarkers of Mo-Rez response may need composite signatures in tumours that widely express B7-H4 such as PROC,” said Stephanie Lheureux, MD, PhD, of the Division of Medical Oncology and Hematology at Princess Margaret Cancer Centre, University Health Network, in Toronto, Ontario, Canada, who presented the data.
Mo-Rez is an investigational ADC that targets B7-H4, an immune checkpoint protein that is widely expressed in gynecologic cancers with minimal expression in normal tissue, and delivers a topoisomerase 1 inhibitor payload. BEHOLD-1 is a 2-part, open-label study with a phase 1a dose-escalation portion in patients with advanced solid tumors and a phase 1b dose-optimization and expansion portion. In phase 1b, patients with PROC, including high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer, were randomly assigned 1:1:1 to Mo-Rez at 2.8 mg/kg, 4.8 mg/kg, or 5.8 mg/kg every 3 weeks; a separate cohort enrolled patients with advanced or recurrent endometrial cancer (EC).
Eligible patients had an ECOG performance status of 0 to 2, at least 1 measurable target lesion per RECIST v1.1, and no prior B7-H4–directed therapy; patients in phase 1b had received 1 to 4 prior lines of therapy and no prior topoisomerase 1 inhibitor. The primary end point was investigator-assessed confirmed objective response rate (ORR) per RECIST v1.1.
As of the November 12, 2025, data cutoff, 131 patients with PROC had been randomly assigned. Baseline B7-H4 expression was assessed by IHC on archival or fresh tumor tissue collected at screening, and WTS was used to characterize differential gene and pathway expression between responders and nonresponders.
Fast gene set enrichment analysis of 50 hallmark gene sets showed that the top pathways upregulated in responders were broadly associated with immune or inflammatory responses. These included TNF-α signaling via NF-κB, inflammatory response, allograft rejection, TGF-β signaling, IL-6/JAK/STAT3 signaling, and IL-2/STAT5 signaling. The matrix remodeling finding came from a gene set variation analysis of 29 tumor microenvironment (TME) signatures.
The investigators noted that, beyond its cytotoxic and bystander effects, Mo-Rez may interact with the immune system within the TME.
The investigators concluded that because tumors such as PROC widely express B7-H4, development of predictive biomarkers of Mo-Rez response may require composite signatures rather than B7-H4 expression alone.
Mo-Rez at 5.8 mg/kg every 3 weeks was selected as the recommended dose for both the PROC and EC cohorts.1 The agent is being compared with standard of care in PROC in the phase 3 BEHOLD-Ovarian01 trial (NCT07286266),3 and it is being evaluated in combination with other anticancer therapies, including dostarlimab-gxly (Jemperli) and bevacizumab (Avastin), in the phase 1/2 BEHOLD-2 trial (NCT06796907).4
Disclosures: Lheureux reported contracts with AbbVie, AstraZeneca, Debiopharm, Eisai, GSK, Merck, Regeneron, Repare Therapeutics, Roche, Seagen, Ottimo Pharma and Gilead.
