Acquired ERBB2 Amplification and Overexpression as On-Target Resistance Mechanisms to Zongertinib With Subsequent Response to Trastuzumab-Deruxtecan: A Case Report

A number of drugs are in development for the treatment of <i>ERBB2</i>(<i>HER2</i>)-mutated NSCLC, including antibody-drug conjugates such as trastuzumab-deruxtecan and tyrosine kinase inhibitors such as zongertinib and sevabertinib. Herein, we report a case of relapsed advanced <i>ERBB2</i>-mutant NSCLC with acquired resistance to zongertinib potentially mediated through <i>ERBB2</i> amplification and <i>HER2</i> 3+ immunohistochemistry overexpression with subsequent durable response to fifth-line trastuzumab-deruxtecan. We propose this as a mechanism for zongertinib resistance, one that may underpin a biological rationale for future <i>ERBB2</i> tyrosine kinase inhibitor-antibody-drug conjugate combination therapy.