Development

GSK's B7-H4 ADC set for 5 Phase III trials in gynecological cancers after strong Phase I

Edited by Robert McTiernan··2 min read

GSK (LSE/NYSE: GSK) reported Phase I data for mocertatug rezetecan, a B7-H4-targeted antibody-drug conjugate, showing confirmed objective response rates of 62% in platinum-resistant ovarian cancer and 67% in recurrent or advanced endometrial cancer — results that prompted the company to announce five pivotal Phase III trials starting in 2026.

BEHOLD-1 (NCT06431594) is a two-part, open-label Phase I study enrolling patients with platinum-resistant ovarian cancer or advanced/recurrent endometrial cancer with one to three prior lines of therapy.

In the Phase Ib dose expansion, mocertatug rezetecan monotherapy achieved a confirmed ORR of 62% (n=21/34; 95% CI: 44–78) at 5.8 mg/kg in platinum-resistant ovarian cancer, and 67% (n=8/12; 95% CI: 35–90) at 4.8 mg/kg in endometrial cancer. Median duration of response had not been reached at the interim analysis. Grade ≥3 treatment-related adverse events occurred in 64% of platinum-resistant ovarian cancer patients and 54% of endometrial cancer patients, predominantly haematologic. Interstitial lung disease or pneumonitis was observed in 3% of patients overall (5 of 178), all grade 1–2. Treatment discontinuation due to adverse events was 0% in platinum-resistant ovarian cancer and 4% in endometrial cancer.

The haematologic toxicity burden — with dose interruptions in 39% of platinum-resistant ovarian cancer patients and reductions in the same proportion — warrants attention as the programme moves to Phase III, though discontinuation rates were low.

Mocertatug rezetecan carries a drug-to-antibody ratio of 6 and links a fully human anti-B7-H4 monoclonal antibody to a topoisomerase inhibitor payload. B7-H4 is an immune checkpoint protein expressed broadly across ovarian and endometrial tumours but at low levels in normal tissues — a profile that supports tumour-selective delivery. GSK licensed exclusive worldwide rights outside greater China from Hansoh Pharma.

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The platinum-resistant ovarian cancer treatment landscape has shifted considerably in 2024–2026. Mirvetuximab soravtansine (Elahere), the only other approved ADC in this space, targets folate receptor alpha and received full FDA approval in March 2024, but is restricted to FRα-high patients — roughly 35–40% of the platinum-resistant ovarian cancer population. Mocertatug rezetecan showed activity across a range of B7-H4 expression levels, which GSK says broadens potential eligibility. Cross-trial comparisons are limited by differences in patient populations, prior therapy lines, and endpoint definitions, so direct efficacy comparisons with Elahere's reported ORRs of approximately 32–42% in FRα-high patients cannot be drawn from these data alone.

Two further approvals in early 2026 — pembrolizumab plus paclitaxel with or without bevacizumab (requiring PD-L1 CPS ≥1) and relacorilant plus nab-paclitaxel — add combination regimens to a field where monotherapy options remain limited. Mocertatug rezetecan is being developed as a monotherapy, which may offer a simpler administration profile, though its comparative convenience and tolerability relative to these combinations will require head-to-head or at least contemporaneous Phase III data to assess.

GSK plans to initiate BEHOLD-Ovarian01 (NCT07286266) and BEHOLD-Endometrial01 (NCT07286331) as the first two Phase III trials, with three additional studies covering platinum-sensitive ovarian cancer and first-line maintenance settings to follow.

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