The phase III HERIZON-GEA-01 trial showed that zanidatamab (Ziihera) plus chemotherapy improves progression-free and overall survival versus trastuzumab plus chemotherapy in first-line metastatic HER2-positive GEA, and adding tislelizumab further enhances outcomes.

Based on these results, the FDA has approved zanidatamab plus tislelizumab and chemotherapy as a first-line standard for unresectable or metastatic GEA.

After trastuzumab-based therapy, a substantial number of patients lose HER2 expression, which reduces the efficacy of T-DXd; therefore, retesting HER2 status after progression is advised.

ASCO-GI analyses and other presentations continue to highlight HER2 heterogeneity and show differing outcomes depending on whether tumors are driven by HER2 amplification or pathogenic mutations when using HER2-targeted therapies.

HER2 testing remains essential for metastatic GEA treatment decisions, with IHC 3+ or confirmatory FISH testing guiding therapy choices.

A broad HER2-positive GEA pipeline includes HLX22, rilvegostomig, volrustomig, zongertinib, and disitamab vedotin, reflecting ongoing diversification of therapeutic options.

DESTINY-Gastric01 positions T-DXd as a key option in later lines, with DESTINY-Gastric04 showing benefits in second-line settings but a higher pneumonitis risk compared with ramucirumab plus paclitaxel.

Real-world data show a notable conversion rate from HER2-positive to HER2-negative upon progression, underscoring tumor heterogeneity and the need for adaptable strategies.

KEYNOTE-811 established pembrolizumab plus trastuzumab and chemotherapy as a first-line standard, with benefits driven by PD-L1–expressing tumors and potential harm in PD-L1–negative cases.

Over the past five years, HER2-positive GEA has seen rapid advances that have reshaped first-line standards and treatment approaches.