Home / Clinical Trial: HERIZON-GEA-01

HERIZON-GEA-01 is a Phase 3 trial that enrolled patients with HER2+ advanced GEA, irrespective of PD-L1 status1,2

HERIZON-GEA-01 is a global, pivotal, randomized, open-label Phase 3 trial evaluating ZIIHERA against trastuzumab. It is the largest trial ever for HER2-positive GEA, enrolling 914 patients across over 200 sites in more than 30 countries.1,3-5

HERIZON-GEA-01 study design flow diagram: 914 patients with HER2-positive advanced gastroesophageal adenocarcinoma were randomized 1:1:1 into three treatment arms, with tumor assessment every 6 weeks and dual primary and select secondary endpoints.
  • Median follow-up for all treatment groups was 26 months6
  • Chemotherapy administered for at least 6 cycles1
  • Prophylaxis with loperamide (4 mg, twice daily, for at least the first 7 days of Cycle 1) to mitigate diarrhea was mandatory with ZIIHERA6
  • Prophylaxis to reduce the risk of IRRs was also mandatory with ZIIHERA6

Key Eligibility Criteria

  • Unresectable, locally advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinomas1
  • HER2-positive (IHC 3+ or IHC 2+/ISH+) per central testing1
  • ECOG PS of 0-11
  • Adequate organ function, including LVEF ≥50%1
  • Previously untreated1
See the dosing details from the trial1
ZIIHERA HERIZON-GEA-01 dosing protocol chart for ZIIHERA + tislelizumab + chemotherapy, ZIIHERA + chemotherapy, or trastuzumab + chemotherapy.

||CAPOX: capecitabine 1000 mg/m² orally twice daily for 14 days plus oxaliplatin 130 mg/m² IV. FP: 5-Fluorouracil 800 mg/m²/day IV infusion for 5 days + cisplatin 80 mg/m² IV. CT was given for at least 6 cycles, every 21-day cycle.1,8

CAPOX=capecitabine and oxaliplatin; FP=fluorouracil and cisplatin; IV=intravenous.

*Tislelizumab (200 mg) was administered intravenously every 3 weeks.1

†Computed tomography (CT)/MRI scans were performed every 6 weeks for the first 54 weeks, then every 9 weeks.6

‡PFS, cORR, and DOR results assessed by blinded independent central review per RECIST v1.1.1

HERIZON-GEA-01 trial updates
Get notified when new data for HERIZON-GEA-01 are released.

RECEIVE UPDATES

Patient demographics1,6

HERIZON-GEA-01 enrolled patients irrespective of PD-L1 status1

Table of baseline patient characteristics for ZIIHERA plus tislelizumab plus chemotherapy (n=302), ZIIHERA plus chemotherapy (n=304), and trastuzumab plus chemotherapy (n=308)

§Total exceeds 100% due to rounding.

One patient receiving ZIIHERA + tislelizumab + CT had an ECOG PS score of 2 at baseline.6

#PD-L1 status was missing for 7.1% (n=65) of patients across arms.6

HERIZON-GEA-01 IS THE ONLY PHASE 3 TRIAL FOR HER2+ ADVANCED GEA TO ENROLL PATIENTS WITH ESOPHAGEAL ADENOCARCINOMA1,3,4

Explore the data that established a ZIIHERA regimen as a potential 1L standard of care in HER2+ advanced GEA

GROUNDBREAKING RESULTS

INDICATIONS

ZIIHERA (zanidatamab-hrii) 50 mg/mL is indicated:

  • In combination with fluoropyrimidine- and platinum-containing chemotherapy and tislelizumab-jsgr, as first-line treatment for adult patients with HER2-positive (IHC 3+ or IHC 2+/ISH+) unresectable locally advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma, as detected by an FDA-authorized test.

  • In combination with fluoropyrimidine- and platinum-containing chemotherapy, as first-line treatment for adult patients with HER2-positive (IHC 3+) unresectable locally advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma, as detected by an FDA-authorized test.

