Zanidatamab-based regimens improved PFS and OS vs chemotherapy in HER2+ gastroesophageal adenocarcinoma, positioning the agent as a potential new standard.
The frontline combination of zanidatamab-hrii (Ziihera) and chemotherapy with or without tislelizumab (Tevimbra) demonstrated meaningful efficacy in patients with HER2-positive locally advanced or metastatic gastroesophageal adenocarcinoma (GEA), according to top-line data from the phase 3 HERIZON-GEA-01 trial (NCT05152147).1
HERIZON-GEA-01 Trial Takeaways With Zanidatamab-Containing Regimens in GEA
Zanidatamab plus chemotherapy with or without tislelizumab significantly improved PFS and delivered OS benefits vs trastuzumab-based therapy in first-line HER2-positive GEA.
Benefits were consistent across PD-L1 subgroups, with both investigational regimens showing higher ORRs and longer DORs than the control regimen.
Safety was manageable with no new signals, supporting zanidatamab-based combinations as potential new SOCs in HER2-positive metastatic GEA.
Specifically, zanidatamab plus chemotherapy with and without tislelizumab led to a statistically significant improvement in progression-free survival (PFS) vs trastuzumab (Herceptin) plus chemotherapy. Moreover, zanidatamab paired with tislelizumab and chemotherapy also led to a statistically significant improvement in overall survival (OS); a strong trend toward a statistically significant improvement in OS was also observed with zanidatamab plus chemotherapy alone.
Notably, PFS and OS benefits were observed with zanidatamab plus tislelizumab and chemotherapy vs trastuzumab and chemotherapy in subgroups of patients with PD-L1 positivity and negativity. Both regimens were also found to elicit improved objective response rates (ORRs) and durations of response (DORs) compared with the control regimen; ORR and DOR represented key secondary end points of the study.
“Advanced GEA represents one of the most common tumor types worldwide and remains an aggressive cancer with a poor prognosis,” Kohei Shitara, MD, director of the Department of Gastrointestinal Oncology and principal trial investigator at the National Cancer Center Hospital East, in Kashiwa, Japan, stated in a news release. “Based on the positive results seen in the HERIZON-GEA-01 trial, the zanidatamab plus chemotherapy combination, with and without tislelizumab, has the potential to become the new standard of care for patients in HER2-positive first-line locally advanced unresectable or metastatic GEA. This is the first phase 3 trial to demonstrate a benefit for a novel HER2-targeted therapy compared to trastuzumab as part of a combination regimen in HER2-positive first-line GEA.”
What was the design of the HERIZON-GEA-01 trial?
The global, open-label, randomized trial enrolled patients with histologically confirmed unresectable locally advanced, recurrent or metastatic HER2-positive GEA defined as having 3+ HER2 expression per immunohistochemistry (IHC) or 2+ HER2 expression per IHC with in situ hybridization positivity according to central assessment.2 Patients were required to have assessable disease defined by RECIST 1.1 criteria, an ECOG performance status no higher than 1, acceptable organ function, and left ventricular ejection fraction of at least 50%.
Those with prior exposure to a HER2-targeted agent; PD-1, PD-L1, or PD-L2 inhibition; or systemic antineoplastic therapy or intraperitoneal chemotherapy were excluded. Other key exclusion criteria comprised having untreated central nervous system (CNS) or symptomatic metastases or receipt of radiation for CNS metastases within 4 weeks ahead of randomization; a history of or current leptomeningeal disease; a known additional malignancy that was not cured or needed treatment within the past 3 years; active hepatitis infection or SARS-CoV-2 infection; or clinically substantive cardiac disease.
A total of 914 patients were randomly assigned to 1 of 3 arms: trastuzumab plus physician’s choice of capecitabine plus oxaliplatin (CAPOX) or 5-fluorouracil plus cisplatin (FP; arm A; control arm), zanidatamab plus physician’s choice of CAPOX or FP (arm B), or zanidatamab plus tislelizumab plus physician’s choice of CAPOX or FP (arm C).1
The primary end points of the study are PFS by blinded independent central review (BICR) and OS, and secondary end points include confirmed ORR and DOR by BICR; investigator-assessed PFS, confirmed ORR, and DOR; evaluation of contribution of components based on PFS by BICR and OS; safety in the form of incidence of toxicities and clinical laboratory abnormalities; health-related quality of life; and pharmacokinetic analyses.2
What was learned about the toxicity profiles of the zanidatamab combinations?
