Acquired 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 ()-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 -mutant NSCLC with acquired resistance to zongertinib potentially mediated through amplification and 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 tyrosine kinase inhibitor-antibody-drug conjugate combination therapy.