Metastatic NSCLC — RET Fusion-Positive

Sequencing for RET fusion-positive metastatic non-small cell lung cancer: a selective RET tyrosine kinase inhibitor (selpercatinib preferred, or pralsetinib) first line, then platinum-pemetrexed chemotherapy with or without immunotherapy on progression.

1L: Selective RET inhibitor (selpercatinib preferred, or pralsetinib)

Preferred first-line targeted therapy with high response rates and CNS activity; RET TKIs remain highly active if the fusion is identified after prior chemotherapy or immunotherapy. Selpercatinib: monitor hypertension, transaminitis, QTc, and hypersensitivity. Pralsetinib: monitor cytopenias and pneumonitis.

• Progression → Platinum-pemetrexed chemotherapy ± pembrolizumab

2L: Platinum-pemetrexed chemotherapy ± pembrolizumab

After RET-directed therapy. Consider platinum-pemetrexed with or without immunotherapy based on PD-L1 status; single-agent immunotherapy activity is limited in RET-driven disease.