Both zanidatamab (Ziihera) plus chemotherapy and zanidatamab plus tislelizumab (Tevimbra) and chemotherapy achieved statistically significant, clinically meaningful improvements in progression-free survival versus trastuzumab plus chemotherapy in first-line HER2-positive gastroesophageal adenocarcinoma. Overall survival was statistically significant for the PD-1 triplet, while the zanidatamab plus chemotherapy doublet showed a clinically meaningful effect with a strong trend toward significance at the first interim. Benefits for the triplet were observed in both PD-L1–positive and PD-L1–negative subgroups. Objective response rate and duration of response improved in both zanidatamab-containing arms, and safety was consistent with known profiles without new signals.
Zymeworks’ partners Jazz Pharmaceuticals and BeOne Medicines reported the Phase 3 HERIZON-GEA-01 topline and intend to submit a supplemental BLA in the first half of 2026 to support zanidatamab with chemotherapy, with or without tislelizumab, as first-line therapy. A further OS interim for the doublet is expected mid-2026. The companies plan near-term scientific disclosure and will seek rapid inclusion in the NCCN Guidelines. Zanidatamab is already commercial in biliary tract cancer, giving the program an existing manufacturing and distribution footprint.
Strategically, the readout is a direct attempt to reset the HER2 backbone in first-line GEA away from trastuzumab. Demonstrating PFS superiority for both zanidatamab regimens and OS superiority for the PD-1 triplet enables two potential label paths: a chemo-based doublet that could simplify first-line HER2 therapy and a triplet designed to neutralize the advantage of PD-1–augmented trastuzumab regimens established by KEYNOTE-811. The PD-L1–agnostic signal for the triplet is notable, positioning the program for a broad population at a time when regulators and payers are increasingly attentive to subgroup consistency and operational simplicity in enrollment. The absence of a head-to-head against pembrolizumab-based regimens keeps competitive positioning unresolved, but superiority to a trastuzumab control is a meaningful first step.
For sites, a zanidatamab backbone largely preserves existing operational workflows: HER2 testing remains central; PD-L1 testing could become less gating if labels do not require it; and infusion logistics mirror current antibody-plus-chemo approaches. If the triplet becomes guideline-preferred, formulary access to tislelizumab will matter; some centers are more accustomed to pembrolizumab contracting and pathways. CROs and sponsors should anticipate an imminent shift in control arms for first-line HER2+ GEA trials, with zanidatamab likely to displace trastuzumab in future protocols and potentially reduce biomarker stratification complexity. Regulators will need to parse dual-arm data for labeling, which could lead to staggered approvals if the doublet’s OS requires further maturity. Vendors supporting pathology and central lab services may see increased demand for standardized HER2 assessment, given gastric tumor heterogeneity and the higher consequence of misclassification under a new backbone.
What matters next are the hazard ratios, medians, and depth/durability of response by key subgroups, plus complete safety tables to understand additive toxicity with PD-1 blockade. If the doublet ultimately delivers a statistically significant OS benefit, it could support a simpler, broad first-line option and complicate PD-1 choice. If only the triplet gains a robust OS label, uptake will hinge on PD-1 interchangeability and payer dynamics relative to entrenched pembrolizumab pathways. Watch for NCCN updates, FDA review designations, and regional filing cadence from Jazz and BeOne, as well as signals on companion diagnostic requirements and manufacturing scale-up that could determine how quickly a new HER2 backbone becomes the operational standard at sites.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
