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HERIZON-GEA-01 — Zanidatamab + chemotherapy ± tislelizumab vs trastuzumab + chemo, 1L HER2+ locally advanced/metastatic gastroesophageal adenocarcinoma

Abstract: 4010 (PD-L1 subgroup analysis), Rapid Oral · Session: Gastrointestinal Cancer—Gastroesophageal, Pancreatic, and Hepatobiliary, Rapid Oral Abstract Session, Mon Jun 1 2026 · Presenter: Sun Young Rha, MD, PhD (Yonsei Cancer Center, Yonsei University College of Medicine, Seoul) · Embargo: May 27 2026 (NEJM publication + topline)

At a glance

  • Sponsor: BeOne Medicines (formerly BeiGene); co-developed with Jazz Pharmaceuticals (Ziihera / zanidatamab-hrii)
  • PI / presenter: Sun Young Rha, MD, PhD (Yonsei Cancer Center, Seoul) — first author of the ASCO 2026 PD-L1 subgroup abstract
  • NCT ID: NCT05152147
  • Phase: 3
  • Design: Global, randomized 1:1:1, open-label, ~300 sites across 30+ countries — (A) trastuzumab + CAPOX/FP; (B) zanidatamab + CAPOX/FP; (C) zanidatamab + tislelizumab + CAPOX/FP. Zanidatamab dosed 1800 mg (<70 kg) or 2400 mg (≥70 kg) IV Q3W; tislelizumab 200 mg IV Q3W
  • N: 914 randomized — arm A (control) n=308; arm B (zani + chemo) n=304; arm C (zani + tisle + chemo) n=302; enrolled Dec 2021–Feb 2025
  • Primary endpoint(s): PFS (BICR) and OS, zanidatamab arms vs trastuzumab control
  • Comparator: Trastuzumab + chemotherapy (CAPOX or FP)
  • Indication: Previously untreated HER2-positive locally advanced, unresectable, or metastatic gastroesophageal adenocarcinoma (stomach, GEJ, esophagus)
  • Line: First-line (1L)

Headline result

At a median follow-up of 26.0 months, both zanidatamab-containing regimens significantly improved both primary endpoints versus trastuzumab + chemo.

  • Triplet (arm C, zanidatamab + tislelizumab + chemo): median OS 26.4 months (95% CI 21.5–30.3) vs 19.2 months (95% CI 16.8–21.8) for control — HR 0.72 (95% CI 0.57–0.90; P=0.0043). PFS by BICR 12.4 months vs 8.1 months (95% CI 7.0–8.9) for control — HR 0.63 (95% CI 0.51–0.78; P<0.0001), a ~37% reduction in risk of progression or death.
  • Doublet (arm B, zanidatamab + chemo): median OS 24.4 months. PFS by BICR 12.4 months vs 8.1 months for control — HR 0.65 (95% CI 0.52–0.81; P<0.0001).
  • Duration of response: 20.7 months (arm C), 14.3 months (arm B), 8.3 months (control).

HERIZON-GEA-01 is the first phase 3 in metastatic GEA to show median PFS >1 year and median OS >2 years.

The ASCO 2026 abstract 4010 PD-L1 subgroup analysis showed benefit was consistent across PD-L1–negative and PD-L1–positive tumors (concordant by TAP and CPS): for PD-L1 TAP <1%, 18-month PFS 50.3% and 24-month OS 63.7%; for TAP ≥1%, 18-month PFS 42.6% and 24-month OS 53.5%. Median OS reached 29.7 months in the PD-L1 TAP <1% subgroup (vs 15.8 months control) with the zanidatamab + tislelizumab + chemo triplet, and 26.4 months in TAP ≥1% (vs 21.2 months control).

Immune-mediated AEs occurred in 37.8% of triplet-arm patients (mostly grade 1–2); grade 5 drug-related AEs were 2.4% (triplet), 0.3% (zani+chemo), and 1.3% (trastuzumab). Primary results were published simultaneously in NEJM.

