The 2026 European Society for Medical Oncology (ESMO) Congress was held in Madrid, Spain, from October 23 to 27. During the Gynecological Cancers Session, an exploratory biomarker analysis from the BEHOLD-1 study attracted considerable attention. The analysis systematically characterized response patterns to Mo-Rez (mocertatug rezetecan), a novel B7-H4-targeted topoisomerase I inhibitor (TOP1i) antibody-drug conjugate (ADC), in patients with platinum-resistant ovarian cancer (PROC). The findings showed that 96% of patients with PROC had B7-H4-positive tumors, while clinical responses to Mo-Rez were observed across different levels of B7-H4 expression. The linker-cleaving enzyme CTSB, the payload sensitivity gene TOP1, stromal remodeling, and immune-related pathways were all associated with response.

During the congress, Oncology Frontier interviewed Professor Stephanie Lheureux, the study’s first author and presenter from the Princess Margaret Cancer Centre, Canada. The discussion focused on determining the B7-H4 expression threshold, clinical benefit in patients with low expression, and biomarker-based patient selection for ADC therapy.

Study Overview: BEHOLD-1 Biomarker Analysis

Mo-Rez is a novel TOP1i ADC targeting the immune checkpoint protein B7-H4. Following binding to B7-H4, the ADC is internalized into tumor cells, where its linker is cleaved by cathepsins to release the topoisomerase I inhibitor payload. This leads to tumor cell killing and produces a bystander effect. B7-H4 is widely expressed in gynecological malignancies but exhibits very low expression in normal tissues, providing a rationale for tumor-selective payload delivery.

BEHOLD-1 (NCT06431594) is a two-part, open-label Phase I study comprising a Phase Ia dose-escalation stage and a Phase Ib dose-optimization/expansion stage. As of the data cutoff date of November 12, 2025, 131 patients with PROC had been randomized to receive Mo-Rez at doses of 2.8, 4.8, or 5.8 mg/kg once every 3 weeks (Q3W). The recommended Phase II dose was 5.8 mg/kg Q3W.

The present report focused on the baseline biomarker analysis of BEHOLD-1. The key findings included:

  • Baseline B7-H4 expression: B7-H4 expression was assessed by immunohistochemistry (IHC) (n=111). B7-H4 positivity was defined as membrane staining of any intensity (≥1+) in ≥1% of tumor cells. Overall, 96% (107/111) of patients had B7-H4-positive tumors. The distribution of expression levels was as follows: 1%–24% (33%), 25%–49% (22%), 50%–74% (22%), and ≥75% (19%).
  • Responses across B7-H4 expression levels: In the 5.8 mg/kg dose group (n=34), responses were observed across different levels of B7-H4 expression.
  • Whole-transcriptome sequencing (WTS): Cathepsin B (CTSB), which is responsible for linker cleavage and payload release, was elevated in responders (P=0.02). TOP1, which is associated with payload sensitivity, showed a trend toward higher expression (P=0.094). Stromal remodeling, which may facilitate ADC penetration into tumors, was significantly elevated (P=0.00065).
  • Immune- and inflammation-related pathways: Responders showed enrichment of several immune- and inflammation-related pathways, including TNFα signaling via NF-κB, inflammatory response, allograft rejection, TGFβ signaling, IL6-JAK-STAT3 signaling, and IL2-STAT5 signaling.

Insights from the Investigator

Professor Lheureux shared her in-depth perspectives on B7-H4 expression, patient selection, and clinical development in the context of the BEHOLD-1 biomarker analysis.

Discussing how the B7-H4 expression threshold was determined, Professor Lheureux explained that this analysis, presented at the congress as part of the BEHOLD-1 study, focused on B7-H4 expression assessed by IHC. Tumors were defined as B7-H4-positive if at least 1% of tumor cells expressed the antigen at any intensity, corresponding to a staining score of at least 1+. Based on this definition, 96% of patients had B7-H4-positive tumors. Although expression levels varied among patients, responses were observed across the different expression levels. Professor Lheureux particularly emphasized that this finding suggests that, in tumors where B7-H4 is widely expressed, efficacy is not strictly dependent on selecting patients with high expression. This represents an important translational signal for the development of B7-H4-targeted ADCs.

Regarding biomarker-based patient selection for ADC therapy, Professor Lheureux acknowledged that this is a particularly interesting and challenging question. Ovarian cancer expresses multiple antigens, creating numerous therapeutic opportunities, but the optimal approach to selecting patients remains unclear. The BEHOLD-1 exploratory analysis was designed to identify potential biomarkers associated with response to Mo-Rez. It examined a range of markers beyond the specific target itself to determine whether any additional characteristics warranted attention. Although this was a highly exploratory, hypothesis-driven analysis, it highlights the importance of understanding both the mechanisms of action of ADCs and the tumor microenvironment.

From a mechanistic perspective, linker-cleaving enzyme CTSB, the payload sensitivity gene TOP1, and stromal remodeling were all associated with response. Responders also showed enrichment of immune- and inflammation-related pathways, suggesting that Mo-Rez may have an immunomodulatory mechanism of action in addition to its direct antitumor activity. These findings indicate that patient selection strategies may need to extend beyond target expression alone, with composite biomarker signatures potentially representing a future direction. They also provide a scientific rationale for exploring combination strategies, including ADCs combined with immunotherapy.

Conclusion

The BEHOLD-1 biomarker analysis represents an important translational research advance in the field of gynecological oncology at this year’s ESMO Congress. In platinum-resistant ovarian cancer, where B7-H4 is widely expressed, Mo-Rez demonstrated antitumor activity across different levels of B7-H4 expression. Responses were also closely associated with mechanistic features involving linker cleavage, payload sensitivity, stromal remodeling, and immune pathways.

These findings suggest that composite biomarker signatures may be needed in the future to identify patients most likely to benefit from treatment more precisely. They also provide a scientific foundation for the further development of ADCs in ovarian cancer and the exploration of combination strategies. We look forward to further validation of Mo-Rez in larger studies and hope that more patients with gynecological malignancies will ultimately benefit from this therapeutic approach.

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