Panel Introduction, Treatment Landscape, and Background on Zanidatamab

In this OncLive® Peer Exchange, Dr. Wainberg moderates a panel with Dr. Elimova, Dr. Shah, and Dr. Shameem and frames the discussion on evolving first-line strategies in HER2-positive metastatic gastroesophageal adenocarcinoma (GEA). Dr. Wainberg opens the Peer Exchange with Dr. Elimova, Dr. Shah, and Dr. Shameem by tracing the first-line arc: trastuzumab plus chemotherapy has been the backbone for roughly a decade, and KEYNOTE-811 added pembrolizumab on top. Two gaps set up the rest of the conversation. First, patients with low programmed death-ligand 1 (PD-L1) combined positive score derive less benefit from pembrolizumab. Second, a new generation of agents, antibody-drug conjugates (ADCs) and bispecific antibodies, is entering the first-line space. The anchor dataset for this discussion is the HERIZON-GEA-01 global phase 3 trial.

Dr. Elimova introduces zanidatamab, the focus of HERIZON-GEA-01. Unlike trastuzumab, zanidatamab is a bispecific antibody that binds two separate parts of the HER2 receptor, extracellular domain 2 (ECD2) and ECD4, at the same time. This cross-links receptors on the cell surface and produces antitumor activity through two routes: direct signaling blockade and immune-mediated killing through the engineered crystallizable fragment (Fc) domain. The Fc mechanisms include antibody-dependent cellular cytotoxicity (ADCC), phagocytosis, and, distinctively, complement-dependent cytotoxicity, supported by preclinical work in Nature Communications. In the phase 1 ZW25-101 study, single-agent zanidatamab produced roughly 30% responses in heavily pretreated patients, and combinations with paclitaxel or capecitabine reached about 50%.