The B7-H4–targeted ADC produced ORRs of 62% and 67% in patients with PROC and endometrial cancer, respectively, in the phase 1 BEHOLD-1 study.
The B7-H4–targeted antibody-drug conjugate (ADC) mocertatug rezetecan (GSK5733584) was active with a manageable safety profile at the highest dose level in patients with platinum-resistant ovarian cancer (PROC) and endometrial cancer, according to interim data from the phase 1 BEHOLD-1 study (NCT06431594) presented during the
At a median follow-up of 6.1 months (IQR, 4.7-6.6), patients with PROC who received the ADC at the maximum tolerated dose of 5.8 mg/kg every 3 weeks (n = 34) achieved a confirmed overall response rate (ORR) of 62% (95% CI, 44%-78%). The median time to response (TTR) was 1.4 months (IQR, 1.4-1.6). Moreover, patients with endometrial cancer treated at the 4.8-mg/kg dose level (n = 12) experienced a confirmed ORR of 67% (95% CI, 35%-90%).
“B7-H4 is widely expressed in gynecological tumors; in the BEHOLD-1 study, [it was present] in more than 95% of [patients with] PROC and endometrial cancer,” presenting author Ana Oaknin, MD, PhD, head of the Gynaecologic Cancer Programme at Vall d’Hebron University Hospital in Barcelona, Spain, said during the presentation. “BEHOLD-1 showed that mocertatug rezetecan delivered rapid and deep responses, with a confirmed ORR of 62% at 5.8 mg/kg in PROC and 67% at 4.8 mg/kg in endometrial cancer.”
BEHOLD-1 was a 2-part, open-label, global study that enrolled adult patients with histologically confirmed advanced solid tumors.1-3 Patients were required to have an ECOG performance status of 0 to 2, have at least 1 measurable target lesion per RECIST 1.1 criteria, and have received no prior B7-H4–directed therapy. Phase 1b included patients with PROC or endometrial cancer who had received 1 to 3 prior lines of therapy; prior treatment with topoisomerase inhibitors was not permitted.
In phase 1b, patients with PROC were randomly assigned 1:1:1 to receive mocertatug rezetecan at 2.8 mg/kg, 4.8 mg/kg, or 5.8 mg/kg every 3 weeks. Those with recurrent/advanced endometrial cancer were randomly assigned 1:1 to receive the agent at 2.8 mg/kg or 4.8 mg/kg every 3 weeks. Study expansion at the recommended dose was informed by the totality of the data.
Baseline patient characteristics were balanced across dose levels. In the PROC cohort (n = 131), the median age was 60 years (range, 38-79). Most patients were White (52%), had high-grade serous carcinoma (98%), had received prior bevacizumab (Avastin; 79%), and had received a prior PARP inhibitor (58%). Fifty percent had an ECG performance status of 0.
In the endometrial cancer cohort (n = 49), the median age was 64 years (range, 31-82). Most patients were White (51%), had an ECOG performance status of 1 (63%), had received a prior PD-L1 inhibitor (82%), and had B7-H4 tumor membrane positivity (97%).
Additional findings from BEHOLD-1 revealed that patients with PROC who received mocertatug rezetecan at the 2.8-mg/kg (n = 35) and 4.8-mg/kg (n = 34) dose levels achieved confirmed ORRs of 31% (95% CI, 17%-49%) and 53% (95% CI, 35%-70%), respectively. The median TTRs were 2.7 months (IQR, 1.4-2.8) and 2.6 months (IQR, 1.5-2.8), respectively. In the endometrial cancer cohort, the confirmed ORR at the 2.8-mg/kg dose (n = 11) was 9% (95% CI, 0.2%-41%).
In terms of safety, patients with PROC who received mocertatug rezetecan at 5.8 mg/kg (n = 44) experienced any-grade adverse effects (AEs) at a rate of 95%; 66% of these were grade 3 or higher AEs. Treatment-related AEs (TRAEs; 95%), grade 3 or higher TRAEs (64%), as well as TRAEs leading to dose interruption/delay (39%) or reduction (39%) also occurred. Any serious AEs (SAEs; 32%), treatment-related SAEs (18%), and fatal SAEs (2%) were reported in some patients. The most common any-grade AEs included nausea (86%), fatigue (77%), neutropenia (73%), anemia (52%), and alopecia (52%).
In the endometrial cancer cohort, patients treated at the 4.8-mg/kg dose (n = 24) experienced any-grade and grade 3 or higher AEs at respective rates of 100% and 63%. TRAEs, grade 3 or higher TRAEs, TRAEs leading to dose interruption/delay, TRAEs leading to dose reduction, TRAEs leading to treatment discontinuation, any SAEs, treatment-related SAEs, and fatal SAEs were reported at respective rates of 92%, 54%, 21%, 17%, 4%, 25%, 8%, and 4%. The most common any-grade AEs included nausea (79%), neutropenia (58%), and anemia (54%).
“The safety profile was manageable with low discontinuation rates,” Oaknin concluded. “Taken together, these promising results support further investigation [of mocertatug rezetecan] in phase 3 trials at 5.8 mg/kg every 3 weeks.”2,3
Disclosures: Oaknin holds consulting or advisory roles 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. She received research funding from AbbVie (Inst), Ability Pharma (Inst), Advaxis (Inst), Aeterna Zentaris (Inst), Agenus, Aprea Therapeutics (Inst), AstraZeneca (Inst), BeiGene (Inst), Belgian Gynaecological Oncology Group (Inst), Bristol Myers Squibb (Inst), Clovis Oncology (Inst), Corcept Therapeutics (Inst), Esai/Dohme (Inst), Mundipharma Research (Inst), Novartis (Inst), Regeneron (Inst), Roche (Inst), Seagen (Inst), Sutro Biopharma (Inst), Tesaro (Inst), and Verastem (Inst). She also received travel, accommodations, and expenses from AstraZeneca, Clovis Oncology, PharmaMar, and Roche.
