Jazz Pharmaceuticals' Ziihera Achieves Unprecedented Survival in Gastric Cancer: Over Two Years Median Overall Survival Marks New Treatment Paradigm

In a landmark achievement that could reshape the treatment landscape for one of medicine's most challenging cancers, Jazz Pharmaceuticals announced on January 6, 2026, that its bispecific HER2-directed antibody Ziihera (zanidatamab-hrii) has achieved unprecedented survival outcomes in patients with HER2-positive gastroesophageal adenocarcinoma (GEA). The Phase 3 HERIZON-GEA-01 trial results, presented at the ASCO Gastrointestinal Cancers Symposium on January 8, represent the longest survival outcomes ever reported in a Phase 3 trial for this devastating disease.

Breaking the Two-Year Survival Barrier

The results mark a watershed moment in GEA treatment, with Ziihera plus tislelizumab and chemotherapy achieving a median overall survival of 26.4 months—more than two years—representing a greater than seven-month improvement over the current standard of care. This represents a 28% reduction in the risk of death compared to trastuzumab plus chemotherapy, the current standard treatment.

"Reaching more than two years of median overall survival in a global Phase 3 trial for HER2+ metastatic GEA is truly unprecedented," said Dr. Elena Elimova from Princess Margaret Cancer Centre, the study's presenting author. "The HERIZON-GEA-01 results represent the longest survival outcomes in a Phase 3 trial ever reported in this setting."

The significance of these results cannot be overstated. GEA, which includes cancers of the stomach, gastroesophageal junction, and esophagus, is the fifth most common cancer worldwide, with approximately 20% of patients having HER2-positive disease. The overall prognosis has historically been grim, with global five-year survival rates of less than 30% for gastric cancer and about 19% for GEA overall.

Dual Success Across Treatment Arms

The HERIZON-GEA-01 trial evaluated two investigational arms against the current standard of care, and both demonstrated remarkable efficacy. The study found that both Ziihera plus tislelizumab and chemotherapy, and Ziihera plus chemotherapy alone, led to statistically significant and clinically meaningful prolongation of progression-free survival with approximately 35% reduction in the risk of disease progression or death.

Median progression-free survival exceeded one year in both investigational arms (12.4 months each), representing a greater than four-month improvement compared to the 8.1-month median achieved with trastuzumab plus chemotherapy. Perhaps more importantly, the 18-month progression-free survival rates were 43.9% for Ziihera plus tislelizumab and chemotherapy and 38.0% for Ziihera plus chemotherapy, compared to just 20.9% for the control arm.

The durability of response was equally impressive, with median duration of response reaching 20.7 months for the triple combination and 14.3 months for Ziihera plus chemotherapy, compared to 8.3 months for the control arm. These extended response durations suggest that patients who benefit from Ziihera treatment experience sustained disease control.

Revolutionary Mechanism of Action

Ziihera's success stems from its unique design as a bispecific HER2-directed antibody that binds to two distinct extracellular sites on the HER2 receptor. This dual binding mechanism results in receptor internalization and reduction in HER2 expression on tumor cell surfaces, while simultaneously inducing multiple immune-mediated anti-tumor effects including complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and antibody-dependent cellular phagocytosis.

This comprehensive approach to HER2 targeting represents a significant advancement over current HER2-directed therapies. The combination with tislelizumab, a PD-1 inhibitor, further enhances the immune system's ability to recognize and eliminate cancer cells, creating a synergistic effect that has translated into the unprecedented survival outcomes observed in the trial.

Practice-Changing Implications

The clinical community has responded with enthusiasm to these results, recognizing their potential to fundamentally alter treatment approaches for HER2-positive GEA. "The results of the HERIZON-GEA-01 study are practice-changing," said Dr. Geoffrey Ku from Memorial Sloan Kettering Cancer Center, a study co-author. "The remarkably long duration of response and consistent benefit across relevant subgroups strongly suggest that zanidatamab plus chemotherapy, with or without tislelizumab, should become the new standard of care."

The consistency of benefit across major prespecified subgroups, including geographic regions and PD-L1 status, supports the broad applicability of these results. This is particularly important given the global nature of GEA and the need for treatments that work across diverse patient populations.

The safety profile of Ziihera combinations was described as manageable and consistent with known effects of HER2-directed therapy and immunotherapy. While rates of Grade 3 or higher treatment-related adverse events were higher in the combination arms (71.8% for triple therapy, 59.0% for dual therapy) compared to control (59.6%), the most common serious side effect was diarrhea, which generally occurred early in treatment and resolved within three weeks.

Regulatory Pathway and Commercial Impact

Jazz Pharmaceuticals is moving rapidly toward regulatory submission based on these compelling results. The company has already secured multiple regulatory designations for Ziihera, including Breakthrough Therapy designation for previously treated HER2 gene-amplified biliary tract cancer, and Fast Track designations for both refractory biliary tract cancer and first-line GEA in combination with chemotherapy.

"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 Dr. Rob Iannone, Jazz Pharmaceuticals' chief medical officer. "These results signal a clear evolution beyond the current standards and give us strong conviction as we move rapidly toward FDA submission."

The commercial implications are substantial, as GEA represents a significant unmet medical need with limited effective treatment options. Ziihera is already approved in the United States for previously treated, unresectable or metastatic HER2-positive biliary tract cancer under accelerated approval, providing a foundation for the expanded indication in GEA.

Broader Pipeline Momentum

The success in GEA adds to growing momentum across Jazz Pharmaceuticals' broader Ziihera development program. The company continues to evaluate the therapy in multiple HER2-driven tumor types, including the ongoing Phase 3 EmpowHER-303 trial in HER2-positive metastatic breast cancer. This diversified approach positions Ziihera as a potential platform therapy across multiple HER2-expressing cancers.

The HERIZON-GEA-01 trial, conducted jointly with BeOne Medicines, randomized 914 patients from approximately 300 trial sites in more than 30 countries, providing robust global evidence for the therapy's efficacy. The trial's design, evaluating dual primary endpoints of progression-free survival and overall survival, meets the highest standards for regulatory approval.

Transforming Patient Outcomes

For patients and families affected by HER2-positive GEA, these results represent a fundamental shift in prognosis and hope. The achievement of median overall survival exceeding two years in a disease where patients historically faced much shorter survival times could transform treatment discussions and patient expectations.

The 30-month overall survival rates further underscore the durability of benefit, with 43.8% of patients in the triple combination arm and 42.2% in the dual combination arm surviving beyond 30 months, compared to 30.0% in the control arm. These long-term survival benefits suggest that a meaningful proportion of patients may achieve extended disease control.

As Jazz Pharmaceuticals prepares for regulatory submissions and potential approval, the HERIZON-GEA-01 results stand as a testament to the power of innovative drug design and rigorous clinical development. The achievement of unprecedented survival outcomes in one of oncology's most challenging diseases demonstrates that meaningful progress remains possible even in areas where therapeutic options have been limited.

With FDA submission expected in the near term and additional data from the broader Ziihera development program anticipated throughout 2026, the therapy's potential to redefine treatment standards across multiple HER2-expressing cancers continues to unfold. For the millions of patients worldwide facing HER2-positive cancers, Ziihera's success in GEA offers both immediate hope and a glimpse of a future where previously intractable diseases may become manageable chronic conditions.