IMPORTANT SAFETY INFORMATION

IMPORTANT SAFETY INFORMATION AND INDICATION

WARNING: DIARRHEA and EMBRYO-FETAL TOXICITY

  • ZIIHERA, in combination with fluoropyrimidine- and platinum-containing chemotherapy, with or without tislelizumab-jsgr, can cause severe diarrhea, including life threatening and fatal cases. Use antidiarrheal prophylaxis during the first cycle when ZIIHERA is given in combination with these drugs. Manage with antidiarrheals and supportive measures as clinically indicated. Interrupt, reduce the dose or discontinue ZIIHERA based on severity.
  • Embryo-Fetal Toxicity: Exposure to ZIIHERA during pregnancy can cause embryo-fetal harm. Advise patients of the risk and need for effective contraception.

Diarrhea

ZIIHERA can cause severe diarrhea.

When ZIIHERA is used in combination with fluoropyrimidine- and platinum-containing chemotherapy with or without tislelizumab-jsgr, severe, life threatening, and fatal cases of diarrhea can occur despite loperamide prophylaxis. The risk of severe and life threatening diarrhea is higher when ZIIHERA is administered with chemotherapy and tislelizumab-jsgr, with a higher risk in patients aged ≥ 65 years compared to younger patients. Advise patients to increase oral fluids, begin antidiarrheals, and notify their healthcare provider immediately if diarrhea occurs.

Administer antidiarrheal prophylaxis with loperamide in cycle 1 for all patients receiving ZIIHERA in combination with fluoropyrimidine- and platinum-containing chemotherapy with or without tislelizumab-jsgr. Begin loperamide at the first loose stool when ZIIHERA is administered in combination with chemotherapy. Administer fluids, electrolytes, and additional antidiarrheal agents as necessary. Before modifying the dose of ZIIHERA, evaluate, modify or discontinue drug(s) contributing to diarrhea in accordance with their respective prescribing information. Withhold, reduce the dose, or permanently discontinue ZIIHERA based on severity.

If treating patients with ZIIHERA in combination with FOLFOX, do not administer the fluorouracil bolus.

ZIIHERA in combination with chemotherapy and tislelizumab-jsgr

Diarrhea was reported in 85% of 330 patients in clinical studies, including Grade 4 (2.1%), Grade 3 (24%), and Grade 2 (31%) events. Fatal outcomes resulting from diarrhea occurred in 1.5% of patients. Diarrhea leading to dose reduction of ZIIHERA occurred in 10% of patients, and permanent discontinuation of ZIIHERA occurred in 3.9% of patients.

In cycle 1, diarrhea at Grade 4 severity occurred in 1.5% and Grade 3 severity occurred in 15% of patients despite use of loperamide prophylaxis. The median time to onset for cycle 1 diarrhea was 6 days and median time to resolution was 18 days.

ZIIHERA in combination with chemotherapy

Diarrhea was reported in 81% of 395 patients in clinical studies, including Grade 4 (1.3%), Grade 3 (20%) and Grade 2 (33%). Diarrhea leading to dose reduction of ZIIHERA occurred in 10% of patients, and permanent discontinuation of ZIIHERA occurred in 1.8% of patients.

In cycle 1, diarrhea at Grade 4 severity occurred in 0.8% and Grade 3 severity occurred in 14% of patients despite use of loperamide prophylaxis. The median time to onset for cycle 1 diarrhea was 6 days and median time to resolution was 18 days.

Embryo-Fetal Toxicity

Based on the mechanism of action, ZIIHERA can cause fetal harm when administered to a pregnant woman. There are no human or animal data on the use of ZIIHERA in pregnancy. In literature reports, use of a HER2-directed antibody during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death.

Verify the pregnancy status of females of reproductive potential prior to the initiation of ZIIHERA. Advise pregnant women and females of reproductive potential that exposure to ZIIHERA during pregnancy or within 4 months prior to conception can result in fetal harm. Advise females of reproductive potential to use effective contraception while receiving ZIIHERA and for 4 months following the last dose of ZIIHERA.

Left Ventricular Dysfunction (LVD)

ZIIHERA can cause decreases in left ventricular ejection fraction (LVEF).

Assess LVEF prior to initiation of ZIIHERA and at regular intervals during treatment. Withhold dose or permanently discontinue ZIIHERA based on severity of adverse reactions.

The safety of ZIIHERA has not been established in patients with a baseline ejection fraction that is < 50%.

