HERIZON-GEA-01: Zanidatamab Plus Chemotherapy ± Tislelizumab Advances First-Line Treatment in HER2-Positive Gastroesophageal Adenocarcinoma

HERIZON-GEA-01 is a pivotal phase III trial evaluating zanidatamab-based regimens, with or without the PD-1 inhibitor tislelizumab, compared with trastuzumab plus standard chemotherapy in patients with HER2-positive gastroesophageal adenocarcinoma (GEA). The study explores whether dual HER2 targeting and immune checkpoint inhibition can meaningfully improve outcomes beyond the current trastuzumab-based first-line standard of care.

Clinical Takeaway

Zanidatamab-containing regimens, particularly when combined with chemotherapy and immunotherapy, demonstrate deeper and more durable responses than trastuzumab-based therapy, supporting a potential shift in first-line treatment for HER2-positive GEA.

Drug Profile & Mechanism

• Agent:  
  • zanidatamab
  • trastuzumab
  • tislelizumab
  • CAPOX (capecitabine + oxaliplatin)
  • 5-fluorouracil (5-FU)
  • cisplatin
• Class & Mechanism of Action:
  • zanidatamab: HER2-targeted, bispecific monoclonal antibody that binds two distinct HER2 epitopes (ECD2 & ECD4), leading to enhanced receptor clustering, inhibition of downstream signaling and robust antibody-dependent cellular cytotoxicity (ADCC)
  • trastuzumab: HER2-targeted monoclonal antibody that binds the HER2 extracellular domain, inhibiting downstream signaling and mediating ADCC
  • tislelizumab: Immune checkpoint inhibitor (PD-1 monoclonal antibody) engineered to minimize Fcγ receptor binding on macrophages, thereby reducing antibody-dependent phagocytosis of T cells and enhancing sustained anti-tumor immune activity
  • CAPOX: Combination cytotoxic chemotherapy consisting of:
    • capecitabine: Oral antimetabolite (pyrimidine analogue), prodrug of 5-fluorouracil, inhibiting thymidylate synthase and DNA synthesis
    • oxaliplatin: Platinum-based alkylating agent that induces DNA crosslinks, impairing replication and transcription
  • 5-FU: Antimetabolite (pyrimidine analogue) that inhibits thymidylate synthase and incorporates into RNA & DNA, disrupting synthesis and function
  • cisplatin: Platinum-based alkylating agent that forms DNA crosslinks and adducts, leading to apoptosis
• Route of Administration & Dosing Schedule: (Dosing reflects standard regimens used in HER2-positive GEA trials; exact protocol dosing may vary by investigator choice)
  • zanidatamab: intravenous (IV) 1800 mg (<70 kg) or 2400 mg (≥ 70 kg) every 3 weeks
  • trastuzumab: IV loading dose 8 mg/kg, followed by 6 mg/kg every 3 weeks
  • tislelizumab: IV, 200 mg every 3 weeks
  • CAPOX: capecitabine: 1000 mg/m² orally twice daily on days 1-14 of a 21-day cycle and oxaliplatin 130 mg/m² IV on day 1 of a 21-day cycle
  • 5-FU: 800–1,000 mg/m²/day continuous IV infusion on Days 1–5
  • cisplatin: 80 mg/m² IV on Day 1, every 3 weeks

(Physician’s choice of CAPOX or 5-FU plus cisplatin permitted per protocol.)

Target Population

• Patients with histologically-confirmed, unresectable, locally advanced, or metastatic GEA with HER2-positive disease, defined as:
  • HER2 IHC 3+, or
  • HER2 IHC 2+ with positive in situ hybridization

HERIZON-GEA-01 Study Design (NCT05152147)

• Study Type: Randomized, international, open-label, phase III clinical trial
• Population: 914 patients with metastatic or locally advanced unresectable GEA
• Randomization:
  • Arm A (Control):
    • trastuzumab + CAPOX or 5-FU + cisplatin (physician’s choice)
  • Arm B:
    • zanidatamab + tislelizumab
  • Arm C:
    • zanidatamab + tislelizumab + CAPOX or 5-FU + cisplatin (physician’s choice)
• Follow-Up Duration:
  • Median follow-up: 25.9 months
• Estimated study completion: July 31, 2026

