Shots:
- Jazz Pharmaceuticals and partners presented seven abstracts from their oncology development program at ASCO 2025
- Robert Iannone, CMO, EVP, Global Head of Research and Development, and Chief Medical Officer at Jazz Pharmaceuticals, in an engaging discussion with PharmaShots, shared four-year follow-up data from an ongoing P-II trial of Ziihera in combination with CT for the first-line treatment of HER2-positive advanced or metastatic gastroesophageal adenocarcinoma (mGEA)
- Robert also highlighted the ongoing P-III HERIZON-GEA-01 study and other clinical trials evaluating Ziihera.
Saurabh: Given the strong median overall survival results in first-line HER2-positive mGEA, what is your timeline for seeking regulatory approval for Ziihera in this indication, both in the US and globally?
Robert: The Phase 3 randomized clinical trial, HERIZON-GEA-01 (NCT05152147), is currently underway. This trial is evaluating Ziihera in combination with standard of care chemotherapy, with and without the addition of a PD-1 agent, as a first-line treatment for human epidermal growth factor receptor 2 (HER2)-expressing metastatic gastroesophageal adenocarcinoma (mGEA). This is an events-based trial, and it is intended to serve as the registrational study for regulatory submissions. Top-line results are expected to read out in the second half of 2025.
Saurabh: How does Ziihera’s efficacy and safety profile compare to current standard-of-care regimens, such as trastuzumab-based combinations, in first-line HER2-positive gastroesophageal adenocarcinoma?
Robert: Ziihera is a bispecific HER2-directed antibody that binds to two extracellular sites on HER2, offering a novel mechanism compared to existing HER2 therapies. In combination with chemotherapy, Ziihera has demonstrated high confirmed objective response rates (cORR), promising long-term survival, and low discontinuation rates in first-line HER2-positive mGEA, where there is a high unmet need for better first-line treatment options.
As presented at ASCO 2025, the four-year follow-up data showing a median overall survival (OS) of 36.5 months and a cORR of 76.2%, in addition to the safety and tolerability profile, which remained manageable, reinforce the promising long-term survival outcomes observed with Ziihera plus chemotherapy. While additional data from the Phase 3 HERIZON-GEA-01 study will be important to characterize the benefit:risk directly compared to traztuzumab-based combinations, these results suggest strong potential for Ziihera in first-line HER2-positive mGEA.
Ziihera plus chemotherapy demonstrated low discontinuation rates, with no new safety signals observed. The most common Grade 3-4 treatment-related adverse events (TRAEs) were diarrhea (39%) and hypokalaemia (22%). The incidence of Grade 3 diarrhea was reduced from 52% to 24% after implementation of mandatory antidiarrheal prophylaxis. No treatment-related deaths occurred, and the overall safety profile remained consistent with prior reports, with five out of the 46 patients discontinuing Ziihera due to TRAEs.
Saurabh: Can you provide more details on the design and endpoints of the ongoing HERIZON-GEA-01 P3 trial, and what are your expectations for the upcoming top-line results later this year?
Robert: HERIZON-GEA-01 is a global, randomized, open-label, active-comparator, Phase 3 study designed to evaluate and compare the efficacy and safety of Ziihera plus chemotherapy, with or without tislelizumab, to the standard of care (trastuzumab plus chemotherapy) as first-line treatment for patients with advanced/metastatic HER2-positive gastroesophageal adenocarcinoma (GEA). The study is designed to include approximately 900 patients with HER2-positive gastroesophageal cancer and explores the efficacy and safety of chemotherapy combined with either trastuzumab, Ziihera, or Ziihera plus tislelizumab.
This trial is intended to serve as the registrational study for regulatory submissions. We look forward to the top line results of the pivotal Phase 3 HERIZON-GEA-01 trial later this year.
Saurabh: Beyond mGEA and biliary tract cancer, what is the broader development plan for Ziihera in other HER2-expressing solid tumors, and are there any specific indications you are prioritizing for future studies?
Robert: Beyond mGEA and biliary tract cancer (BTC), Ziihera is also being investigated in metastatic breast cancer and other tumor types. The Phase 3 EmpowHER-303 trial is currently underway (NCT06435429) comparing the efficacy and safety of zanidatamab to trastuzumab, each in combination with physician’s choice chemotherapy, for the treatment of participants with metastatic HER2-positive breast cancer who have progressed on, or are intolerant to, previous T-DXd treatment.
In partnership with the MD Anderson Cancer Center, a Phase 2 single-arm open-label pilot trial is exploring zanidatamab in patients with early-stage, low-risk, HER2-positive breast cancer to better understand its role in this less advanced setting.
Zanidatamab is also being assessed in the imaging and molecular analysis 2 (I-SPY 2) trial, a Phase 2 study being led with QuantumLeap Healthcare Collaborative. Through this innovative, an adaptive trial is designed to evaluate the efficacy of investigational therapies in combination with standard chemotherapy using advanced imaging and molecular profiling to help inform personalized treatment strategies intended to improve efficacy and tolerabilty.
The DiscovHER PAN-206 trial is a global, open-label Phase 2 trial evaluating the efficacy and safety of zanidatamab in adult participants with locally advanced or metastatic HER2-positive solid tumors (except BTC) who have progressed following at least 1 prior systemic treatment for advanced or metastatic disease.
Saurabh: The Phase 2 data show a reduction in severe diarrhea rates after implementing antidiarrheal prophylaxis. What additional steps are being taken to optimize the safety and tolerability of Ziihera in clinical practice?
Robert: Ziihera has been generally well-tolerated in studies to date and has exhibited a manageable safety profile, with minimal discontinuations due to adverse events (AEs).
Specifically with regards to any diarrhea related AEs, prophylactic loperamide has been effective in reducing rates of Grade 3 diarrhea and has been implemented in the ongoing trials.
Saurabh: How has the collaboration between Jazz, BeOne, and Zymeworks influenced the development strategy and global potential of zanidatamab for HER2-expressing solid tumors?
Robert: Jazz, along with its partners, is redefining what is possible in the treatment of cancer by improving the standards of care across the oncology spectrum with lifesaving or life-extending therapies, and a focus on innovative areas of research like targeted therapy. Together, we are excited to be leading the next-generation of HER2-targeted therapy development with a unique bispecific antibody, and we continue to explore zanidatamab’s promise beyond its approved indication in BTC as a potential new option for multiple HER2-expressing cancers.
About the Author:
Robert Iannone
M.D., M.S.C.E. / CMO, EVP, Global Head of Research and Development
Robert Iannone has been Jazz’s executive vice president and global head of research and development since May 2019. Dr. Iannone oversees all aspects of preclinical research and clinical development, clinical operations and regulatory affairs. Dr. Iannone brings more than 18 years of experience in clinical drug development, having worked across therapeutic areas and phases of development, most recently on immuno-oncology programs at Merck, AstraZeneca and Immunomedics.
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