The frontline combination of zanidatamab-hrii (Ziihera) and chemotherapy with or without tislelizumab (Tevimbra) demonstrated meaningful efficacy in patients with HER2-positive locally advanced or metastatic gastroesophageal adenocarcinoma (GEA), according to top-line data from the phase 3 HERIZON-GEA-01 trial (NCT05152147).1
HERIZON-GEA-01 Trial Takeaways With Zanidatamab-Containing Regimens in GEA
- Zanidatamab plus chemotherapy with or without tislelizumab significantly improved PFS and delivered OS benefits vs trastuzumab-based therapy in first-line HER2-positive GEA.
- Benefits were consistent across PD-L1 subgroups, with both investigational regimens showing higher ORRs and longer DORs than the control regimen.
- Safety was manageable with no new signals, supporting zanidatamab-based combinations as potential new SOCs in HER2-positive metastatic GEA.
Specifically, zanidatamab plus chemotherapy with and without tislelizumab led to a statistically significant improvement in progression-free survival (PFS) vs trastuzumab (Herceptin) plus chemotherapy. Moreover, zanidatamab paired with tislelizumab and chemotherapy also led to a statistically significant improvement in overall survival (OS); a strong trend toward a statistically significant improvement in OS was also observed with zanidatamab plus chemotherapy alone.
Notably, PFS and OS benefits were observed with zanidatamab plus tislelizumab and chemotherapy vs trastuzumab and chemotherapy in subgroups of patients with PD-L1 positivity and negativity. Both regimens were also found to elicit improved objective response rates (ORRs) and durations of response (DORs) compared with the control regimen; ORR and DOR represented key secondary end points of the study.
“Advanced GEA represents one of the most common tumor types worldwide and remains an aggressive cancer with a poor prognosis,” Kohei Shitara, MD, director of the Department of Gastrointestinal Oncology and principal trial investigator at the National Cancer Center Hospital East, in Kashiwa, Japan, stated in a news release. “Based on the positive results seen in the HERIZON-GEA-01 trial, the zanidatamab plus chemotherapy combination, with and without tislelizumab, has the potential to become the new standard of care for patients in HER2-positive first-line locally advanced unresectable or metastatic GEA. This is the first phase 3 trial to demonstrate a benefit for a novel HER2-targeted therapy compared to trastuzumab as part of a combination regimen in HER2-positive first-line GEA.”
What was the design of the HERIZON-GEA-01 trial?
The global, open-label, randomized trial enrolled patients with histologically confirmed unresectable locally advanced, recurrent or metastatic HER2-positive GEA defined as having 3+ HER2 expression per immunohistochemistry (IHC) or 2+ HER2 expression per IHC with in situ hybridization positivity according to central assessment.2 Patients were required to have assessable disease defined by RECIST 1.1 criteria, an ECOG performance status no higher than 1, acceptable organ function, and left ventricular ejection fraction of at least 50%.
Those with prior exposure to a HER2-targeted agent; PD-1, PD-L1, or PD-L2 inhibition; or systemic antineoplastic therapy or intraperitoneal chemotherapy were excluded. Other key exclusion criteria comprised having untreated central nervous system (CNS) or symptomatic metastases or receipt of radiation for CNS metastases within 4 weeks ahead of randomization; a history of or current leptomeningeal disease; a known additional malignancy that was not cured or needed treatment within the past 3 years; active hepatitis infection or SARS-CoV-2 infection; or clinically substantive cardiac disease.
A total of 914 patients were randomly assigned to 1 of 3 arms: trastuzumab plus physician’s choice of capecitabine plus oxaliplatin (CAPOX) or 5-fluorouracil plus cisplatin (FP; arm A; control arm), zanidatamab plus physician’s choice of CAPOX or FP (arm B), or zanidatamab plus tislelizumab plus physician’s choice of CAPOX or FP (arm C).1
The primary end points of the study are PFS by blinded independent central review (BICR) and OS, and secondary end points include confirmed ORR and DOR by BICR; investigator-assessed PFS, confirmed ORR, and DOR; evaluation of contribution of components based on PFS by BICR and OS; safety in the form of incidence of toxicities and clinical laboratory abnormalities; health-related quality of life; and pharmacokinetic analyses.2