The safety profiles of zanidatamab plus chemotherapy with or without tislelizumab were consistent with what has previously been reported with each drug.1 Notably, no new safety signals were observed in the investigational arms, thus supporting the risk-benefit profile of zanidatamab in this indication, according to Jazz Pharmaceuticals, plc.
What prior data have been reported with zanidatamab plus chemotherapy in HER2+ GEA?
Follow-up data from a phase 2 study (NCT03929666) examining frontline zanidatamab plus chemotherapy in patients with HER2-positive advanced or metastatic GEA were previously reported at the 2025 ASCO Annual Meeting.3
At a median follow-up of 48 months (range, 20-59), the median OS with the combination in this subset (n = 41) was 36.5 months (95% CI, 23.6-not evaluable); the median PFS was 15.2 months (95% CI, 9.5-33.4). Moreover, the confirmed ORR with the regimen was 83.8% (95% CI, 68.0%-93.8%), and the median DOR was 20.4 months (95% CI, 8.3-44.1), with a 24-month DOR rate of 41% (95% CI, 22%-59%).
In an exclusive interview with OncLive®, Elena Elimova, MD,4 further discussed the data from the phase 2 trial:
The HERIZON-GEA-01 trial is ongoing, and an additional OS interim analysis for zanidatamab plus chemotherapy is planned for mid-2026.1
Zanidatamab is also under examination in several other trials:
The phase 3 HERIZON-BTC-302 trial (NCT06282575) is assessing the safety and efficacy of zanidatamab and SOC cisplatin plus gemcitabine with or without the addition of a PD-(L)1 inhibitor vs cisplatin and gemcitabine with or without a PD-(L)1 inhibitor in adult patients with HER2-positive biliary tract cancer.5
The phase 3 EmpowHER-303 trial (NCT06435429) is comparing the safety and efficacy of zanidatamab with trastuzumab, each in combination with physician’s choice of chemotherapy, in patients with metastatic HER2-positive breast cancer who have progressed on or are intolerant to prior fam-trastuzumab deruxtecan-nxki (Enhertu).6
The phase 2 DiscovHER PAN-206 trial (NCT06695845) is evaluating the safety and efficacy of single-agent zanidatamab in patients with previously treated HER2-positive cancers.7
The phase 2 neoadjuvant EmpowHER-208 trial (NCT07102381) is examining the safety and efficacy of zanidatamab plus chemotherapy in patients with HER2-positive breast cancer.8
References
Positive HERIZON-GEA-01 phase 3 results support Ziihera (zanidatamab-hrii) as HER2-targeted agent-of-choice and Ziihera combination regimens as new standard of care in first-line HER2-positive locally advanced or metastatic gastroesophageal adenocarcinoma. News release. Jazz Pharmaceuticals, plc. November 17, 2025. Accessed November 17, 2025. https://investor.jazzpharma.com/news-releases/news-release-details/positive-herizon-gea-01-phase-3-results-support-ziiherar
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. Updated October 22, 2025. Accessed November 17, 2025. https://www.clinicaltrials.gov/study/NCT05152147
Elimova E, Ajani JA, Burris HA, et al. Long-term outcomes and overall survival (OS) for zanidatamab + chemotherapy in HER2-positive (HER+) advanced or metastatic gastroesophageal adenocarcinoma (mGEA): 4-year follow-up of a phase 2 trial. J Clin Oncol. 2025;43(suppl 16):4013. doi:10.1200/JCO.2025.43.16_suppl.4013
Efficacy and safety of zanidatamab with standard-of-care therapy against standard-of-care therapy for advanced HER2-positive biliary tract cancer. ClinicalTrials.gov. Updated October 22, 2025. Accessed November 17, 2025. https://www.clinicaltrials.gov/study/NCT06282575
A study comparing the efficacy and safety of zanidatamab to trastuzumab, each in combination with physician’s choice chemotherapy, for the treatment of participants with metastatic HER2-positive breast cancer. ClinicalTrials.gov. Updated October 28, 2025. Accessed November 17, 2025. https://www.clinicaltrials.gov/study/NCT06435429
A phase 2 study of zanidatamab in patients with HER2-expressing tumors. ClinicalTrials.gov. Updated October 10, 2025. Accessed November 17, 2025. https://www.clinicaltrials.gov/study/NCT06695845
A phase 2 neoadjuvant study of zanidatamab in combination with chemotherapy in participants with HER2-positive breast cancer (EmpowHER 208). ClinicalTrials.gov. Updated October 7, 2025. Accessed November 17, 2025. https://clinicaltrials.gov/study/NCT07102381
