Jazz Pharmaceuticals (NASDAQ:JAZZ) used an investor call following the ASCO Gastrointestinal Cancer Symposium to highlight results from the phase III Horizon-GEA-01 trial evaluating zanidatamab-based regimens in first-line HER2-positive gastroesophageal adenocarcinoma (GEA). Management said the study delivered the first global randomized phase III dataset for zanidatamab and, in their view, supports a potential shift in first-line HER2-positive GEA treatment.
Phase III design and patient population
Memorial Sloan Kettering’s Dr. Geoffrey Ku, a contributing author on the ASCO GI oral presentation, reviewed the trial, which randomized 914 patients (roughly 300 per arm) outside the U.S. in a 1:1:1 design:
- Arm A: trastuzumab plus chemotherapy (control)
- Arm B: zanidatamab plus chemotherapy
- Arm C: zanidatamab plus tislelizumab plus chemotherapy
Patients were enrolled globally, with about half from Asia and the remainder from Europe, North America, and other regions. Approximately 10% had esophageal tumors. Most tumors (about 80%–85%) were HER2 IHC3+. The trial reported a higher-than-typical share of PD-L1–negative patients, with about 40% below a 1% cutoff and about 60% at 1% or higher (with some missing data). Most patients (about 90%) received CAPOX as the chemotherapy backbone.
Efficacy: PFS gains in both zanidatamab arms; OS benefit for triplet
Dr. Ku said Horizon-GEA-01 showed a 35% reduction in the risk of progression or death for both zanidatamab-containing regimens versus trastuzumab plus chemotherapy, translating into a median PFS improvement of more than four months.
For zanidatamab plus chemotherapy (Arm B), median PFS was 12.4 months versus 8.1 months for control (hazard ratio 0.65, highly statistically significant). For zanidatamab plus tislelizumab plus chemotherapy (Arm C), median PFS was also 12.4 months versus 8.1 months (hazard ratio 0.63, highly statistically significant). Two-year PFS rates were reported as 31.5% (Arm B) and 38.2% (Arm C).
On OS, Dr. Ku described a “strong trend” but not statistical significance for Arm B at the first interim analysis. Median OS was 24.4 months for Arm B versus 19.2 months for control (hazard ratio 0.80, p=0.0564). By contrast, Arm C achieved a statistically significant OS benefit: median OS 26.4 months versus 19.2 months for control (hazard ratio 0.72, highly statistically significant), which he characterized as a 28% reduction in risk of death and more than seven months of median OS improvement.
Both presenters emphasized that benefit was observed across key subgroups, including patients below and above the PD-L1 cutoff. Dr. Ku noted an apparent exception in the smaller HER2 IHC2+ FISH-positive subgroup on some analyses, but he and the company cautioned that the smaller numbers may confound interpretation.
Responses and durability
Objective response rates were similar across arms: 66% in the control group versus 70% in both zanidatamab-containing arms, according to Dr. Ku. However, the complete response rate was higher in Arm C at 19.6% versus 11% in the control arm.
Duration of response was highlighted as a differentiator. Dr. Ku reported a median DOR of 20.7 months in Arm C versus 8.3 months in the control arm and 14.3 months in the zanidatamab-plus-chemotherapy arm, calling the durability “truly unprecedented” in this disease.
Safety: higher grade ≥3 events in triplet; diarrhea and infusion reactions in focus
Safety was described as consistent with known profiles of the component therapies, though with higher rates of certain events in the zanidatamab arms. Grade 3 or higher toxicities were reported as 59.6% in control, 59% in Arm B, and 71.8% in Arm C.
Discontinuations attributed to the HER2 antibody were higher with zanidatamab: 8.5% in Arm B and 11.9% in Arm C versus 2.3% in the trastuzumab control arm. Infusion-related reactions occurred in about 25% of patients receiving zanidatamab (both Arms B and C) versus 13.2% with trastuzumab. Non-infectious pulmonary toxicities were increased in Arm C, which Dr. Ku said was consistent with known tislelizumab risks, while left ventricular dysfunction appeared comparably low across arms.
Diarrhea was identified as a notable toxicity. The protocol included mandatory prophylaxis (loperamide twice daily for the first seven days) for patients in the zanidatamab arms. Grade 3 diarrhea occurred in 20% (Arm B) and 24.5% (Arm C) versus 12.9% in control. Dr. Ku said time to onset was about one week for diarrhea overall and about two weeks for grade 3 diarrhea, with resolution around three weeks regardless of severity.
Regulatory plans and commercial positioning
Chief Medical Officer Dr. Rob Iannone said Jazz plans to engage the FDA and submit a supplemental biologics license application in the first half of this year, and to seek NCCN listing based on the data. He said an additional planned interim OS analysis for the Arm B versus Arm A comparison is currently expected in mid-2026.
On questions about the lack of U.S. enrollment, Iannone argued the regulatory standard is representativeness rather than U.S.-only recruitment, and pointed to similar performance of the trastuzumab-plus-chemotherapy control arm versus the control in KEYNOTE-811 as a comparability reference. He also said Jazz intends to seek broad labeling, including a PD-L1–agnostic position for the triplet, and said the company believes the data could support priority review, while acknowledging that decision rests with FDA.
Chief Commercial Officer Sam Pearce framed the opportunity around unmet need and testing infrastructure, citing that GEA is the fifth most common cancer globally and that about 20% of patients have HER2-positive disease. He estimated roughly 63,000 cases annually across the U.S., Europe, and Japan, including about 8,000 in the U.S. He also said HER2 testing adoption exceeds 80%. Pearce said Jazz believes the Horizon results support positioning zanidatamab (marketed as Zyhera) as a first-line option that could replace trastuzumab, and highlighted that Zyhera already has a permanent J code following its FDA approval in second-line HER2-positive biliary tract cancer, which he said should simplify reimbursement.
During Q&A, Dr. Ku said he expects the regimen to be adopted quickly once listed by NCCN and approved, and noted a colleague had already been able to obtain private insurance coverage for a first-line patient following the press release and data presentation.
About Jazz Pharmaceuticals (NASDAQ:JAZZ)
Jazz Pharmaceuticals plc is a global biopharmaceutical company focused on developing and commercializing therapies in neuroscience and oncology. The company’s research and development efforts target unmet medical needs in sleep disorders, hematologic malignancies, rare neurological conditions and solid tumors. Jazz’s product portfolio includes therapies for narcolepsy, hepatic veno-occlusive disease, acute myeloid leukemia and other serious disorders.
Flagship products from Jazz Pharmaceuticals include Xyrem® (sodium oxybate) and Xywav® (calcium, magnesium, potassium, and sodium oxybates) for the treatment of cataplexy and excessive daytime sleepiness in patients with narcolepsy.
