FDA Approves Jazz's Bispecific HER2 Antibody Ziihera, With and Without BeOne's Tevimbra, for First-Line HER2-Positive Gastroesophageal Adenocarcinoma

Two regimens, two HER2 thresholds

The indication is not one approval but two, and the dividing line runs through the pathology report. Patients whose tumors score IHC 3+ can receive either regimen. Patients whose tumors score IHC 2+ with ISH amplification are covered only by the version that adds BeOne's PD-1 antibody.

The label gives the reason in a prespecified exploratory analysis of the IHC 2+/ISH+ subgroup, where zanidatamab plus chemotherapy without tislelizumab produced a hazard ratio for progression-free survival of 1.73 (95% CI 1.06 to 2.83), with a median of 6.2 months against 10.0 months for trastuzumab and chemotherapy. The FDA's approval notice says the doublet's benefit in the overall population "was primarily attributed to the subgroup of patients with HER2 IHC 3+ tumors," In that IHC 3+ group the doublet posted a median PFS of 14.2 months against 7.6 months (HR 0.55, 95% CI 0.43 to 0.69). Its overall survival was immature at the interim analysis, and Jazz said in May that a second interim look was expected around mid-2026.

The triplet's IHC 2+/ISH+ numbers were also weaker than its headline. The label lists a PFS hazard ratio of 1.08 and an OS hazard ratio of 0.83 in that subgroup, both with confidence intervals crossing 1, against a PFS HR of 0.54 and an OS HR of 0.70 in IHC 3+ disease.

Ventana's 4B5 and Dual ISH join the companion-diagnostic list

HER2 status by central assessment was a stratification factor, and the prescribing information now directs patient selection to FDA-authorized tests and points to the agency's companion-diagnostic list, where the two Ventana products were added on approval day. PD-L1 testing plays no part in the indication, and BeOne's release reports a median overall survival of 29.7 months against 15.8 months in patients whose tumors were PD-L1 negative by tumor area positivity below 1%.

Geoffrey Ku, M.D., of the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center and a study co-author, said in the Jazz release that HER2 testing at the time of diagnosis for advanced or metastatic gastroesophageal adenocarcinoma "is critical to optimally guide treatment selection." Jazz disclosed that Ku has financial interests related to the company.

Diarrhea drove the boxed warning

Across 330 patients who received the triplet in clinical studies, diarrhea occurred in 85%, with grade 3 in 24%, grade 4 in 2.1% and fatal outcomes in 1.5%, despite loperamide prophylaxis in cycle 1. The label tells prescribers not to give the fluorouracil bolus when Ziihera is combined with FOLFOX, to assess left ventricular ejection fraction before starting and at intervals, and to premedicate before every infusion. Dosing is weight based, 1,800 mg or 2,400 mg every three weeks depending on whether the patient is under or over 70 kg.

The FDA ran the application under Project Orbis with Health Canada and the MHRA, both of which are still reviewing.

Who sells it where

Zymeworks discovered the molecule, Jazz holds rights outside Asia under a 2022 deal, and BeOne holds Asia excluding India and Japan, plus Australia and New Zealand. BioPharma Dive reported that the approval triggered an $81 million payment to Zymeworks from BeOne, and quoted Stifel analyst Annabel Samimy estimating about 12,000 eligible U.S. patients against roughly 1,500 for the biliary tract indication Ziihera has held under accelerated approval since 2024.

"Ziihera is now the first and only bispecific HER2-targeted antibody combined with a PD-1 inhibitor and chemotherapy approved for all HER2+ advanced GEA patients, regardless of PD-L1 status," said Rob Iannone, M.D., M.S.C.E., Jazz's executive vice president, global head of research and development and chief medical officer.

Why This Matters to the APO|APE Reader

For the first time in this disease the difference between a 2+ and a 3+ HER2 score changes which regimen a patient can legally receive, and the 17% of HERIZON-GEA-01 patients in the lower category are the reason. Trastuzumab's gastric label never drew that line, so an equivocal 2+ call that goes to ISH now carries a treatment consequence beyond eligibility, and the Dual ISH probe approved alongside the antibody becomes the reflex test of record. Laboratories that run HER2 on gastric biopsies with a different platform will need to check the agency's companion-diagnostic list before the first orders arrive.