ZIIHERA in combination with chemotherapy and tislelizumab-jsgr

LVEF decrease (an absolute decline in LVEF of > 10%, resulting in a final value of < 50%) was observed in 9% of 330 patients in clinical studies. LVD leading to permanent discontinuation of ZIIHERA was reported in 3% of patients. Fatal outcomes due to LVD occurred in one patient (0.3%). The median time to first occurrence of LVD was 6.9 months (range: 1.2 to 29.1 months). LVD resolved in 78% of patients.

ZIIHERA in combination with chemotherapy

LVEF decrease was observed in 5% of 395 patients. LVD leading to permanent discontinuation of ZIIHERA was reported in 1.0% of patients. The median time to first occurrence of LVD was 6.0 months (range: 1.4 to 15.0 months). LVD dysfunction resolved in 70% of patients.

Infusion-Related Reactions

ZIIHERA can cause infusion-related reactions (IRRs).

Prior to each dose of ZIIHERA, administer premedication to prevent potential IRRs. Monitor patients for signs and symptoms of IRR during ZIIHERA administration and as clinically indicated after completion of infusion. Have medications and emergency equipment to treat IRRs available for immediate use.

If an IRR occurs, slow or stop the infusion, and administer appropriate medical management. Monitor patients until complete resolution of signs and symptoms before resuming. Permanently discontinue ZIIHERA in patients with recurrent severe or life-threatening IRRs.

ZIIHERA in combination with chemotherapy and tislelizumab-jsgr

An IRR was reported in 22% of 330 patients in clinical studies, including Grade 4 (0.3%), Grade 3 (1.2%), and Grade 2 (16%) despite use of prophylaxis. IRRs leading to permanent discontinuation of ZIIHERA were reported in 0.3% of patients. IRRs occurred on the first day of dosing in 17% of patients. Of all patients who experienced IRRs, 60% of reactions resolved within the first day.

ZIIHERA in combination with chemotherapy

An IRR was reported in 24% of 395 patients in clinical studies, including Grade 4 (0.3%), Grade 3 (1.5%), and Grade 2 (18%) despite use of prophylaxis. IRRs leading to permanent discontinuation of ZIIHERA were reported in 1.3% of patients. IRRs occurred on the first day of dosing in 22% of patients. Of all patients who experienced IRRs, 83% of reactions resolved within the first day.

Adverse Reactions

ZIIHERA in combination with chemotherapy and tislelizumab-jsgr

Serious adverse reactions occurred in 59% of 294 patients in HERIZON-GEA-01. Serious adverse reactions in > 2% of patients included diarrhea (17%), IRR (5%), vomiting (4.8%), hypokalemia (4.4%), acute kidney injury (3.7%), pneumonia (3.7%), nausea (2.4%), decreased appetite (2.4%), and anemia (2.4%). Fatal adverse reactions occurred in 2.4% of patients and included acute kidney injury (N=2), cardiac failure, diarrhea, dehydration, hypovolemic shock and intestinal obstruction (all N=1).

Permanent discontinuation of ZIIHERA occurred in 13% of patients. Adverse reactions that resulted in permanent discontinuation of ZIIHERA in ≥ 1% of patients included diarrhea (4.4%) and ejection fraction decreased (2.7%).

The most common adverse reactions (≥ 20%) were diarrhea (83%), nausea (56%), decreased appetite (46%), vomiting (44%), hypokalemia (39%), fatigue (37%), rash (36%), peripheral neuropathy (27%), and IRR (25%).

ZIIHERA in combination with chemotherapy

Serious adverse reactions occurred in 49% of 305 patients in HERIZON-GEA-01. Serious adverse reactions in > 2% of patients included diarrhea (11%), vomiting (3.3%), decreased appetite (2.6%), pneumonia (2.6%), sepsis (2.6%), hypokalemia (2.3%), and nausea (2.3%).

Permanent discontinuation of ZIIHERA occurred in 10% of patients. Adverse reactions that resulted in permanent discontinuation of ZIIHERA in ≥ 1% of patients included ejection fraction decreased (2.0%), IRR (1.6%), and diarrhea (1.6%).

The most common adverse reactions (≥ 20%) were diarrhea (79%), nausea (54%), vomiting (44%), decreased appetite (40%), fatigue (36%), hypokalemia (33%), peripheral neuropathy (32%), IRR (25%), and rash (22%).

Pediatric Use

Safety and efficacy of ZIIHERA have not been established in pediatric patients.

