Zanidatamab Plus Chemo ± Tislelizumab Improves Survival in HER2+ Gastroesophageal Adenocarcinoma

First-line zanidatamab-hrii (Ziihera) plus chemotherapy and tislelizumab-jsgr (Tevimbra) significantly improved both progression-free survival (PFS) and overall survival (OS) vs trastuzumab (Herceptin) plus chemotherapy across patient subgroups in previously untreated, HER2-positive advanced gastroesophageal adenocarcinoma (GEA), including those defined by PD-L1 tumor area positivity (TAP) score status, according to results from the phase 3 HERIZON-GEA-01 trial (NCT05152147) published in The New England Journal of Medicine.¹

Both zanidatamab-containing regimens demonstrated statistically significant and clinically meaningful improvements in PFS over trastuzumab plus chemotherapy. At a median follow-up of 25.9 months (range, 7.5-46.0), the median PFS as assessed by blinded independent central review (BICR) was 12.4 months (95% CI, 9.8-18.5) with zanidatamab plus tislelizumab and chemotherapy (n = 302) and 12.4 months (95% CI, 9.8-14.5) with zanidatamab plus chemotherapy (n = 304), compared with 8.1 months (95% CI, 7.0-8.9) with trastuzumab plus chemotherapy (n = 308). The HRs for disease progression or death were 0.63 (95% CI, 0.51-0.78; P < .001) for the triplet vs control and 0.65 (95% CI, 0.52-0.81; P < .001) for the doublet vs control. The estimated PFS rates at 18 months were 43.9% (95% CI, 37.4%-50.1%) in the triplet group, 38.0% (95% CI, 31.5%-44.4%) in the doublet group, and 20.9% (95% CI, 15.3%-27.2%) in the control group. Investigator-assessed PFS results were consistent with those from BICR, and prespecified sensitivity analyses under alternative censoring assumptions yielded results consistent with the primary analysis.

At the first interim analysis, the zanidatamab triplet demonstrated a superior OS compared with trastuzumab plus chemotherapy, with a median OS of 26.4 months (95% CI, 21.5-30.3) vs 19.2 months (95% CI, 16.8-21.8), respectively. This corresponded to a 28% reduction in the risk of death (HR, 0.72; 95% CI, 0.57-0.90; P = .004). The estimated OS rates at 24 months were 54.3% (95% CI, 47.6%-60.5%) with the triplet and 38.8% (95% CI, 32.2%–45.4%) with trastuzumab plus chemotherapy. At 30 months, the estimated OS rates were 43.8% (95% CI, 36.5%-50.9%) and 30.0% (95% CI, 23.4%-36.8%), respectively. OS results were consistent across subgroups, including those defined by PD-L1 status.

For zanidatamab plus chemotherapy, the median OS at this interim analysis was 24.4 months (95% CI, 20.4-30.0) compared with 19.2 months (95% CI, 16.8-21.8) with trastuzumab plus chemotherapy (HR, 0.80; 95% CI, 0.64-1.01; P = .06); this did not meet the prespecified criterion for significance. The estimated OS rate at 24 months in the doublet group was 50.3% (95% CI, 43.6%-56.6%). No significant deviations from the proportional-hazards assumption for OS were noted. Additional prespecified analyses of OS for this regimen are planned.

“Zanidatamab has proven itself to be a superior anti-HER2 agent to trastuzumab,” Geoffrey Y. Ku, MD, a gastrointestinal medical oncologist at Memorial Sloan Kettering Cancer Center, shared in an exclusive interview with OncLive® about the expanded results. “To the degree that adding pembrolizumab to trastuzumab and chemotherapy slightly improved outcomes in [the phase 3] KEYNOTE 811 [NCT03615326], we likely will see the same thing with the addition of tislelizumab to zanidatamab and chemotherapy. The one difference, and a happy one, is that tislelizumab seems to be active in both PD-1–negative and –positive tumors. Long-term follow-up and subgroup analyses…will allow us to get a better sense of whether this is a robust phenomenon. If it is, this would be good news for many patients, irrespective of PD-1 status.”

Of note, data from the primary analysis of HERIZON-GEA-01 were first shared at the 2026 Gastrointestinal Cancers Symposium, prior to the current publication.²

How is HERIZON-GEA-01 designed?

