Zanidatamab outdoes trastuzumab as first-line treatment of HER2-positive mGEA

Treatment with zanidatamab combined with tislelizumab and/or chemotherapy (CT) significantly improves progression-free survival (PFS) in patients with HER2-positive locally advanced, unresectable, or metastatic gastroesophageal adenocarcinoma (mGEA), as shown in the primary analysis from HERIZON-GEA-01.

“The clinically meaningful survival benefit further supports zanidatamab plus tislelizumab and CT as an important new treatment option for this patient population,” said lead study author Dr Elena Elimova, Princess Margaret Cancer Centre, Toronto, Canada.

Apart from PFS, zanidatamab plus tislelizumab and CT also “demonstrated a clinically meaningful and statistically superior prolongation of overall survival (OS) vs trastuzumab plus CT,” with more than 7-month prolongation of median OS, she added.

In HERIZON-GEA-01, Elimova and her team randomized a total of 914 patients with previously untreated HER2-positive mGEA to receive zanidatamab (n=302; 1,800/2,400 mg intravenously [IV] once every 3 weeks [Q3W]) plus tislelizumab (200 mg IV Q3W) and capecitabine/oxaliplatin (CAPOX) or 5-FU/cisplatin (FP), zanidatamab plus CAPOX or FP (n=304), or trastuzumab plus CAPOX or FP (n=308).

Demographics and baseline disease characteristics were balanced. PFS by blinded independent central review (BICR) and OS were the primary endpoints, with a median follow-up of 26 months at data cutoff. The secondary endpoint was antitumour activity.

Survival benefits

Both zanidatamab plus tislelizumab and CT (median PFS, 12.4 months, 95 percent confidence interval [CI], 9.8‒18.5) and zanidatamab plus CT (median PFS, 12.4 months, 95 percent CI, 9.8‒14.5) significantly extended PFS compared with trastuzumab plus CT (median PFS, 8.1 months, 95 percent CI, 7.0‒8.9). [ASCO GI 2026; abstract LBA285]

“Treatment with zanidatamab-containing regimens led to a clinically meaningful prolongation of PFS that was statistically superior to trastuzumab plus CT (>4-month prolongation of median PFS),” Elimova said.

OS also significantly improved with zanidatamab plus tislelizumab and CT (median OS, 26.4 months, 95 percent CI, 21.5‒30.3) compared with trastuzumab plus CT (median OS, 19.2 months, 95 percent CI, 16.8‒21.8). At the interim analysis, OS for zanidatamab plus CT did not reach significance (hazard ratio, 0.80, 95 percent CI, 0.64‒1.01; p=0.0564), but a strong trend favouring this combination was noted.

Similarly, PFS and OS improved across major subgroups, including by region and PD-L1 TAP score.

For the secondary endpoint, confirmed objective response rates (ORRs) were also higher with zanidatamab-containing regimens (plus tislelizumab and CT: ORR, 70.7 percent, 95 percent CI, 65.0‒76.0; plus CT only: ORR, 69.6 percent, 95 percent CI, 63.9‒75.0) than with trastuzumab plus CT (ORR, 65.7 percent, 95 percent CI, 59.9‒71.2).

Likewise, the median duration of response (DoR) was greater with zanidatamab plus tislelizumab and CT (20.7 months, 95 percent CI, 12.6‒37.7) and zanidatamab plus CT (14.3 months, 95 percent CI, 11.5‒21.9) than with trastuzumab plus CT (8.3 months, 95 percent CI, 6.7‒9.8).

The confirmed ORR was defined as the “proportion of patients achieving a best overall response of complete or partial response, as determined by BICR using RECIST v1.1.” DOR, on the other hand, was assessed among “patients with measurable disease at baseline who achieved a confirmed response by BICR per RECIST v1.1,” according to Elimova and colleagues.

Safety profile

Grade ≥3 treatment-related adverse events (TRAEs) occurred in significantly more patients in the zanidatamab plus tislelizumab and CT arm than in the zanidatamab plus CT and trastuzumab plus CT arms (71.8 percent vs 59.0 percent and 59.6 percent, respectively).

The most common grade ≥3 TRAEs in the zanidatamab containing arms were diarrhoea, hypokalemia, and anaemia, while those in the trastuzumab plus CT arm were diarrhoea, anaemia, neutrophil count decreased, and platelet count decreased.

“For patients who experienced diarrhoea, events generally occurred early in treatment and resolved within 3 weeks,” Elimova said.

Furthermore, treatment due to AEs were discontinued in 11.9 percent of patients in the zanidatamab plus tislelizumab and CT arm, 8.5 percent in the zanidatamab plus CT arm, and 2.3 percent in the trastuzumab plus CT arm.

“The safety profile was consistent with known profiles of each individual treatment,” Elimova said.

The results from the HERIZON-GEA-01 trial support zanidatamab as a “promising new standard in HER2-targeting agents, with potential to replace trastuzumab in first-line treatments for HER2-positive mGEA,” according to Elimova.

“HERIZON-GEA-01 is the first phase III study in mGEA to demonstrate a median PFS >1 year and a median OS >2 years,” she added. The trial is still ongoing, and the researchers are planning further OS analyses for zanidatamab plus CT.

Previous studies report modest benefits with standard of care for first-line HER2-positive mGEA, with median PFS and OS of <1 year and <2 years, respectively. [J Clin Oncol 2017;35:446-464; Ann Oncol 2022;33:1005-1020; Lancet 2010;376:687-697; N Eng J Med 2024;391:1360-1362; Lancet 2023;402:2197-2208; Nat Commun 2025;16:4293]

Zanidatamab is “a dual HER2-targeted bispecific IgG1-like antibody that binds to extracellular domain 2 and 4 on HER2 in a transfiguration,” which enables the agent to “crosslink neighbouring HER2 proteins, leading to receptor clustering.” [Nat Commun 2023;14:1394]