Biparatopic HER2 Binding and the JACOB Trial: Rationale for Single-Molecule Dual-Epitope Targeting

In this episode, Dr. Wainberg and Dr. Shah revisit the JACOB trial and discuss whether zanidatamab's biparatopic mechanism differs from combining trastuzumab and pertuzumab. Dr. Wainberg poses the central question: Zanidatamab binds to extracellular domains that pertuzumab and trastuzumab bind separately, yet JACOB, which added pertuzumab to trastuzumab and chemotherapy in gastric cancer, did not meet its primary endpoint. Does that change the interpretation of biparatopic HER2 targeting?

Dr. Shah starts with HER2 biology. The receptor has no ligand; it works by pairing with itself or with other surface receptors. Trastuzumab binds one site, pertuzumab binds another, and zanidatamab binds both. He argues JACOB is more nuanced than "negative." The p-value was about 0.055, and median overall survival (OS) was roughly 17 versus 14 months. He attributes the narrow miss partly to era effects in central HER2 confirmation and to the variability inherent in any single phase 3 readout. Dual HER2 blockade, he notes, is a proven principle in breast cancer.

His bottom line: zanidatamab is likely doing something mechanistically distinct from giving trastuzumab plus pertuzumab together. Zanidatamab's roughly 30% single-agent response rate in heavily pretreated patients points toward a synergistic rather than additive effect, possibly through receptor clustering and complement activation. Dr. Shah flags the main operational challenge ahead: managing toxicity, particularly diarrhea.

In the next episode, “Approaching First-Line Treatment in PD-L1 CPS <1 HER2-Positive GEA,” Dr. Shameem discusses his current approach to patients with PD-L1 CPS <1, where KEYNOTE-811 showed no pembrolizumab benefit.