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

## TL;DR

This case report describes a patient with ERBB2-mutant lung cancer who developed resistance to zongertinib but responded to trastuzumab-deruxtecan.

## Contribution

The study identifies ERBB2 amplification and overexpression as a resistance mechanism to zongertinib and suggests a potential treatment strategy.

## Key findings

- Acquired ERBB2 amplification and HER2 overexpression were observed in a patient resistant to zongertinib.
- The patient showed a durable response to trastuzumab-deruxtecan after resistance to zongertinib.
- The findings suggest a possible mechanism for resistance and a rationale for combination therapy.

## Abstract

A number of drugs are in development for the treatment of ERBB2(HER2)-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 ERBB2-mutant NSCLC with acquired resistance to zongertinib potentially mediated through ERBB2 amplification and HER2 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 ERBB2 tyrosine kinase inhibitor–antibody-drug conjugate combination therapy.