Targeted Therapy Decision in HER2 Exon 20–Mutant Non-Small Cell Lung Cancer with Leptomeningeal Disease: A Case-Based Perspective
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We report 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. In the absence of LMD-specific therapeutic guidelines for HER2-driven NSCLC, we initiated treatment with trastuzumab deruxtecan (Enhertu), based on extrapolated evidence from clinical trials in systemic NSCLC and HER2-positive breast cancer with central nervous system involvement. Our patient, a 69-year-old woman with stable 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, our treatment strategy was informed by data from DESTINY-Lung02, the DEBRA and ROSET-BM studies, and supporting literature on 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.
