First results from the global phase I BEHOLD-1 study suggest that the investigational B7-H4–targeted antibody-drug conjugate mocertatug rezetecan showed activity in two difficult-to-treat gynecologic cancers: platinum-resistant ovarian cancer and recurrent or advanced endometrial cancer.1 At the highest doses evaluated, confirmed objective response rates were 62% in platinum-resistant ovarian cancer and 67% in endometrial cancer, with responses observed across a range of B7-H4 expression levels.
Ana Oaknin, MD
The findings were presented at the 2026 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer by Ana Oaknin, MD, of Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain. In an interview with The ASCO Post, Dr. Oaknin said the activity seen in both tumor types “reinforces the broad potential of this investigational agent in gynecologic cancers and further validates the relevance of targeting B7-H4.”
Mocertatug rezetecan, also known as Mo-Rez, is a B7-H4–targeted humanized monoclonal antibody linked to a topoisomerase I inhibitor. In BEHOLD-1, more than 95% of evaluable ovarian and endometrial tumors were B7-H4–positive by immunohistochemistry.
Study Design
BEHOLD-1 is a two-part, open-label, global phase I study. Phase IA evaluated dose escalation in patients with advanced solid tumors, whereas phase IB focused on dose expansion and optimization in patients with platinum-resistant ovarian cancer and recurrent or advanced endometrial cancer. In phase IA, the maximum tolerated dose was not reached, and the maximum applicable dose was established at 5.8 mg/kg every 3 weeks.
In phase IB, patients with platinum-resistant ovarian cancer were randomly assigned to receive 2.8, 4.8, or 5.8 mg/kg every 3 weeks, whereas patients with recurrent or advanced endometrial cancer were assigned to receive 2.8 or 4.8 mg/kg every 3 weeks. Eligible patients had received one to three prior lines of therapy and had not received prior B7-H4–directed therapy or topoisomerase I inhibitor therapy.
At data cutoff, 131 patients had been enrolled in the ovarian cancer cohort and 49 in the endometrial cancer cohort. In the ovarian cohort, median age was 60 years; most patients had high-grade serous histology, 79% had previously received bevacizumab, and 58% had received a PARP inhibitor. In the endometrial cohort, the median age was 64 years; histologies were mixed, 82% had received prior PD-(L)1 inhibitor therapy, and 27% had received lenvatinib. Baseline characteristics were described as balanced across dose levels.
Activity in Platinum-Resistant Ovarian Cancer
Among 103 efficacy-evaluable patients with platinum-resistant ovarian cancer, confirmed objective response rates were 31% at 2.8 mg/kg, 53% at 4.8 mg/kg, and 62% at 5.8 mg/kg every 3 weeks. Dr. Oaknin described a dose-response relationship, with the deepest responses observed at the highest dose level. Median follow-up for the overall ovarian cancer cohort was 6.1 months.
Responses occurred early, with a median time to response of 2.7 months at 2.8 mg/kg, 2.6 months at 4.8 mg/kg, and 1.4 months at 5.8 mg/kg. At the highest dose level, only 1 of 21 responders had experienced disease progression at the time of data cutoff.
Dr. Oaknin highlighted the activity observed despite patients not being selected on the basis of B7-H4 expression. She noted that this is particularly relevant because treatment options remain limited and currently available therapies generally produce only modest response rates in platinum-resistant ovarian cancer.
Activity in Endometrial Cancer
In the recurrent or advanced endometrial cancer cohort, 23 patients were evaluable for efficacy. Confirmed objective response rates were 9% at 2.8 mg/kg and 67% at 4.8 mg/kg every 3 weeks. Median follow-up for the overall cohort was 4.0 months. At the higher dose level, all but one patient experienced a reduction in target lesion diameter, Dr. Oaknin reported.
She added that the activity observed in this cohort is particularly notable given the limited treatment options for patients with recurrent or advanced endometrial cancer.
Safety and Tolerability
Treatment-related adverse events increased with dose in both tumor cohorts. In the ovarian cancer cohort, grade 3 or higher treatment-related adverse events occurred in 19%, 42%, and 64% of patients treated at 2.8, 4.8, and 5.8 mg/kg, respectively. In the endometrial cancer cohort, the corresponding rates were 17% and 54% at 2.8 and 4.8 mg/kg, respectively. Dose interruptions, delays, and reductions also became more common at higher dose levels.
Discontinuation rates, however, were relatively low. Treatment-related adverse events led to discontinuation in two patients in the ovarian cancer cohort and two in the endometrial cancer cohort. No treatment-related fatal serious adverse events were reported.
The most common severe toxicities were generally hematologic, particularly neutropenia, anemia, thrombocytopenia, and leukopenia. Gastrointestinal toxicities, including nausea, vomiting, diarrhea, and constipation, were common but largely low grade. Dr. Oaknin noted that at the 5.8-mg/kg dose in the ovarian cancer cohort, nausea was the most frequent gastrointestinal adverse event, whereas neutropenia was the most frequent grade 3/4 hematologic adverse event.
Interstitial lung disease/pneumonitis, an adverse event of special interest, was infrequent, occurring in 5 of 178 treated patients (3%), including three grade 1 and two grade 2 events. No treatment-related fatal cases were reported.
Dr. Oaknin characterized the hematologic toxicity profile as manageable and consistent with expectations for a topoisomerase I–based antibody-drug conjugate. She added that few patients needed to discontinue treatment because of treatment-related adverse events.
In her concluding remarks, Dr. Oaknin said the findings support further investigation of mocertatug rezetecan in phase III trials. Global phase III studies are planned in both platinum-resistant ovarian cancer and advanced/recurrent endometrial cancer, using the 5.8-mg/kg dose every 3 weeks. She emphasized that the phase III trials will need to demonstrate that Mo-Rez can improve outcomes compared with the current standard of care while maintaining a manageable safety profile.
Commenting more broadly on early antibody-drug conjugate studies presented at the meeting, Stéphanie Gaillard, MD, PhD, a medical oncologist specializing in the treatment of gynecologic malignancies at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, said the promising early results also raised important questions about how these agents will ultimately be integrated into clinical practice, including whether target prescreening will be needed, how the agents should be sequenced, and what mechanisms of resistance may emerge.
DISCLOSURE: Dr. Oaknin has had a consulting or advisory role with Agenus, Amgen, AstraZeneca, Clovis Oncology, Corcept Therapeutics, Deciphera, Eisai, EMD Serono, Genmab, GSK, Immunogen, ITeos Therapeutics, Medison, Merck Sharp & Dohme, Mersana, Novocure, PharmaMar, prIME Oncology, Roche, Shattuck Labs, Sutro Biopharma, and Tesaro; and has received research funding from AbbVie, Ability Pharma, Advaxis, Aeterna Zentaris, Agenus, Aprea Therapeutics, AstraZeneca, BeiGene, Belgian Gynaecological Oncology Group, Bristol Myers Squibb International Corporation, Clovis Oncology, Corcept Therapeutics, Eisai, ImmunoGen, Iovance Biotherapeutics, Lilly, Medimmune, Merck, Merck Sharp & Dohme, Mundipharma Research, Novartis, Regeneron, Roche, Seagen, Sutro Biopharma, Tesaro, and Verastem.
REFERENCE
1. Oaknin A, McKean W, van Dongen MG, et al: Mocertatug rezetecan (GSK5733584), a B7-H4-targeted antibody-drug conjugate (ADC), in platinum-resistant ovarian cancer (PROC) and endometrial cancer (EC): first results from the global BEHOLD-1 study. 2026 SGO Annual Meeting. Presented April 10–13, 2026.
