How to Treat Metastatic NSCLC with Targetable Mutations – Treatment Algorithm with Dr. Eric Singhi

Metastatic non-small cell lung cancer treatment in the frontline setting requires a precision medicine approach centered on comprehensive DNA and RNA NGS testing. For common EGFR mutations, combination therapies such as amivantamab-lazertinib or osimertinib-chemotherapy offer superior progression-free and overall survival compared to single-agent osimertinib, particularly for patients with high-risk features like CNS metastases. In ALK-positive disease, lorlatinib demonstrates significant long-term efficacy, while taletrectinib serves as the standard for ROS1-positive cases. BRAF V600E mutations are best managed with encorafenib-binimetinib due to favorable toxicity profiles, and zongertinib has emerged as a frontline option for HER2-mutated disease. Across all actionable mutations, re-biopsy at the time of disease progression remains critical to identify resistant mutations or histological transformations, ensuring that subsequent treatment strategies remain targeted and effective.