Two Ziihera Combination Regimens Enter First-Line Treatment

On August 25, 2026, the U.S. FDA approved Jazz Pharmaceuticals' Ziihera (zanidatamab-hrii) as a first-line treatment for unresectable locally advanced or metastatic HER2-positive gastric/GEJ adenocarcinoma (GEA). This bispecific antibody binds to two extracellular sites on HER2, inducing receptor internalization and antibody-dependent cell-mediated cytotoxicity. Patients with IHC 3+ can receive Ziihera in combination with a fluoropyrimidine and platinum-based chemotherapy, while those with IHC 3+ or IHC 2+/ISH+ can also add BeiGene's PD-1 inhibitor Tevimbra (tislelizumab-jsgr). The label for PD-L1-independent immunotherapy combinations broadens the patient population and prescribing access.

Phase 3 Trial Supports Survival Advantage

In the Phase 3 HERIZON-GEA-01 trial, Ziihera-based regimens reduced the risk of disease progression or death by 35% compared to Roche's Herceptin (trastuzumab) and chemotherapy, with a median progression-free survival of 12.4 months versus 8.1 months. The three-drug regimen including Tevimbra reduced the risk of death by 28%, achieving a median overall survival of 26.4 months versus 19.2 months in the control group. However, as Merck's Keytruda (pembrolizumab)-Herceptin-chemotherapy is also part of the current U.S. standard of care, the choice between non-comparable immunotherapy combinations will be key in real-world market competition. The high incidence of diarrhea in the Ziihera combination group and the FDA boxed warning require preventive loperamide use and strong dosing management capabilities.

U.S. Revenue Potential Significantly Expands Beyond Biliary Cancer

The estimated U.S. treatable patient population is approximately 12,000, which is about eight times the 1,500 HER2-positive biliary cancer patients previously targeted. RBC Capital Markets estimates the market opportunity at over USD 1.5B, while Stifel projects U.S. gastric/GEJ cancer revenue at USD 650M–700M. Given Ziihera's 2025 revenue of USD 24.8M, this approval marks a significant commercial scale-up. Competition will intensify with Herceptin and biosimilars on pricing, Keytruda-based standard of care, and Astellas' Claudin 18.2 antibody Vyloy (zolbetuximab-clzb) in biomarker-driven patient capture.

Approval History and Licensing Economics Are Linked

Ziihera received accelerated approval in the U.S. on November 20, 2024, for previously treated HER2-positive biliary cancer and conditional marketing authorization in the European Union on June 27, 2025, for the same indication. Jazz secured rights to the drug, discovered by Zai Lab, in the U.S., Europe, and Japan in 2022, with an upfront payment of USD 50M and option exercise fees of USD 325M. With this FDA approval, Zai Lab received a USD 250M regulatory milestone, with additional milestones of approximately USD 1.3B and tiered royalties of 10–20% of Jazz's net sales. BeiGene, the rights holder in Asia, Australia, and New Zealand, also paid USD 81M, linking global approvals directly to the three companies' cash flows.