This OncLive educational discussion focuses on treatment approaches for HER2-mutant mNSCLC. The conversation outlines the clinical relevance of HER2 alterations and evaluates the complexity of HER2 molecular testing in oncology practice. The session aims to examine the treatment evolution for HER2 mutations, covering the progression from initial off-label use of breast cancer therapies to current FDA-approved targeted therapies.

The discussion highlights the treatment journey from early therapies like ado-trastuzumab emtansine, which showed modest efficacy, to fam-trastuzumab deruxtecan, and ultimately to zongertinib, the first FDA-approved targeted therapy that has provided meaningful improvement in patient outcomes. The session also addresses treatment sequencing strategies and explores the potential role of combination therapy approaches in this therapeutic space.

HER2 alterations represent a critical biomarker in lung cancer management, as lung cancer encompasses multiple distinct diseases requiring biomarker-guided treatment strategies. HER2 alterations include mutations (most commonly exon 20 insertion mutations occurring in 2% to 4% of NSCLC patients), overexpression at the 3+ level (relatively uncommon at 1% and tested by immunohistochemistry), and amplification. The focus centers primarily on HER2 mutations, which represent an emerging area of targeted therapy development where patients are experiencing improved outcomes and longer survival with targeted therapeutic approaches. This biomarker-driven strategy exemplifies the personalized medicine approach that has revolutionized lung cancer treatment.