Endpoints

• Primary Endpoint:
  • Progression-free survival (PFS)
  • Overall survival (OS)
• Secondary Endpoints:
  • Objective response rates (ORR)
  • Duration of Response (DoR)
  • Safety and tolerability

Efficacy Outcomes

• Primary Endpoint Results: At the time of reporting, the co-primary endpoints of PFS and OS have not yet fully matured
• ORR: Higher ORR observed with zanidatamab-containing arms compared with trastuzumab-based therapy
• DoR: Responses were more durable in zanidatamab-based regimens, with a greater proportion lasting ≥6 months
• PFS: Interim analyses demonstrate a clinically meaningful improvement in PFS favoring zanidatamab plus chemotherapy ± tislelizumab
• OS: Data are immature but trending favorably toward zanidatamab-containing arms

Safety

• Overall Safety Profile: Consistent with known profiles of HER2-targeted therapies, immune checkpoint inhibitors, and platinum-based chemotherapy.
• Grade ≥3 Events: More frequent in chemotherapy-containing arms, driven primarily by hematologic and gastrointestinal toxicities
• Treatment discontinuation: Low rates of discontinuation due to zanidatamab-related toxicity
• Notable toxicity patterns:
  • Diarrhea and infusion-related reactions (zanidatamab)
  • Immune-related adverse events (tislelizumab)
  • Peripheral neuropathy (oxaliplatin)
  • Myelosuppression and GI toxicity (chemotherapy)

No new safety signals were identified, and adverse events were generally manageable with standard supportive care and dose modifications.

Regulatory Milestones

• Approval Status: Zanidatamab not yet FDA approved for GEA (as of January 2026)
• Current Standard of Care: Trastuzumab plus platinum-based chemotherapy ± immunotherapy
• Regulatory Pathway: HERIZON-GEA-01 supports potential regulatory submission for zanidatamab-based first-line therapy in HER2-positive GEA

Key Clinical Implications

✔ Dual HER2 targeting may improve depth and durability of response

✔ Zanidatamab demonstrates activity beyond traditional trastuzumab-based therapy

✔ Addition of immunotherapy may further enhance outcomes in select patients

✔ Chemotherapy-free regimens may be feasible for some patients

✔ HER2-positive GEA treatment paradigms are likely to evolve

Bottom Line

HERIZON-GEA-01 positions zanidatamab, particularly in combination with chemotherapy and immunotherapy, as a potential new first-line standard for HER2-positive gastroesophageal adenocarcinoma, with encouraging efficacy and a manageable safety profile.

Sources:

• American Society of Clinical Oncology. (2026, January 6). Zanidatamab and chemotherapy can slow cancer growth, extend survival in some people with gastroesophageal adenocarcinoma. ASCO. https://www.asco.org/about-asco/press-center/news-releases/zanidatamab-and-chemotherapy-can-slow-cancer-growth
• National Library of Medicine. (n.d.). A randomized, multicenter, phase 3 study of zanidatamab in combination with chemotherapy with or without tislelizumab in subjects with HER2‑positive unresectable locally advanced or metastatic gastroesophageal adenocarcinoma (HERIZON‑GEA‑01) (NCT05152147). ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT05152147?tab=researcher
• Jazz Pharmaceuticals. (n.d.). Zanidatamab GEA clinical trial. https://www.jazzpharma.com/science/clinical-trials/gea-trial
• OncLive. (2026, January 8). Zanidatamab plus chemo ± tislelizumab may replace first‑line standard of care in HER2+ gastroesophageal adenocarcinoma. https://www.onclive.com/view/zanidatamab-plus-chemo-tislelizumab-may-replace-first-line-standard-of-care-in-her2-gastroesophageal-adenocarcinoma