HER2-targeted therapy in metastatic oesophagogastric cancer

In this video, Prof Dr Eric Van Cutsem speaks with Dr Kohei Shitara about the evolving role of HER2-targeted therapy in metastatic oesophagogastric cancer. The discussion focuses on new strategies beyond trastuzumab and trastuzumab deruxtecan (T-DXd), with particular attention to zanidatamab, and to how emerging biomarker complexity may influence future treatment selection.

A central topic is the phase III HERIZON-GEA-01 trial, which evaluated first-line zanidatamab plus chemotherapy, with or without tislelizumab, versus trastuzumab plus chemotherapy in HER2-positive metastatic gastro-oesophageal adenocarcinoma. Zanidatamab-containing regimens improved progression-free survival, and the triplet combination with tislelizumab also improved overall survival. Dr Shitara notes that a regulatory decision is pending and could support zanidatamab as a new first-line option. Diarrhoea was more frequent with zanidatamab-based treatment, but was described as generally manageable with prophylactic loperamide and, where needed, interruption of capecitabine. The interview also addresses resistance to HER2-targeted therapy. Dr Shitara presents examples of disease progression after zanidatamab in which reduced HER2 expression and MET amplification were observed as potential escape mechanisms. These cases illustrate that, although zanidatamab may represent an important step forward, resistance remains a major clinical challenge. 

Other investigational approaches are being explored in the first-line setting, including T-DXd combinations with chemotherapy and immune checkpoint inhibition, and HLX22, a monoclonal antibody targeting a HER2 epitope distinct from trastuzumab.

A substantial part of the discussion focuses on the relationship between HER2, PD-L1 and CLDN18.2. Dr Shitara notes that zanidatamab plus anti-PD-1 therapy appeared to show benefit even in PD-L1-negative patients, which he links to the stronger complement-dependent cytotoxicity of zanidatamab compared with trastuzumab and pertuzumab and its potential effect on the tumour microenvironment. He also discusses overlap between HER2 and CLDN18.2 expression, with co-expression seen in a subset of tumours. At a high CLDN18.2 positivity threshold (≥75% of cells), roughly one in five HER2-positive tumours also express CLDN18.2, with greater overlap expected at lower thresholds. Dr Shitara notes that, in prior analyses, patients with co-expression of both markers had poorer outcomes following T-DXd, providing a rationale for combining a CLDN18.2-targeted agent in HER2-positive disease. This overlap may become relevant for future combination strategies, particularly as CLDN18.2-directed antibody-drug conjugates are developed. Unlike zolbetuximab, these agents may have a bystander effect and could potentially be active at lower CLDN18.2 expression thresholds, raising the question of whether current biomarker cut-offs will need to evolve.

Overall, the interview illustrates a rapidly changing treatment landscape in HER2-positive and biomarker-defined metastatic oesophagogastric cancer. As new HER2- and CLDN18.2-directed agents enter clinical development, optimising treatment sequencing and refining biomarker selection will become increasingly important.