Zanidatamab Plus Chemo ± Tislelizumab May Replace First-Line Standard of Care in HER2+ Gastroesophageal Adenocarcinoma

Treatment with zanidatamab-hrii (Ziihera) and chemotherapy with or without tislelizumab (Tevimbra) significantly reduced the risk of disease progression or death in the first-line setting for patients with HER2-positive locally advanced or metastatic gastroesophageal adenocarcinoma (GEA), according to results from an interim analysis of the phase 3 HERIZON-GEA-01 trial (NCT05152147) presented at the 2026 Gastrointestinal Cancers Symposium.¹

Patients who received zanidatamab plus tislelizumab and chemotherapy (n = 302) experienced a median progression-free survival (PFS) of 12.4 months (95% CI, 9.8-18.5) vs 8.1 months (95% CI, 7.0-8.9) in the trastuzumab (Herceptin) plus chemotherapy arm (n = 308; HR, 0.63; 95% CI, 0.51-0.78; P < .0001). The 9-, 18-, and 24-month PFS rates with the zanidatamab combination were 59.7% (95% CI, 53.6%-65.4%), 43.9% (95% CI, 37.4%-50.1%), and 38.2% (95% CI, 31.4%-45.0%), respectively. Corresponding rates in the trastuzumab arm were 43.7% (95% CI, 37.5%-49.7%), 20.9% (95% CI, 15.3%-27.2%), and 15.6% (95% CI, 10.1%-22.1%).

The median overall survival (OS) was also superior in the zanidatamab/tislelizumab and chemotherapy arm compared with the trastuzumab arm, at 26.4 months (95% CI, 21.5-30.3) vs 19.2 months (95% CI, 16.8-21.8), respectively (HR, 0.72; 95% CI, 0.57-0.90; P = .0043). The 24- and 30-month OS rates with the zanidatamab combination were 54.3% (95% CI, 47.6%-60.5%) and 43.8% (95% CI, 36.5%-50.9%), respectively. Corresponding rates in the trastuzumab arm were 38.8% (95% CI, 32.2%-45.4%) and 30.0% (95% CI, 23.4%-36.8%).

“In this study, we have surpassed a PFS of 12 months…and the median OS reached 26 months, which is a new benchmark in metastatic GEA,” presenting author Elena Elimova, MD, shared in an exclusive interview with OncLive®at the meeting. “I never thought we’d be talking about those kinds of survival [outcomes]. We always strive to think of novel treatment options, and these seem to work for this patient population.”

These findings support zanidatamab as a promising new standard HER2-targeted agent with the potential to replace trastuzumab in the first-line setting, Elimova and colleagues asserted.

Elimova is an associate professor in the Department of Medicine at the University of Toronto, as well as a staff medical oncologist at Princess Margaret Cancer Centre in Ontario, Canada.

What is the design of HERIZON-GEA-01?

HERIZON-GEA-01 is a global, open-label, randomized, phase 3 trial evaluating the efficacy and safety of zanidatamab plus chemotherapy with or without tislelizumab compared with trastuzumab plus chemotherapy in previously untreated, HER2-positive metastatic GEA.

To be eligible for enrollment, patients needed to be 18 years or older; have histologically-confirmed, unresectable, locally advanced, or metastatic GEA; and have HER2-positive disease, defined as having 3+ HER2 expression per immunohistochemistry (IHC) or 2+ HER2 expression per IHC with positive in situ hybridization.^1,2 An ECOG performance status of 0 or 1, assessable disease defined by RECIST 1.1 criteria, acceptable organ function, and a left ventricular ejection fraction of at least 50% were also required.² No prior exposure to treatment for locally advanced/metastatic disease or HER2-targeted treatments and immunotherapy was permitted.^1,2

Eligible patients (n = 914) were stratified according to geographic region, HER2 status, and ECOG performance status, and then randomly assigned 1:1:1 to 1 of 3 treatment arms:¹

• Arm A: Trastuzumab and physician’s choice of either capecitabine plus oxaliplatin (CAPOX) or 5-fluorouracil (5-FU) plus cisplatin
• Arm B: Intravenous (IV) zanidatamab at 1800 mg (if weighing < 70 kg) or 2400 mg (≥ 70 kg) plus IV tislelizumab at 200 mg every 3 weeks and physician’s choice of chemotherapy (n = 304)
• Arm C: Zanidatamab plus IV tislelizumab at 200 mg every 3 weeks; and physician’s choice of chemotherapy

Treatment continued until death, disease progression, or unacceptable toxicity. Of note, chemotherapy could be discontinued after 6 cycles, and prophylaxis to prevent infusion-related reactions (IRRs) and diarrhea was mandatory in arms B and C.

