Clinical Pearls for the Testing and Treatment of HER2-Mutation mNSCLC in the Community Setting

Final Clinical Pearls for Testing and Treatment of HER2-Mutation Metastatic NSCLC in Community Settings

The fundamental principle for community oncologists managing HER2-mutated non–small cell lung cancer (NSCLC) centers on comprehensive molecular testing, as patients cannot benefit from novel therapeutics without proper biomarker identification. The therapeutic landscape has evolved dramatically beyond historical second-line options like docetaxel, which offered modest response rates around 20% and progression-free survival measured in months. Current HER2-targeted therapies deliver transformative outcomes, with zongertinib achieving 75% response rates and progression-free survival (PFS) exceeding 12 months, meaning half of patients remain on therapy for over a year with substantial quality-of-life improvements.

Treatment selection requires understanding the distinct characteristics of available HER2-targeted options. Zongertinib represents true targeted therapy with HER2-specific activity that spares EGFR, delivering best-in-class safety and efficacy profiles comparable to the osimertinib experience in EGFR-mutated disease. In contrast, trastuzumab deruxtecan, while demonstrating good response rates around 55% and PFS in the 9- to 10-month range, functions more as chemotherapy than targeted therapy with corresponding toxicity considerations. These distinct profiles support sequential use with zongertinib preferred first line followed by trastuzumab deruxtecan, particularly given their different tolerability profiles.

The comprehensive approach to HER2 biomarker assessment extends beyond mutations to include immunohistochemistry (IHC) testing for HER2 overexpression, which should not be neglected in clinical practice. For patients without oncogenic driver mutations who progress on initial chemotherapy, trastuzumab deruxtecan provides an additional second-line option beyond traditional chemotherapy agents, with preferential use in HER2 3+ IHC expressors despite lower and less durable response rates. The multilayered molecular profiling platform incorporating DNA, RNA, and protein analysis represents a paradigm shift offering new hope for patients with HER2-mutated disease. This comprehensive, biomarker-driven approach exemplifies the evolution toward personalized medicine in lung cancer, requiring community oncologists to embrace broad molecular testing to optimize patient outcomes in this rapidly advancing therapeutic landscape.