HERIZON-GEA-01 is an international, open-label, randomized, active-comparator, phase 3 trial enrolling patients 18 years of age or older with histologically confirmed, unresectable, locally advanced, recurrent, or metastatic HER2-positive adenocarcinoma of the stomach, gastroesophageal junction (GEJ), or esophagus, as confirmed by central laboratory testing.¹ Patients were required to have an ECOG performance-status score of 0 or 1 and could not have received prior systemic treatment for advanced or metastatic disease or prior HER2-targeted agents or checkpoint inhibitors in any context. PD-L1 expression was retrospectively assessed using the VENTANA PD-L1 (SP263) assay with a TAP score.

Between December 3, 2021, and February 17, 2025, a total of 914 patients were enrolled in the trial at 225 sites across 33 countries. Patients were randomly assigned 1:1:1 to receive:

• Zanidatamab plus tislelizumab and chemotherapy (n = 302)
• Zanidatamab plus chemotherapy (n = 304)
• Trastuzumab plus chemotherapy (n = 308)

Patients were stratified by geographic region (Asia vs European Union or North America vs rest of the world), centrally assessed HER2 status (immunohistochemistry [IHC] 3+ vs IHC 2+ with in situ hybridization–positive status), and ECOG performance status score (0 vs 1). All patients received standard-dose chemotherapy in 21-day cycles; investigator's choice of chemotherapy backbone was capecitabine plus oxaliplatin or fluorouracil plus cisplatin, with the option to discontinue chemotherapy after 6 cycles at the treating physician's discretion. Zanidatamab was administered intravenously at 1800 mg in patients weighing less than 70 kg, or 2400 mg in patients weighing 70 kg or more every 3 weeks; tislelizumab was administered intravenously at 200 mg every 3 weeks. Trastuzumab was administered intravenously at a loading dose of 8 mg/kg followed by 6 mg/kg every 3 weeks. Patients in the zanidatamab-containing groups received mandatory prophylaxis for infusion-related reactions and diarrhea during cycle 1.

The study’s dual primary end points were PFS by BICR per RECIST 1.1 and OS. Key secondary end points included investigator-assessed PFS, confirmed objective response rate (cORR) and duration of response (DOR), and safety.

What were the baseline characteristics?

Demographic and clinical characteristics were balanced across the 3 treatment groups. Key baseline features of the overall population were as follows:

• Median age: 63 years (range, 22-81) in the triplet group; 62.5 years (range, 25-87) in the doublet group; and 64 years (range, 21-84) in the control group
• Sex: male patients represented 80.8%, 80.3%, and 77.3% of patients across the 3 respective arms
• Geographic region: approximately 52% to 54% of patients were enrolled from Asia; approximately 30% from the European Union or North America; and approximately 16% from the rest of the world across all 3 groups; no patients were enrolled from the United States or the Middle East
• Primary tumor site: stomach was the most common site (68.9%, 67.1%, and 73.4%, respectively); GEJ in 24.5%, 20.1%, and 19.5%, respectively; and esophagus in 6.6%, 12.8%, and 7.1%, respectively
• Extent of disease: metastatic in 94.0%, 97.0%, and 97.1%, respectively
• HER2 IHC 3+: 83.1%, 82.6%, and 82.8%, respectively; IHC 2+ with ISH-positive: 16.9%, 16.8%, and 16.9%, respectively
• PD-L1 TAP score ≥ 1%: 61.9%, 58.6%, and 61.0%, respectively
• Chemotherapy backbone: capecitabine plus oxaliplatin was chosen for 90.4%, 90.8%, and 91.6% of patients, respectively

At the data cutoff of October 1, 2025, 29.1% of patients in the zanidatamab plus tislelizumab and chemotherapy group, 22.7% in the zanidatamab plus chemotherapy group, and 12.0% in the trastuzumab plus chemotherapy group were still receiving treatment.

What were the responses with the doublet and triplet regimens?

The cORR by BICR was 70.7% (95% CI, 65.0%-76.0%) with zanidatamab plus tislelizumab and chemotherapy, 69.6% (95% CI, 63.9%-75.0%) with zanidatamab plus chemotherapy, and 65.7% (95% CI, 59.9%-71.2%) with trastuzumab plus chemotherapy. Confirmed complete responses were observed in 19.6%, 17.1%, and 11.0% of patients, respectively.¹ Among patients who achieved a cORR, the median DOR was 20.7 months (95% CI, 12.6-37.7) with the triplet, 14.3 months (95% CI, 11.5–21.9) with the doublet, and 8.3 months (95% CI, 6.7-9.8) with trastuzumab plus chemotherapy.

What was the safety profile across the 3 treatment arms?

The safety population included 294 patients in the zanidatamab plus tislelizumab and chemotherapy group, 305 in the zanidatamab plus chemotherapy group, and 302 in the trastuzumab plus chemotherapy group. The median treatment durations were 43.1, 31.0, and 30.0 weeks, respectively.

