Metastatic NSCLC — ROS1-Rearranged

Sequencing for ROS1-rearranged metastatic non-small cell lung cancer: a CNS-active ROS1 tyrosine kinase inhibitor (entrectinib or repotrectinib) when brain metastases are present or crizotinib otherwise, repotrectinib for crizotinib-refractory disease, then platinum-pemetrexed chemotherapy. Immunotherapy is not recommended in this oncogene-driven subtype.

CNS metastases present at diagnosis?

• CNS metastases present → Entrectinib (CNS-active ROS1 TKI)
• No CNS metastases → Crizotinib

1L: Entrectinib (CNS-active ROS1 TKI)

Preferred when brain metastases are present, given strong CNS penetration. Monitor weight gain, dysgeusia, and neurologic effects. Repotrectinib is an alternative CNS-active first-line option.

• Progression → Repotrectinib

1L: Crizotinib

Effective first-line option for extracranial-predominant disease; limited CNS penetration. Monitor for visual disturbance, edema, transaminitis, and QTc prolongation.

• Progression → Repotrectinib

2L: Repotrectinib

For progression after crizotinib, including the G2032R solvent-front resistance mutation. Repeat biopsy or ctDNA to characterize resistance.

• Progression → Platinum-pemetrexed chemotherapy ± bevacizumab

3L+: Platinum-pemetrexed chemotherapy ± bevacizumab

After ROS1-directed options are exhausted. Platinum-pemetrexed is standard; single-agent immunotherapy is not recommended in ROS1-driven disease. Prioritize a clinical trial.