The study’s dual primary end points are PFS by blinded independent central review and OS. Secondary end points include confirmed objective response rate (ORR), duration of response (DOR) per investigator assessment, safety, health-related quality of life, and pharmacokinetics.²

What baseline characteristics from the HERIZON-GEA-01 trial population are important to note?

Demographic and baseline characteristics were balanced across all 3 arms. The median ages in the zanidatamab/tislelizumab, zanidatamab, and trastuzumab arms were 63 (range, 22-81), 62.5 (range, 25-87), and 64 (range, 21-84) years, respectively. Most patients in all 3 arms were male (80.8%; 80.3%; 77.3%), had an ECOG performance status of 1 (59.6%; 55.9%; 61.0%), metastatic disease (94%; 97%; 97.1%), HER2 IHC 3+ status (83.1%; 82.6%; 82.8%), a PD-L1 tumor area positivity (TAP) score of 1% or greater (61.9%; 58.6%; 61%), and received CAPOX as their chemotherapy backbone (90.4%; 90.8%; 91.6%).

Patients were from Asia (52.6%; 53.6%; 53.6%), Europe/North America (31.5%; 29.9%; 30.2%), and the rest of the world (15.9%; 16.4%; 16.2%). Anatomical subtypes included gastric (68.9%; 67.1%; 73.4%), gastroesophageal junction (24.5%; 20.1%; 19.5%), and esophageal (6.6%; 12.8%; 7.1%) cancer.

What additional efficacy data from HERIZON-GEA-01 were reported?

The median follow-up was 25.9 months (range, 7.9-45.5) in the zanidatamab/tislelizumab arm, 26 months (range, 7.6-46) in the zanidatamab arm, and 25.8 months (range, 7.5-45.6) in the trastuzumab arm.

In the zanidatamab plus chemotherapy arm, Elimova noted that, “there was a favorable trend towards statistical significance for zanidatamab plus chemotherapy, with a median [OS] of more than 5 months.…[However], this was only our first interim analysis.”

The PFS and OS benefits with these zanidatamab-based regimens were generally consistent across key prespecified subgroups, including geographic region and PD-L1 TAP score. However, the median PFS did not favor the zanidatamab combination over trastuzumab in the HER2-positive subgroup; this is likely reflective of the small sample size in this population, Elimova noted.

Responses in the zanidatamab-containing arms were deeper and more durable than those in the trastuzumab arm. In patients with measurable disease, the confirmed ORRs were 70.7% (95% CI, 65%-76%) with zanidatamab plus tislelizumab and chemotherapy (n = 195), which comprised a complete response (CR) rate of 19.6% and a partial response (PR) rate of 51.1%; 69.6% (95% CI, 63.9%-75%) with zanidatamab plus chemotherapy (n = 186), including a CR rate of 17.1% and a PR rate of 52.5%; and 65.7% (95% CI, 59.9%-71.2%) with tislelizumab plus chemotherapy (n = 198), including a CR rate of 11% and a PR rate of 54.8%.

The median DORs for these respective regimens were 20.7 months (95% CI, 12.6-37.7), 14.3 months (95% CI, 11.5-21.9), and 8.3 months (95% CI, 6.7-9.8).

What were the safety profiles of these zanidatamab-based regimens?

The median durations of treatment in the zanidatamab/tislelizumab, zanidatamab, and trastuzumab arms were 43.1 weeks (interquartile range [IQR], 56.7), 31 weeks (IQR, 53.8), and 30 weeks (IQR, 32.2), respectively.

The regimen’s safety profile was deemed generally manageable by investigators, and no unexpected safety signals were identified. Any-grade treatment-emergent adverse effects (TEAEs) occurred in 99.7%, 98.7%, and 98.3% of patients in these respective treatment arms. Any-grade treatment-related AEs (TRAEs) were reported in 98.3%, 97.0%, and 96.4% of patients, respectively; of these, 71.8%, 59% and 59.6% were grade 3 or higher.

Serious TEAEs occurred in 58.5%, 49.2%, and 42.4% of patients in these respective arms; corresponding rates of treatment-related serious TEAEs were 41.2%, 28.2%, and 20.2%. TEAEs leading to death occurred in 9.5%, 8.2%, and 7.3% of patients; of these, 2.4%, 0.3% and 1.3% were deemed treatment-related in each corresponding group. AEs of special interest included IRRs (25.2%; 25.2%; 13.2%), noninfectious pulmonary toxicities (6.8%; 1.3%; 1%), and left ventricular dysfunction (8.8%; 6.2%, 4.3%). Immune-mediated AEs were presented in 37.8%, 12.5%, and 10.3% of patients, respectively.

