Jazz Pharmaceuticals Reports Positive Phase 3 Results For Ziihera In First-Line HER2-Positive Gastroesophageal Cancer

Jazz Pharmaceuticals plc, announced positive efficacy and safety results from the Phase 3 HERIZON-GEA-01 trial evaluating Ziihera® (zanidatamab-hrii) in combination with chemotherapy, with or without the PD-1 inhibitor Tevimbra® (tislelizumab), as first-line treatment for adults with HER2-positive locally advanced or metastatic gastroesophageal adenocarcinoma (GEA), including cancers of the stomach, gastroesophageal junction, and esophagus.

At the first interim analysis, both investigational regimens, Ziihera plus tislelizumab and chemotherapy, and Ziihera plus chemotherapy, demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with trastuzumab plus chemotherapy. Each regimen reduced the risk of disease progression or death by approximately 35%, resulting in a median PFS exceeding one year, representing an improvement of more than four months versus the control arm.

"The results of the HERIZON-GEA-01 study are practice-changing," said Geoffrey Ku, M.D., associate attending physician on the Gastrointestinal Oncology Service in the Department of Medicine at Memorial Sloan Kettering Cancer Center and study co-author. "In addition to the progression-free survival and overall survival benefits, the remarkably long duration of response and consistent benefit across relevant subgroups, including PD-L1 positive and negative tumors, strongly suggest that zanidatamab plus chemotherapy, with or without tislelizumab, should become the new standard of care for patients with HER2+ first-line locally advanced unresectable or metastatic GEA."

The combination of Ziihera plus tislelizumab and chemotherapy also achieved a statistically significant overall survival (OS) benefit, with a median OS of 26.4 months, the longest reported in a Phase 3 trial for GEA to date. This corresponds to a greater than seven-month improvement in median OS and a 28% reduction in the risk of death compared with trastuzumab plus chemotherapy.

For Ziihera plus chemotherapy, median OS also exceeded two years, with a strong trend toward statistical significance favoring the Ziihera regimen. An additional planned interim OS analysis for this arm is expected in mid-2026. The observed PFS and OS benefits were generally consistent across major prespecified subgroups, including geographic region and PD-L1 expression status.

"Reaching more than two years of median overall survival in a global Phase 3 trial for HER2+ metastatic GEA is truly unprecedented," said Elena Elimova, M.D., Princess Margaret Cancer Centre, the presenting author of the late-breaking data. "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 overall survival by more than seven months versus the control arm. The fact that both zanidatamab plus chemotherapy and zanidatamab plus tislelizumab and chemotherapy achieved median progression-free survival beyond one year further reinforces the depth and durability of benefit. These findings signal a meaningful step forward for patients who have historically faced very limited long-term outcomes."

The safety profile of Ziihera, when combined with chemotherapy, with or without tislelizumab, was consistent with the known effects of HER2-directed therapies and immunotherapy, with no new safety signals identified. The treatment duration was the longest in the Ziihera plus tislelizumab and chemotherapy arm. Rates of Grade ≥3 treatment-related adverse events were 71.8% for Ziihera plus tislelizumab and chemotherapy, 59.0% for Ziihera plus chemotherapy, and 59.6% for trastuzumab plus chemotherapy.

The most common Grade ≥3 adverse event was diarrhea, which occurred early in treatment and typically resolved within three weeks. Discontinuation due to treatment-related diarrhea was uncommon across all arms, supporting the manageability and feasibility of Ziihera-based regimens in the first-line metastatic setting.

"The strength of the HERIZON-GEA-01 data firmly positions Ziihera as the HER2-targeted agent-of-choice capable of reshaping first-line treatment for HER2+ metastatic GEA patients," said Rob Iannone, M.D., M.S.C.E., executive vice president, global head of research and development, and chief medical officer of Jazz Pharmaceuticals. "These results signal a clear evolution beyond the current standards and give us strong conviction as we move rapidly toward FDA submission. We are equally energized by the momentum we see across our broader development program, and we continue to evaluate Ziihera in multiple HER2-driven tumor types, including in HER2+ metastatic breast cancer with the ongoing Phase 3 EmpowHER-303 trial. This is the kind of scientific advancement that can redefine outcomes for patients, and we are committed to delivering it with urgency."