Mechanism / class

Zanidatamab (Ziihera / zanidatamab-hrii) is a bispecific, biparatopic HER2-directed antibody binding two non-overlapping HER2 epitopes (ECD2 and ECD4), driving receptor clustering, internalization, and enhanced effector function. Already FDA-approved (Nov 2024) for previously treated HER2-positive (IHC 3+) biliary tract cancer. Tislelizumab (Tevimbra) is an anti–PD-1 monoclonal antibody engineered to minimize FcγR binding to macrophages.

Discussant takeaway

The ASCO 2026 abstract is framed against the KEYNOTE-811 precedent, where the FDA narrowed pembrolizumab's HER2+ gastric indication to CPS ≥1 over durability concerns in PD-L1–low tumors. The HERIZON-GEA-01 PD-L1 subgroup data argue that the zanidatamab + tislelizumab benefit is not restricted to PD-L1–high disease, with the triplet showing among the longest OS reported in PD-L1–negative patients — a point likely to feature in indication-breadth discussion. (No named ASCO discussant reported in available sources.)

Practice-changing?

Pending / likely yes. Both combinations are positioned by the sponsors as a new 1L standard of care, with the triplet delivering a ~7-month OS gain over trastuzumab + chemo and benefit retained across PD-L1 strata. The FDA granted priority review to the sBLA for zanidatamab + chemo ± tislelizumab in 1L HER2+ gastric/GEJ/GEA with a target action date of August 25, 2026. Primary data are published in NEJM. The ASCO 2026 subgroup analysis supports broad applicability across PD-L1 status but is confirmatory rather than itself registrational.

Sources

  • ASCO 2026 abstract 4010 (PD-L1 subgroup), BeOne Medical Affairs congress page: https://beonemedaffairs.com/us/congress-resources/asco-2026/herizon-gea-01-pd-l1-subgroup-analysis-zanidatamab-chemotherapy-tislelizumab-in-her2+-mgea/
  • ASCO Meeting Library — primary analysis abstract (LBA285), J Clin Oncol: https://ascopubs.org/doi/10.1200/JCO.2026.44.2_suppl.LBA285
  • BeOne Medicines press release (NEJM + ASCO 2026), May 27 2026 (Business Wire): https://www.businesswire.com/news/home/20260527389623/en/BeOne-Medicines-Announces-Phase-3-HERIZON-GEA-Data-Published-in-NEJM-and-Presented-at-ASCO-2026
  • BeOne Medicines press release (NEJM + ASCO 2026), May 27 2026 (BioSpace): https://www.biospace.com/press-releases/beone-medicines-announces-phase-3-herizon-gea-data-published-in-nejm-and-presented-at-asco-2026
  • Jazz Pharmaceuticals NEJM press release (PR Newswire): https://www.prnewswire.com/news-releases/phase-3-herizon-gea-01-results-published-in-the-new-england-journal-of-medicine-show-durable-and-consistent-survival-benefit-with-ziihera-zanidatamab-hrii-combinations-in-first-line-her2-locally-advanced-or-metastatic-gea-302783494.html
  • Jazz Pharmaceuticals NEJM press release (investor): https://investor.jazzpharma.com/news-releases/news-release-details/phase-3-herizon-gea-01-results-published-new-england-journal
  • CancerNetwork (PFS/OS detail, arm-level N): https://www.cancernetwork.com/view/zanidatamab-regimens-extend-pfs-os-in-advanced-metastatic-gastric-cancer
  • OncLive (survival improvement coverage): https://www.onclive.com/view/zanidatamab-plus-chemo-tislelizumab-improves-survival-in-her2-gastroesophageal-adenocarcinoma
  • AJMC coverage: https://www.ajmc.com/view/herizon-gea-01-results-indicate-potential-1l-use-of-zanidatamab-for-gastroesophageal-adenocarcinoma
  • OncUpdates ASCO 2026 GI abstracts to watch (abstract 4010, KEYNOTE-811 framing): https://oncupdates.com/article/asco-2026-gastrointestinal-abstracts-to-watch/
  • ClinicalTrials.gov NCT05152147: https://clinicaltrials.gov/study/NCT05152147