Any-grade adverse effects (AEs) occurred in at least 98% of patients across all 3 treatment groups. Grade 3 or higher AEs occurred in 83.3% of patients receiving the triplet, 73.8% receiving the doublet, and 74.5% receiving trastuzumab plus chemotherapy. Grade 5 treatment-related AEs occurred in 2.4%, 0.3%, and 1.3% of patients, respectively. Serious AEs were reported in 58.5%, 49.2%, and 42.4% of patients in these respective groups.

AEs leading to discontinuation of any study drug occurred in 45.6%, 37.0%, and 30.5% of patients, respectively; discontinuation of zanidatamab or trastuzumab specifically occurred in 13.3%, 10.5%, and 5.6% of patients. Tislelizumab was discontinued due to an AE in 17.0% of patients in the triplet arm. AEs leading to dose interruption were more frequent in the zanidatamab triplet (24.1%) and doublet (23.6%) arms than the control arm (10.6%).

Diarrhea was the most common any-grade AE in all 3 groups (83.0% with the triplet; 79.0% with the doublet; 53.3% with the control). Grade 3 or higher diarrhea occurred in 24.8%, 20.0%, and 12.9% of patients, respectively, making it the most common high-grade AE across all arms. The study investigators noted that mandatory antidiarrheal prophylaxis with loperamide during cycle 1 likely contributed to the relatively lower incidence of high-grade diarrhea in the zanidatamab-containing groups compared with earlier-phase studies.

Additional common any-grade AEs occurring in 20% or more of patients in at least 2 groups included nausea (55.8%; 54.4%; 47.7%), anemia (47.3%; 44.3%; 48.7%), decreased appetite (45.9%; 40.3%; 36.1%), vomiting (42.9%; 43.6%; 33.1%), hypokalemia (38.8%; 32.8%; 21.5%), weight decrease (35.4%; 35.7%; 21.5%), peripheral sensory neuropathy (26.5%; 32.1%; 32.5%), and infusion-related reactions (25.2%; 25.2%; 13.2%).

Immune-mediated AEs (imAEs) were reported in 37.8% of patients in the zanidatamab plus tislelizumab and chemotherapy group; the most common was rash (14.3%). Most immune-mediated events were grade 1 or 2, though grade 3 or higher iMAEs occurred in 12.2% of patients in that arm, which was consistent with the known safety profile of tislelizumab.

What is next for zanidatamab?

On April 27, 2026, the FDA accepted and granted priority review to the supplemental biologics license application (sBLA) seeking the approval of zanidatamab in combination with chemotherapy with/without tislelizumab for the treatment of adult patients with HER2-positive unresectable, locally advanced, or metastatic gastric cancer, GEJ cancer, or GEA in the front line.³

The sBLA was supported by data from HERIZON-GEA-01, and the FDA set an August 25, 2026, target action date for the application under the Prescription Drug User Fee Act.

Additional analyses from HERIZON-GEA-01 were presented at the 2026 ASCO Annual Meeting.⁴ Sun Young Rha, MD, PhD, presented a PD-L1 subgroup analysis examining outcomes with zanidatamab plus tislelizumab and chemotherapy across PD-L1 expression levels on June 1, 2026, in a rapid oral session (Abstract 4010). A separate poster presentation (Abstract 25) characterized and detailed the management of gastrointestinal AEs, including the diarrhea observed across treatment arms, from the trial on May 30, 2026.

References

1. Shitara K, Elimova E, Liu T, et al; HERIZON-GEA-01 Investigators. Zanidatamab with and without tislelizumab in HER2-positive gastroesophageal cancer. N Engl J Med. 2026;394(20):2002-2014. doi:10.1056/NEJMoa2517729
2. 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
3. Jazz Pharmaceuticals announces FDA acceptance and priority review of supplemental biologics license application for Ziihera (zanidatamab-hrii) combinations in first-line HER2+ locally advanced or metastatic GEA. News release. Jazz Pharmaceuticals. April 27, 2026. Accessed May 27, 2026. https://investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-announces-fda-acceptance-and-priority-0
4. BeOne Medicines sets the pace in oncology at ASCO and EHA 2026 with 60+ abstracts. News release. BeOne Medicines. May 21, 2026. Accessed May 27, 2026. https://ir.beonemedicines.com/news/beone-medicines-sets-the-pace-in-oncology-at-asco-and-eha-2026-with-60-abstracts/4a61ff99-a44a-4fcd-b82a-e94566abf124