Ziihera bags a gastric win

Jazz, BeOne and Zymeworks are celebrating success with their HER2 x HER2 bispecific MAb Ziihera in first-line HER2-positive gastric cancer, in the Herizon-GEA-01 trial. The partners highlighted a topline win with a Ziihera/Tevimbra/chemo triplet regardless of patients’ PD-L1 status, suggesting that this regimen could reach a patient population that Merck & Co’s Keytruda cannot.

However, the elephant in the room is the advance of Daiichi and AstraZeneca’s HER2 ADC Enhertu, which is also taking aim at PD-L1 negatives in the Destiny-Gastric05 study. Jazz is moving quickly, with plans to file Ziihera with the FDA for the new use in the first half of 2026, perhaps aware that it will need to make its head start count.

Zymeworks, which originated Ziihera, closed up 29% on Monday following the news. Jazz, which has rights to the drug in the US, Europe and Japan, climbed 21%, while BeOne, which has rights in the rest of Asia, Australia and New Zealand, was up 3%.

New Herizon?

Herizon-GEA-01 tested Ziihera plus chemo, or Ziihera plus Tevimbra plus chemo, versus Herceptin plus chemo, in patients with HER2-positive front-line gastric and oesophageal cancers. The co-primary endpoints were progression-free and overall.

The partners are holding back details for a medical meeting in the first quarter of 2026, but said that the both regimens showed “highly statistically significant and clinically meaningful improvements” on PFS.

As for OS, the triplet hit significance, while the doublet merely showed a trend towards an OS improvement at the first interim analysis. An additional OS interim analysis is expected in mid-2026.

With the triplet, PFS and OS benefits were seen in both the PD-L1 positive and negative subgroups, the companies said.

Setting expectations, Evercore ISI’s Jonathan Miller noted that based on data presented at ASCO this year from a phase 2 trial of Ziihera plus chemo, “mPFS should be into the teens, and mOS could be north of 30 months” – which, he said, “would support robust commercial usage”. In phase 2, the doublet led to mPFS of 12.5 months, and mOS of 36.5 months among 46 patients with HER2-expressing gastroesophageal adenocarcinoma.

Miller added that the preferred regimen would come down to the specifics of the data – assuming one or both combos gets approved for first-line gastric cancer.

If this does come to pass, Zymeworks will receive $440m in milestones: $250m for the US, $100m for the EU, $75m for Japan and $15m for China.

A first-line gastric cancer nod would pit Ziihera against a Keytruda/Herceptin/chemo combo, which gained accelerated US approval in 2021 in HER2-positive first-line gastric cancer regardless of PD-L1 status; however, this was later restricted to PD-L1 ≥1% expressers. 

Competition

The Destiny-Gastric05 trial of Enhertu, meanwhile, has an exploratory PD-L1-negative cohort, but results could be some way off. That study started earlier this year and isn’t set to complete until 2028.

Another potential competitor is Pfizer and RemeGen’s HER2-targeting ADC disitamab vedotin, which showed promise at ASCO in the phase 2 portion of a Chinese phase 2/3 trial. RemeGen has now started a phase 3 testing disi-V plus Tevimbra plus chemo in HER2-low first-line gastric cancer.

Ziihera got accelerated approval last November for previously treated, HER2-positive biliary tract cancer, and carries warnings of left ventricular dysfunction, infusion-related reactions and severe diarrhoea.

Cross-trial comparison in first-line HER2+ve gastric/GEJ adenocarcinoma

Notes: *data from ph2 portion. Source: OncologyPipeline.