Case 1, presented by Dr. Le, reviewed a 45-year-old with EGFR-mutant lung adenocarcinoma, rapid metastatic relapse, initial osimertinib response, later progression, and challenges managing liver metastases and toxicity. The panel discussed Case 2, presented by Dr. Riess, a 75-year-old with metastatic EGFR G719S NSCLC and brain mets, favoring afatinib for best PFS, chemo-osimertinib for CNS disease, and trials for rare EGFR variants. Case 3, presented by Dr. Piotrowska, reviewed a 35-year-old woman with ALK-positive lung adenocarcinoma. Panel favored first-line lorlatinib for strong efficacy and CNS control; patient responding well. Dr. Rotow presented Case 4, a 72-year-old with ALK-positive lung cancer developing resistance to alectinib and later lorlatinib. Post-lorlatinib progression highlighted need for rebiopsy, MET targeting, and trials. Dr. Elamin’s Case 5, highlighted a 55-year-old never-smoker with mucinous adenocarcinoma and high PD-L1. RNA-based NGS uncovered an NRG1 fusion after progression, stressing need for RNA testing and novel drivers.