TRAEs led to discontinuation of any component of treatment (42.5%; 34.4%; 29.1%), zanidatamab or trastuzumab (11.9%; 8.5%; 2.3%), and tislelizumab (14.3%; not applicable [N/A]; N/A). The most common TRAE was diarrhea (82%; 76%; 48%), followed by nausea (51%; 50%; 42%), vomiting (38%; 39%; 28%), decreased appetite (40%; 36%; 28%), anemia (38%; 35%; 37%), peripheral sensory neuropathy (27%; 31%; 32%), weight decrease (22%; 26%; 12%), neutrophil count decrease (25%; 22%; 29%), hypokalemia (21%; 21%; 14%), platelet count decrease (22%; 20%; 30%), and palmar-plantar erythrodysesthesia syndrome (18%; 16%; 21%).

“Even in the control arm, the [rate of] diarrhea was higher than previously reported in other phase 3 studies,” Elimova noted in her presentation. “However, if diarrhea did occur, it generally occurred within the first cycle. It generally resolved within 3 weeks, and few patients had to discontinue zanidatamab due to diarrhea.”

What next steps are planned for the evaluation of zanidatamab in frontline metastatic GEA?

The HERIZON-GEA-01 trial is ongoing, and an additional OS interim analysis for zanidatamab plus chemotherapy is planned for mid-2026, Elimova noted.³ Zanidatamab is also under investigation in the following trials:

• The phase 3 HERIZON-BTC-302 trial (NCT06282575) evaluating zanidatamab and standard-of-care cisplatin plus gemcitabine with/without a PD-(L)1 inhibitor vs cisplatin/gemcitabine with/without a PD-(L)1 inhibitor in patients with HER2-positive biliary tract cancer⁴
• The phase 3 EmpowHER-303 trial (NCT06435429) investigating 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)⁵
• The phase 2 DiscovHER PAN-206 trial (NCT06695845) evaluating single-agent zanidatamab in patients with previously treated HER2-positive solid tumors⁶
• The phase 2 neoadjuvant EmpowHER 208 trial (NCT07102381) examining zanidatamab plus chemotherapy in patients with HER2-positive breast cancer⁷

Disclosures: Elimova disclosed receiving honoraria from Daiichi Sankyo/Astra Zeneca and Roche Canada; serving in a consulting or advisory role for AbbVie,Adaptimmune, Astellas Pharma, AstraZeneca, BeiGene, Bristol-Myers Squibb, Jazz Pharmaceuticals, Signatera, Viracta Therapeutics, and Zymeworks; and receiving institutional research funding from Amgen, Arcus Biosciences, AstraZeneca Canada, Bold Therapeutics, Bristol-Myers Squibb, Jazz Pharmaceuticals, and Zymeworks.

References

1. Elimova E, Rha SY, Shitara K, et al. Zanidatamab + chemotherapy (CT) ± tislelizumab for first-line (1L) HER2-positive (HER2+) locally advanced, unresectable, or metastatic gastroesophageal adenocarcinoma (mGEA): primary analysis from HERIZON-GEA-01. J Clin Oncol. 2026, 44(suppl 4):LBA285.doi:10.1200/JCO.2026.44.2_suppl.LBA285
2. 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 December 17, 2025. Accessed January 8, 2026. https://www.clinicaltrials.gov/study/NCT05152147
3. 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 January 8, 2026. https://investor.jazzpharma.com/news-releases/news-release-details/positive-herizon-gea-01-phase-3-results-support-ziiherar
4. 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 December 17, 2025. Accessed January 8, 2026. https://www.clinicaltrials.gov/study/NCT06282575
5. 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 December 2, 2025. Accessed January 8, 2026. https://www.clinicaltrials.gov/study/NCT06435429
6. A phase 2 study of zanidatamab in patients with HER2-expressing tumors. ClinicalTrials.gov. Updated December 18, 2025. Accessed January 8, 2026. https://www.clinicaltrials.gov/study/NCT06695845
7. A phase 2 neoadjuvant study of zanidatamab in combination with chemotherapy in participants with HER2-positive breast cancer (EmpowHER 208). ClinicalTrials.gov. Updated December 18, 2025. Accessed January 8, 2026. https://clinicaltrials.gov/study/NCT07102381