HERIZON-GEA-01: Zanidatamab for HER2+ Advanced Gastroesophageal Cancer
Key Points
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In the HERIZON-GEA-01 trial, frontline zanidatamab plus chemotherapy and tislelizumab improved progression-free survival (PFS) and overall survival (OS) for patients with HER2–positive locally advanced, unresectable, or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.
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Zanidatamab may replace trastuzumab as the standard of care in first-line treatment.
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The most notable side effect of zanidatamab was diarrhea, although prophylactic loperamide and treatment modifications may help manage it.
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Further analyses are needed to determine whether tislelizumab should be offered to all patients or only to those with PD-L1–positive disease.
HERIZON-GEA-01 Data at 2026 ASCO Gastrointestinal Cancers Symposium
At the 2026 ASCO Gastrointestinal Cancers Symposium, the primary analysis of the HERIZON-GEA-01 trial showed zanidatamab improved survival compared with the frontline standard of care for patients with HER2–positive, locally advanced, unresectable, or metastatic gastric and GEJ adenocarcinomas. Zanidatamab is a novel bispecific antibody that binds to two different HER2 extracellular domains, leading to HER2 downregulation and greater immune activation.
Cohosts of the Oncology Brothers podcast, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, discussed the presentation with four medical oncologists: Geoffrey Ku, MD, of Memorial Sloan Kettering Cancer Center; Rutika Mehta, MD, MPH, of Weill Cornell Medicine, Manish Shah, MD, of Weill Cornell Medicine; and Nataliya Uboha, MD, PhD, of University of Wisconsin School of Medicine and Public Health.
Frontline Zanidatamab Versus Trastuzumab Efficacy
Currently, the first-line standard of care for HER2–positive advanced gastric and GEJ adenocarcinoma is trastuzumab and chemotherapy with or without pembrolizumab based on PD-L1 status. The HERIZON-GEA-01 trial compared zanidatamab and chemotherapy (arm B) or zanidatamab, tislelizumab, and chemotherapy (arm C) against trastuzumab and chemotherapy (arm A). In all arms, chemotherapy was the physician’s choice of capecitabine plus oxaliplatin or 5-fluorouracil plus cisplatin.
Compared with arm A, arm B had significantly improved median PFS (HR, 0.65; 95% CI, 0.52-0.81; P < .0001) and numerically improved median OS (interim HR, 0.80; 95% CI, 0.64-1.01; P = .0564), while arm C had significantly improved median PFS (HR, 0.63; 95% CI, 0.51-0.78; P < .0001) and median OS (HR, 0.72; 95% CI, 0.57-0.90; P = .0043). The presentation reported the following PFS and OS outcomes for each arm.
| Arm A | Arm B | Arm C | |
| Median PFS | 8.1 months (95% CI, 7.0-8.9) | 12.4 months (95% CI, 9.8-14.5) | 12.4 months (95% CI, 9.8-18.5) |
| 18-month PFS | 20.9% | 38% | 43.9% |
| Median OS | 12.4 months (95% CI, 9.8-18.5) | 24.4 months (95% CI, 20.4-30.0) | 26.4 months (95% CI, 21.5-30.3) |
| 24-month OS | 38.8% | 50.3% | 54.3% |
The data showed that zanidatamab was superior to trastuzumab, and the OS improvement in arm B may reach statistical significance in additional planned OS analyses. Moving forward, subgroup analyses may help determine whether tislelizumab should be given to all patients or only to those with PD-L1–positive disease, said Dr. Uboha.
Zanidatamab Clinical Trial Safety Data
In the trial, grade 3 or higher treatment-related adverse events (TRAEs) occurred in 71.8% of patients in arm C, 59% of those in arm B, and 59.6% of those in arm A. Grade 3 or higher TRAEs occurring in more than 10% of patients in arms B and C were diarrhea, hypokalemia, and anemia, and in arm A were diarrhea, anemia, neutropenia, and thrombocytopenia. Anti-HER2 therapy was discontinued for related AEs in 11.9% of arm C, 8.5% of arm B, and 2.3% of arm A.
Diarrhea was the most prominent side effect associated with zanidatamab treatment in HERIZON-GEA-01. The study included standard prophylaxis with loperamide twice daily for 1 week. Dr. Mehta said she will include this prophylaxis when implementing zanidatamab, and potentially extend beyond one week in patients with persistent toxicity.
Modifying or discontinuing chemotherapy may also be effective for managing toxicity. The HERIZON-GEA-01 protocol allowed chemotherapy discontinuation after 6 cycles, although longer follow-up is needed to verify that the treatment benefit is maintained. As a point of comparison, zanidatamab monotherapy has been well tolerated in patients with unresectable or metastatic biliary tract cancer since its approval in November 2024, said Dr. Ku.
Overall, the doctors agreed that, once approved, zanidatamab should replace trastuzumab in the first-line standard of care for all patients with locally advanced, unresectable, or metastatic HER2–positive gastric and GEJ adenocarcinomas. The only population where zanidatamab’s use might be limited is patients with underlying bowel issues who likely would not tolerate any immunotherapy, said Dr. Ku.