The B7-H4–targeted antibody-drug conjugate produced confirmed response rates of 62% in PROC and 67% in endometrial cancer at the doses selected for phase 3 development.
Mocertatug rezetecan (Mo-Rez), a novel B7-H4–directed antibody-drug conjugate (ADC), demonstrated rapid and deep responses in patients with platinum-resistant ovarian cancer (PROC) and recurrent or advanced endometrial cancer (EC) across a range of B7-H4 expression levels, according to additional data from an interim analysis of the phase 1 BEHOLD-1 study (NCT06431594) presented at the
In the PROC cohort, the confirmed objective response rate (cORR) with Mo-Rezat at the 5.8 mg/kg dose level (n = 34) was 62% (95% CI, 44%-78%), and 31 patients achieved stable disease or better. The median time to response (TTR) with Mo-Rez at 5.8 mg/kg was 1.4 months (interquartile range [IQR], 1.4-1.6), and the median follow-up was 6.1 months (IQR, 3.7-6.8). Among patients treated at the 2.8 mg/kg (n = 35) and 4.8 mg/kg (n = 34) doses, respective cORRs were 31% (95% CI, 17%-49%) and 53% (95% CI, 35%-70%). The median TTR in the 2.8 mg/kg groups was 2.7 months (IQR, 1.4-2.8), and the median follow-up was 6.1 months (IQR, 5.1-6.5). In the 4.8 mg/kg group, the median TTR was 2.6 months (IQR, 1.5-2.8) and the median follow-up was 6.0 months (IQR, 2.9-7.0).
In the recurrent or advanced EC cohort, the cORR with Mo-Rez at the 4.8 mg/kg dose level (n = 12) was 67% (95% CI, 35%-90%). The median TTR was 1.5 months (IQR, 1.2-2.7) at 4.8 mg/kg, with a median follow-up of 4.2 months (IQR, 1.7-5.8). At the 2.8 mg/kg dose (n = 11), the cORR was 9% (95% CI, 0.2%-41%). The median TTR in this group was 1.4 months (IQR, 1.4-1.4) with a median follow-up of 4.0 months (IQR, 1.4-5.8).
Based on these results, both the 5.8 mg/kg dose and the 4.8 mg/kg dose have been selected for further evaluation in global phase 3 trials in PROC (BEHOLD-Ovarian01; NCT07286266) and recurrent or advanced EC (BEHOLD-Endometrial01; NCT07286331), respectively.2,3
"We also saw promising clinical activity in the PROC subgroup after [prior] PARP [inhibition] or bevacizumab [(Avastin) exposure], and owing to the few number of patients who discontinued treatment due to treatment-related adverse effects [TRAEs], we can confirm the manageable safety profile with few pneumonitis [events]” -Isabelle L. Ray-Coquard, MD, PhD, HDR, presenting author, medical oncologist at the Centre Léon Bérard, and professor of medical oncology at Université Claude Bernard Lyon 1 in Lyon, France
This 2-part, open-label, phase 1 study enrolled patients at least 18 years of age with histologically confirmed advanced solid tumors and no prior exposure to B7-H4–directed therapy, with an ECOG performance status (PS) of 0 to 2 and at least 1 measurable lesion per RECIST 1.1 criteria.1 In phase 1b, patients were also required to have received 1 to 3 prior lines of therapy and have no prior exposure to a topoisomerase 1 inhibitor.
In the phase 1a dose escalation portion (n = 44), patients with advanced solid tumors received Mo-Rez at escalating doses of 2.8 mg/kg, 4.8 mg/kg, 5.8 mg/kg, and 7.2 mg/kg every 3 weeks (Q3W). The maximum tolerated dose was not reached, and 5.8 mg/kg Q3W was identified as the maximum applicable dose. The data cutoff was July 1, 2025.
In the phase 1b dose optimization/expansion portion, which is the focus of the current analysis, patients with PROC were randomly assigned 1:1:1 to receive Mo-Rez at a dose of 2.8 mg/kg, 4.8 mg/kg, or 5.8 mg/kg Q3W; patients with recurrent or advanced EC were randomly assigned 1:1 to receive Mo-Rez at a dose of 2.8 mg/kg or 4.8 mg/kg Q3W. Expansion at the recommended dose was informed by the totality of data.
