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HERIZON-GEA-01 — Zanidatamab + chemo +/- tislelizumab in 1L HER2+ G/GEJ adenocarcinoma

Headline: Both zanidatamab arms produced statistically significant and clinically meaningful PFS gains over trastuzumab + chemo in 1L HER2+ locally advanced unresectable or metastatic gastroesophageal adenocarcinoma; the IO-containing arm (zanidatamab + tislelizumab + chemo) added an OS benefit. Practice-changing — trastuzumab + chemo is no longer the SOC reference frame for 1L HER2+ G/GEJ.

At a glance

  • Sponsor / PI / institution: Jazz Pharmaceuticals (co-developed with BeiGene for tislelizumab arm); presented by Yelena Janjigian, Memorial Sloan Kettering
  • NCT ID: NCT05152147
  • Phase / arms / N: Phase 3, three-arm randomized; zanidatamab + chemo vs zanidatamab + tislelizumab + chemo vs trastuzumab + chemo; ~900 patients globally
  • Primary endpoint(s): PFS (BICR) and OS, hierarchical
  • Indication / line: 1L HER2+ (IHC 3+ or IHC 2+/FISH+) locally advanced unresectable or metastatic gastroesophageal adenocarcinoma
  • Comparator: Trastuzumab + chemo (CAPOX or FP)
  • Session: Day 3 (Sat Jan 10, 2026), Gastric/GEJ General Session, Moscone West

Headline result

Both zanidatamab-containing arms showed statistically significant and clinically meaningful PFS improvement vs trastuzumab + chemo; the zanidatamab + tislelizumab + chemo arm additionally demonstrated an OS gain over the trastuzumab + chemo control. Subgroup signal was consistent across PD-L1 CPS strata and HER2 IHC 3+ vs 2+/FISH+. Safety was manageable; no new safety signals beyond known zanidatamab GI/infusion-reaction profile plus tislelizumab IO toxicities.

Mechanism / class

Zanidatamab is a bispecific HER2-targeted antibody binding two non-overlapping HER2 epitopes (ECD4 + ECD2), driving receptor clustering, internalization and ADCC — distinct from trastuzumab monovalency. Tislelizumab is an anti–PD-1 mAb engineered to minimize Fc-gamma binding.

Trial design deep dive

Study architecture. Phase 3 global, three-arm randomized 1:1:1 across zanidatamab + chemo, zanidatamab + tislelizumab + chemo, and trastuzumab + chemo control; stratification by region (Asia vs ex-Asia), PD-L1 CPS (≥1 vs <1), and chemo backbone (CAPOX vs FP). Open-label by necessity (chemo backbone differs functionally from triplet), with BICR for the imaging endpoint to mitigate bias.

Endpoint definitions. Dual primary endpoints PFS by BICR and OS, tested hierarchically arm-by-arm against the trastuzumab + chemo control. PFS censoring per RECIST 1.1 standard rules; OS analyzed under ITT with no crossover permitted. Key sensitivity analyses included investigator-assessed PFS and per-protocol population — TBD whether full sensitivity table has been released.

Key subgroup analyses.

  • HER2 IHC 3+ vs IHC 2+/FISH+: consistent PFS benefit reported across both strata; magnitude favoring IHC 3+ as expected (TBD on exact HRs).
  • PD-L1 CPS ≥1 vs <1: IO-add benefit (zani + tisle + chemo arm) concentrated in CPS ≥1 per discussant framing; CPS <1 benefit driven primarily by zanidatamab itself.
  • Geography (Asia vs ex-Asia): consistent direction across regions per ASCO press release framing.
  • Chemo backbone (CAPOX vs FP): TBD — not yet broken out publicly.

Comparator context. Trastuzumab + chemo has been 1L SOC since ToGA (2010); KEYNOTE-811 added pembrolizumab for CPS ≥1 in 2023. HERIZON-GEA-01 directly displaces both reference frames — zanidatamab beats trastuzumab; IO-add still beneficial but now layered on the new HER2 backbone.

FDA / regulatory implications. Jazz filed sBLA Q1 2026 based on HERIZON-GEA-01. Ziihera already carries 2L+ accelerated approval in BTC (Nov 2024). Breakthrough designation in 1L HER2+ G/GEJ was granted prior to readout; full approval conversion in 1L gastric expected 2026.

Discussant takeaway

Yelena Janjigian framed this as the trastuzumab-displacement moment in 1L HER2+ G/GEJ. The open discussant questions are now: which HER2 agent in 1L vs 2L+ sequencing; and how PD-L1 CPS interacts with the IO-add decision.

Practice-changing verdict

Yes. FDA submission was triggered Q1 2026; NCCN reconsideration expected through 2026. Reshapes 1L SOC reference frame for HER2+ G/GEJ.

  • ASCO 2026 — subgroup / biomarker correlates session expected at the May GI track
  • AACR 2026 — HER2 bispecific mechanism sessions
  • ESMO 2026 — OS-mature follow-up expected Oct 2026
  • JPM 2026 — Jazz Pharma investor framing of Ziihera same week

Sources