Zanidatamab clears FDA for first-line HER2-positive gastro-oesophageal cancer

The US Food and Drug Administration approved zanidatamab (Ziihera) on 25 August 2026 as a first-line treatment for advanced HER2-positive gastro-oesophageal adenocarcinoma, in combination with chemotherapy and, for most patients, the immunotherapy tislelizumab [s1][s3]. The clearance rests on the phase 3 HERIZON-GEA-01 trial, in which zanidatamab plus chemotherapy extended median progression-free survival to 12.4 months against 8.1 months for the long-standing HER2 antibody trastuzumab — but a clear gain in how long patients lived appeared only in the arm that also received tislelizumab [s2].

HER2, a growth-driving receptor, is over-expressed in roughly one in five stomach and oesophageal adenocarcinomas, and trastuzumab added to chemotherapy has been the reference first-line treatment for that group for more than a decade. Zanidatamab is a bispecific antibody: rather than binding HER2 at one site as trastuzumab does, it grips two separate parts of the receptor at once. The drug already carried a 2024 US approval in HER2-positive biliary tract cancer; this decision moves it into a far larger disease.

What the approval covers

The FDA cleared two first-line uses [s1]. The first is zanidatamab plus fluoropyrimidine- and platinum-based chemotherapy and tislelizumab, for tumours that are HER2-positive by immunohistochemistry score 3+ or 2+ with confirmatory in-situ hybridisation. The second is zanidatamab plus chemotherapy alone, restricted to the strongly HER2-positive IHC 3+ group [s1]. In both, HER2 status must be confirmed with an FDA-authorised test [s1]. The split matters: the broader, immunotherapy-containing indication is where the survival evidence is strongest, and the chemotherapy-only option is reserved for the tumours most likely to respond to HER2 blockade on its own.

What the trial showed

HERIZON-GEA-01 randomly assigned patients with previously untreated, centrally confirmed HER2-positive advanced gastro-oesophageal adenocarcinoma in a 1:1:1 ratio to zanidatamab plus tislelizumab plus chemotherapy (302 patients), zanidatamab plus chemotherapy (304 patients), or trastuzumab plus chemotherapy (308 patients) [s2]. The two primary endpoints were progression-free survival and overall survival.

At a median follow-up of 25.9 months, both zanidatamab regimens delayed progression longer than trastuzumab: median progression-free survival was 12.4 months with either zanidatamab combination against 8.1 months with trastuzumab [s2]. The hazard ratio for progression or death was 0.63 (95% confidence interval, 0.51 to 0.78) for the tislelizumab-containing arm and 0.65 (95% confidence interval, 0.52 to 0.81) for zanidatamab plus chemotherapy, with P<0.001 for both comparisons [s2].

Survival is where the two zanidatamab arms diverge. Overall survival was longer with zanidatamab-tislelizumab-chemotherapy than with trastuzumab — a median of 26.4 against 19.2 months, a hazard ratio for death of 0.72 (95% confidence interval, 0.57 to 0.90; P=0.004) [s2]. For zanidatamab plus chemotherapy without tislelizumab, median overall survival was 24.4 months, and at this interim analysis the difference from trastuzumab was not statistically significant (hazard ratio, 0.80; 95% confidence interval, 0.64 to 1.01; P=0.06) [s2]. That is the honest limit of the chemotherapy-only indication: it delays progression, but its effect on length of life has not yet been established, and the trial's authors say further analyses of that arm are planned [s2].

The safety ledger

Serious toxicity rose with the more intensive regimens. Grade 3 or higher adverse events occurred in 83.3% of patients on zanidatamab-tislelizumab-chemotherapy, 73.8% on zanidatamab-chemotherapy, and 74.5% on trastuzumab-chemotherapy [s2]. Diarrhoea was the most common such event, in 24.8%, 20.0% and 12.9% of patients respectively — a recognised effect of HER2-directed antibodies that is more frequent with the bispecific [s2].

What it settles, and what it does not

The trial answers a specific question — whether a dual-epitope HER2 antibody beats trastuzumab in the first-line setting — and for progression, the answer is yes for both zanidatamab regimens [s2]. The survival case is narrower: it holds where tislelizumab is part of the combination, and remains open for zanidatamab with chemotherapy alone [s2]. The approval's structure mirrors that evidence rather than overreaching past it.

Zanidatamab is the second bispecific antibody to reach a gastrointestinal cancer in recent US decisions, after zenocutuzumab in NRG1-fusion tumours, and part of a wider run of HER2-directed approvals built on precise molecular selection. For a cancer that is still most often found late — and for which population screening is limited to a few countries — a first-line regimen that adds four months of progression-free time, and in one configuration seven months of median survival, is a real step, measured against a trastuzumab standard that had not moved in years.

Sources

• [s1] U.S. Food and Drug Administration. BLA 761416/S-002 Supplement Approval Letter — Ziihera (zanidatamab-hrii) injection. 25 August 2026.
• [s2] Shitara K, Elimova E, Liu T, et al. Zanidatamab with and without Tislelizumab in HER2-Positive Gastroesophageal Cancer (HERIZON-GEA-01). New England Journal of Medicine. 28 May 2026.
• [s3] U.S. Food and Drug Administration. Drugs@FDA: BLA 761416 (Ziihera) — approval record. 25 August 2026.