One-Two Punch for Gynecologic Oncology
Antibody–drug conjugate shows promising response rates in difficult‑to‑treat ovarian and endometrial cancer.
A first‑in‑class antibody–drug conjugate targeting the B7‑H4 protein has shown striking early signs of efficacy in some of the most treatment‑resistant gynecologic cancers, according to the late-breaking abstract, “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.”
The results were a part of the global phase 1 BEHOLD‑1 trial and were detailed by the study’s lead investigator, Ana Oaknin, MD, PhD, at her late-breaking abstract presentation earlier today. Dr. Oaknin leads the Gynecologic Cancer Program at the Hospital Universitario Puerta de Hierro-Majadahonda in Madrid, Spain.
Researchers studied the investigational therapy, mocertatug rezetecan (Mo‑Rez, GSK5733584) for platinum‑resistant ovarian cancer (PROC) and advanced or recurrent endometrial cancer — two areas of high unmet clinical need.
“B7-H4 is an immunoregulatory protein that is widely expressed in ovarian cancer (OC) and endometrial cancer but has low expression in normal tissue, making it an attractive target in gynecological tumors,” Dr. Oaknin said.
Mo-Rez is a humanized anti-B7-H4 IgG1 antibody conjugated to a cyclopropyl-modified topoisomerase inhibitor (TOP1i). It is designed for enhanced stability and tumor penetration, with a drug-to-antibody ratio of six, she said.
BEHOLD‑1 is the first study to evaluate the drug in a diverse, worldwide patient population. The two‑part trial included dose escalation in solid tumors followed by a randomized dose‑optimization phase in PROC and endometrial cancer.
In the study, researchers followed 224 patients across phase 1a and 1b trials. In the dose‑optimization cohort, nearly all evaluable patients (96% in PROC and 97% in endometrial cancer) had B7‑H4–positive tumors.
At the highest tested doses, researchers noted:
- PROC (5.8 mg/kg every three weeks)
- There was a 62% confirmed objective response rate (ORR)
- The median time-to-response was 1.4 months
- Endometrial cancer (4.8 mg/kg every three weeks)
- There was a 67% confirmed objective response rate
- The median time-to-response was 1.5 months
For both cohorts, the median duration of response was not achieved, and responses deepened over time. In the PROC cohort, only 5% of responders at the highest dose had experienced disease progression after a median follow‑up of 6.1 months — a figure that exceeds current historical benchmarks for this population, Dr. Oaknin said.
Investigators noted clear evidence of a dose–response relationship, with deeper and faster responses at higher dose levels.
Additionally, according to data from early phase studies in China, Dr. Oaknin said when Mo-Rez monotherapy for the treatment of PROC was used in combination with the drug bevacizumab for the treatment of PSOC, the regimen demonstrated “promising activity.”
“Taken together, these promising safety and efficacy data validate B7-H4 as a prospective target in both ovarian cancer and endometrial cancer and support further investigation of Mo-Rez in phase 3 studies,” she said.
According to Dr. Oaknin, the most common treatment‑related adverse events were gastrointestinal (mostly low‑grade nausea) and hematologic toxicities, including neutropenia, anemia, and thrombocytopenia.
Grade 3 or higher adverse events occurred in:
- 42% of patients with PROC
- 35% of patients with endometrial cancer
These events were dose‑dependent, but importantly:
- Discontinuations due to side effects were rare (2% in PROC, 4% in endometrial cancer)
- No fatal adverse events occurred
BEHOLD‑1 generates the largest dataset to date for a B7‑H4‑directed therapy in gynecologic cancers, according to Dr. Oaknin. The results reinforce B7‑H4 as a promising biological target and demonstrate that an ADC approach can achieve significant antitumor activity even in heavily pretreated, difficult‑to‑treat diseases like PROC.
The study’s rigorous dose‑optimization strategy also bodes well for regulatory objectives, Dr. Oaknin said.
“The rigorous dose optimization, including randomized evaluation of three doses in the PROC cohort (131 patients) and two doses in the endometrial cancer cohort (49 patients), is of significant interest to regulatory bodies like the U.S. Food and Drug Administration (FDA) and aligns with the FDA’s Project Optimus,” she said.
Dr. Oaknin said Mo‑Rez is now advancing into the following multiple phase 3 studies:
- BEHOLD‑Ovarian01 for PROC
- BEHOLD‑Endometrial01 for advanced or recurrent endometrial cancer
- Additional trials planned earlier in the treatment course
The broader Mo‑Rez development program also includes BEHOLD‑2, a phase 1 and 2 combination study evaluating the ADC with existing standards of care, she said.
The early global results from BEHOLD‑1 are highly encouraging, Dr. Oaknin said, with Mo‑Rez delivering rapid, deep, and frequent responses in two aggressive gynecologic cancers while maintaining a manageable safety profile.
“BEHOLD-1 offers valuable evidence for the potential of targeting B7-H4 in gynecologic cancers and supports advancing studies to evaluate Mo-Rez as a new therapeutic option for patients with ovarian or endometrial cancer,” Dr. Oaknin said.
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