Geriatric Use

ZIIHERA in combination with chemotherapy and tislelizumab-jsgr

Of 302 patients randomized to ZIIHERA in combination with chemotherapy and tislelizumab-jsgr in HERIZON-GEA-01, there were 139 (46%) patients aged ≥ 65 years. One hundred and six (35%) were aged 65-74 years and 33 (11%) were aged ≥ 75 years.

There was a higher incidence of Grade ≥ 3 adverse reactions observed in patients aged ≥ 65 years (87%) as compared to younger patients (80%). The incidence of Grade 3 or 4 diarrhea was higher in patients aged ≥ 65 years (32%) compared to younger patients (20%).

There was an increased incidence of fatal adverse reactions in patients aged ≥ 65 years (4.4%); including acute kidney injury (N=2), cardiac failure, dehydration, hypovolemic shock and intestinal obstruction (all N=1), compared to younger patients (0.6%), including diarrhea (N=1).

ZIIHERA in combination with chemotherapy

Of 304 patients randomized to ZIIHERA in combination with chemotherapy in HERIZON-GEA-01, there were 130 (43%) patients aged ≥ 65 years. One hundred (33%) were aged 65-74 years and 30 (10%) were aged ≥ 75 years.

No overall differences in safety were observed between patients aged ≥ 65 years and younger adult patients.

Please click here to see the full Prescribing Information, including BOXED WARNINGS and Medication Guide.

1L=first-line; AR=adverse reaction; CAPOX=capecitabine and oxaliplatin; cORR=confirmed objective response rate; CT=chemotherapy; DOR=duration of response; ECOG PS=Eastern Cooperative Oncology Group performance status; EU=European Union; FP=fluorouracil and cisplatin; GEA=gastroesophageal adenocarcinoma; GEJ=gastroesophageal junction; HER2=human epidermal growth factor receptor 2; IHC=immunohistochemistry; IRR=infusion-related reaction; ISH=in situ hybridization; MRI=magnetic resonance imaging; OS=overall survival; PD-L1=programmed death-ligand 1; PFS=progression-free survival; RECIST=Response Evaluation Criteria in Solid Tumors; TAP=tumor area positivity.

References: 1. ZIIHERA (zanidatamab-hrii) Prescribing Information. Palo Alto, CA: Jazz Pharmaceuticals, Inc. 2026. 2. Tabernero J, Shen L, Elimova E, et al. HERIZON-GEA-01: zanidatamab + chemo ± tislelizumab for 1L treatment of HER2-positive gastroesophageal adenocarcinoma. Future Oncol. 2022;18(29):3255-3266. doi:10.2217/fon-2022-0595 3. Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687-697. doi:10.1016/S0140-6736(10)61121-X 4. Janjigian YY, Kawazoe A, Bai Y, et al. Final overall survival for the phase III, KEYNOTE-811 study of pembrolizumab plus trastuzumab and chemotherapy for HER2+ advanced, unresectable or metastatic G/GEJ adenocarcinoma. Ann Oncol. 2024;35(S2):S877-S878. doi:10.1016/j.annonc.2024.08.1466 5. A study of zanidatamab in combination with chemotherapy plus or minus tislelizumab in patients with HER2-positive advanced or metastatic gastric and esophageal cancers (HERIZON-GEA-01). ClinicalTrials.gov. NCT05152147. Updated July 17, 2026. Accessed August 18, 2026. clinicaltrials.gov/study/NCT05152147 6. Shitara K, Elimova E, Liu T, et al. Zanidatamab with and without tislelizumab in HER2-positive gastroesophageal cancer. N Engl J Med. 2026;394(20):2002-2014. doi:10.1056/NEJMoa2517729 7. Elimova E, Rha SY, Shitara K, et al. Zanidatamab + chemotherapy ± tislelizumab for first-line HER2-positive locally advanced, unresectable, or metastatic gastroesophageal adenocarcinoma: primary analysis from HERIZON-GEA-01. Presented at: American Society of Clinical Oncology Gastrointestinal Cancers Symposium; January 8-10, 2026; San Francisco, CA. 8. Shitara K, Elimova E, Liu T, et al. Zanidatamab with and without tislelizumab in HER2-positive gastroesophageal cancer. N Engl J Med. 2026;394(20):2002-2014. doi:10.1056/NEJMoa2517729. Supplementary appendix.