The primary end point was clinical activity of Mo-Rez assessed by cORR per investigator review using RECIST 1.1 criteria.
In the PROC cohort (n = 131), baseline characteristics included:
In the recurrent or advanced EC cohort (n = 49), baseline characteristics were as follows:
At the data cutoff, 5% of responders in the 5.8 mg/kg arm experienced disease progression compared with 17% in the 4.8 mg/kg group and 18% in the 2.8 mg/kg group. Among responders at the 4.8 mg/kg dose, 12% had progressed at the data cutoff of November 15, 2025; no patients had progressed at this time in the 2.8 mg/kg group.
Among patients with PROC previously treated with a PARP inhibitor in the 2.8 mg/kg (n = 22), 4.8 mg/kg (n = 17), and 5.8 mg/kg (n = 23) groups, cORRs were 18%, 53%, and 65%, respectively. The respective cORRs for patients with prior bevacizumab exposure in the 2.8 mg/kg (n = 29), 4.8 mg/kg (n = 26), and 5.8 mg/kg (n = 27) groups were 24%, 46%, and 59%.
Of note, first results from BEHOLD-1 were also shared during the
The median duration of treatment exposure in the PROC cohort was 4.1 months (range, 0-8) at 2.8 mg/kg, 5.6 months (range, 0-8) at 4.8 mg/kg, and 5.9 months (range, 0-9) at 5.8 mg/kg.1 The median relative dose intensity (RDI) in these respective groups was 99.2% (range, 88%-102%), 98.8% (range, 63%-101%), and 95.4% (range, 61%-103%). In the EC cohort, the median duration of treatment exposure was 2.4 months (range, 0-7) in the 2.8 mg/kg group and 4.0 months (range, 0-6) in the 4.8 mg/kg group. Respective median RDIs were 99.6% (range, 85%-207%) and 98.8% (range, 43%-102%).
The incidence of TRAEs leading to treatment discontinuation remained low across all dose levels. In the PROC cohort, any-grade TRAEs were reported in 93% of patients at 2.8 mg/kg, 86% at 4.8 mg/kg, and 95% at 5.8 mg/kg. Grade 3 or higher TRAEs occurred in 19%, 42%, and 64% at these 3 respective doses. TRAEs leading to dose interruption/delay were reported in 5%, 28%, and 39% of patients, and TRAEs leading to dose reduction occurred in 0%, 14%, and 39%, respectively. TRAEs leading to treatment discontinuation were reported in 0%, 5%, and 0% of patients at these respective dose levels. Treatment-related serious AEs (SAEs) occurred in 5%, 12%, and 18% of patients. One treatment-related fatal SAE was reported at 5.8 mg/kg.
In the recurrent or advanced EC cohort, any-grade TRAEs were reported in 92% of patients at both the 2.8 mg/kg and 4.8 mg/kg dose levels. Grade 3 or higher TRAEs occurred in 17% of patients at 2.8 mg/kg and 54% at 4.8 mg/kg. TRAEs leading to dose interruption/delay were reported in 13% and 21% of patients, respectively; TRAEs leading to dose reduction occurred in 0% and 17% of patients. TRAEs leading to treatment discontinuation were reported in 4% of patients at both dose levels. Treatment-related SAEs occurred in 0% and 8%, and 1 fatal SAE was reported in the 4.8 mg/kg EC cohort, though it was not considered treatment-related.
Interstitial lung disease (ILD)/pneumonitis was reported in 3% of patients across the phase 1b safety population (n = 178), including 3 grade 1 and 2 grade 2 events; no grade 3 or higher ILD/pneumonitis events were reported at the 5.8 mg/kg Q3W dose level.
Disclosures: Ray-Coquard disclosed contracts with Bristol Myers Squibb, BeiGene, GSK, AstraZeneca, Genmab, Eisai, Corcept, Gilead, Daiichi Sankyo, Novartis, Pharma&, Deciphera, MSD, Regeneron, Roche, Sutro Biopharma, TORL BioTherapeutics, Tubulis, AbbVie, Agenus, Scorpion Therapeutics, Incyte, and Zentalis Pharmaceuticals.
