# Targeted Therapy in HER2 Exon 20-Mutant Non-small Cell Lung Cancer With Leptomeningeal Disease: A Case-Based Approach to Treatment Decision-Making

## TL;DR

This paper presents a rare case of brain cancer caused by a specific lung cancer mutation and discusses treatment options using targeted therapy.

## Contribution

The paper highlights the use of trastuzumab deruxtecan in treating HER2-mutant NSCLC with leptomeningeal disease, where no standard guidelines exist.

## Key findings

- Trastuzumab deruxtecan was used based on evidence from other cancers with CNS involvement.
- The case emphasizes the need for clinical trials addressing CNS complications in HER2-mutant NSCLC.
- Precision oncology was applied in the absence of approved therapies for this rare condition.

## Abstract

A rare and clinically challenging case of leptomeningeal disease (LMD) secondary to HER2-mutated non-small cell lung cancer (NSCLC), marked by both exon 20 insertion and gene amplification, is presented. In the absence of LMD-specific therapeutic guidelines for HER2-driven NSCLC, treatment was initiated with trastuzumab deruxtecan (Enhertu), based on extrapolated evidence from clinical trials in systemic NSCLC and HER2-positive breast cancer with central nervous system involvement. The patient, a 69-year-old woman with good performance status, developed LMD following prior systemic therapy and local CNS treatments. MRI and CSF cytology confirmed the diagnosis. Given the lack of approved therapies for HER2-mutant NSCLC with LMD, the treatment strategy was informed by available clinical data and supporting literature on the CNS activity of Enhertu. Other options such as poziotinib and zongertinib were considered but not pursued. This case underscores the urgent need for inclusive clinical trials addressing CNS complications in molecularly defined NSCLC and demonstrates the real-world application of precision oncology beyond trial populations.