Though targeting B7-H4 has proven tricky, GSK reckons it’s bucked the trend with its Hansoh-originated ADC mocertatug rezetecan. At the Society of Gynecologic Oncology conference on Sunday the company reported promising results from a global phase 1 trial, Behold-1, that seem to have exceeded previous Chinese data.
The headline figures were 62% and 67% ORRs in platinum-resistant ovarian and endometrial cancers respectively, for the highest mo-rez doses tested. GSK said it saw responses across a range of expression levels, but didn’t give more information. If this claim holds up, it could differentiate mo-rez from other anti-B7-H4 contenders.
Notably, Pfizer last year ditched its similarly acting ADC, felmetatug vedotin, after showing that the benefit with this project was driven by high B7-H4 expressers. Mersana, meanwhile, focused on patients with B7-H4 levels of 70% or higher with its asset, emiltatug ledadotin. That company was bought by Day One, which was then picked up by Servier, but emilta-L wasn’t the focus of that deal.
B7-H4 high
Other B7-H4 rivals include AstraZeneca’s puxitatug samrotecan, which produced less impressive data in ≥25% expressers, and BeOne’s DualityBio-originated BG-C907, which has looked competitive, albeit in “B7-H4 high” patients (for which BeOne hasn’t disclosed the cutoff).
Therefore, more details on responses across B7-H4 expression levels will be awaited for mo-rez. But it’s notable that GSK’s upcoming global pivotal trials, Behold-Ovarian01 in PROC and Behold-Endometrial01 in relapsed endometrial cancer, don’t appear to require certain B7-H4 expression levels, although patients’ B7-H4 status must be known before randomisation.
Astra, meanwhile, mandates B7-H4 expression in its phase 3 study, Bluestar-Endometrial01, although the cutoff hasn't been disclosed. Details of BeOne’s upcoming pivotal study aren’t yet available.
GSK, which licensed mo-rez for just $85m up front in 2023, is testing a 5.8mg/kg dose in both Behold-Ovarian01 and Behold-Endometrial01. One curiosity is that the latest data in endometrial only go up to a 4.8mg/kg dose.
Around 97% of patients in Behold-1 were B7-H4 positive, defined as 1% or more tumour cells with membrane staining.
As with all ADCs, toxicity could be an issue with mo-rez. However, GSK noted a 3% rate of interstitial lung disease across 178 patients in Behold-1, all at grade 1 or 2. Treatment-related discontinuation rates were low, and there were no treatment-related deaths, although there were two fatal adverse events deemed unrelated, both at the highest doses tested.
GSK now plans to start five global phase 3 trials in total his year. As well as Behold-Ovarian01 and Behold-Endometrial01, this includes Behold-Ovarian02 in platinum-sensitive ovarian cancer, Behold-Ovarian03 in first‑line maintenance in ovarian cancer without homologous recombination deficiency, and Behold-Endometrial02 in and mismatch repair-proficient endometrial cancer.
Data from Behold-1 trial of mocertatug rezetecan
| Platinum-resistant ovarian cancer | Endometrial cancer |
|---|
| Dose | 2.8mg/kg | 4.8mg/kg | 5.8mg/kg | 2.8mg/kg | 4.8mg/kg |
| ORR | 31% (11/35) | 53% (18/34) | 62% (21/34) | 9% (1/11) | 67% (8/12) |
| ≥Gr3 TRAEs | 19% | 42% | 64% | 17% | 54% |
| TR discontinuations | 0 | 5% | 0 | 4% | 4% |
| Deaths | 0 | 0 | 2% | 0 | 4% |
| TR deaths | 0 | 0 | 0 | 0 | 0 |
