Zanidatamab Regimens Extend PFS/OS in Advanced/Metastatic Gastric Cancer

Zanidatamab-hrii (Ziihera) plus chemotherapy, with or without tislelizumab-jsgr (Tevimbra) displayed prolonged overall survival (OS) and progression-free survival (PFS) benefit as a first-line treatment for patients with HER2-positive locally advanced or metastatic gastroesophageal adenocarcinoma (GEA) in the phase 3 HERIZON-GEA-01 trial (NCT05152147), according to a news release from the developer, Jazz Pharmaceuticals.¹

Data from the first interim analysis of the trial revealed that in patients treated with or without tislelizumab, a clinically meaningful and statistically significant extension of PFS and approximately a 35% reduction in the risk of progression or death occurred vs the control arm, which was treated with standard-of-care (SOC) trastuzumab (Herceptin) plus chemotherapy. Moreover, the median PFS exceeded 1 year at 12.4 months (95% CI, 9.8-14.5) vs 8.1 months (95% CI, 7.0-8.9) in the trastuzumab arm, an improvement of more than 4 months (P <.0001).

Additionally, zanidatamab/tislelizumab and chemotherapy elicited a median OS of 26.4 months (95% CI, 21.5-30.3), which is the longest reported OS in a phase 3 trial in patients with GEA, compared with 19.2 months (95% CI, 16.8-21.8) with trastuzumab (HR, 0.72; 95% CI, 0.57-0.90; P = .0043). This translated to a greater than 7-month improvement in median OS vs the control arm as well as a 28% reduction in the risk of death vs SOC. Data from the first interim analysis suggest the zanidatamab-based combination has a strong trend toward statistical significance vs the trastuzumab-based combination, with an additional planned OS interim analysis planned for later in 2026.

OS and PFS benefits with the zanidatamab-based combination were consistent among prespecified subgroups, including geographic region and PD-L1 status.

Furthermore, 70.7% of patients treated with zanidatamab/tislelizumab and chemotherapy experienced an objective response vs 65.7% in the trastuzumab arm, and the median duration of response (DOR) was 20.7 months vs 8.3 months, respectively. Moreover, the 18-month PFS rates were 43.9% vs 20.9%, and the 30-month OS rates were 43.8% vs 30.0%.

"Reaching more than 2 years of median [OS] in a global phase 3 trial for [HER2-positive] metastatic GEA is truly unprecedented," Elena Elimova, MD, gastrointestinal medical oncologist at the Princess Margaret Cancer Centre, and the presenting author of the late-breaking data, stated in the news release.¹ "The HERIZON-GEA-01 results represent the longest survival outcomes in a phase 3 trial ever reported in this setting, with the zanidatamab plus tislelizumab and chemotherapy regimen improving median [OS] by more than 7 months vs the control arm. The fact that both zanidatamab plus chemotherapy and zanidatamab plus tislelizumab and chemotherapy achieved median [PFS] beyond 1 year further reinforces the depth and durability of benefit. These findings signal a meaningful step forward for patients who have historically [had] very limited long-term outcomes."

A total of 914 patients with unresectable locally advanced, recurrent or metastatic HER2-positive GEA in the phase 3 trial were randomly assigned to receive zanidatamab plus chemotherapy with or without tislelizumab or trastuzumab plus chemotherapy.

The dual primary end points of the trial included PFS per blinded independent review and OS. Secondary end points included objective response rate, DOR, PFS per investigator assessment, and safety.²

The safety profiles of the zanidatamab-based combinations were consistent with the known effects of HER2-directed and immune therapies, with no new safety signals identified. Grade 3 or higher treatment-related adverse effects (TRAEs) occurred in 71.8% of the zanidatamab/tislelizumab arm, 59.0% of the zanidatamab arm, and 59.6% of the trastuzumab arm. Treatment discontinuations due to TRAEs occurred in 11.9%, 8.5%, and 2.3% of each respective arm.

"The strength of the HERIZON-GEA-01 data firmly position [zanidatamab] as the HER2-targeted agent-of-choice capable of reshaping first-line treatment for [patients with HER2-positive] metastatic GEA," Rob Iannone, MD, MSCE, executive vice president, global head of research and development, chief medical officer of Jazz Pharmaceuticals, concluded in the news release.¹ "These results signal a clear evolution beyond the current standards and give us strong conviction as we move rapidly toward FDA submission.”

References

1. Ziihera® (zanidatamab-hrii) combinations achieve unprecedented results in first-line HER2+ locally advanced or metastatic GEA including more than two years median overall survival benefit. News release. Jazz Pharmaceuticals. January 6, 2026. Accessed January 7, 2026. https://tinyurl.com/mr385fw9
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 7, 2026. https://tinyurl.com/44nue8he