Metastatic NSCLC — ALK-Rearranged

Sequencing for ALK-rearranged metastatic non-small cell lung cancer: a next-generation ALK tyrosine kinase inhibitor first line (alectinib or brigatinib, or third-generation lorlatinib for maximal CNS control), lorlatinib on progression after a second-generation inhibitor, then platinum-pemetrexed chemotherapy. Immunotherapy is not recommended in this oncogene-driven subtype.

First-line ALK inhibitor selection (CNS burden and toxicity tolerance)?

• Extensive CNS disease / maximal PFS → Lorlatinib (third-generation ALK TKI)
• Standard first line → Alectinib or brigatinib (second-generation ALK TKI)

1L: Alectinib or brigatinib (second-generation ALK TKI)

Preferred, well-tolerated first-line options with strong CNS activity. Alectinib: monitor LFTs, myalgia, bradycardia, photosensitivity. Brigatinib: titrate to reduce early pulmonary events.

Evidence: ALEX

• Progression → Lorlatinib

1L: Lorlatinib (third-generation ALK TKI)

Longest first-line progression-free survival and deepest CNS control; favored for extensive brain metastases. Monitor hyperlipidemia, weight gain, edema, and neurocognitive/mood effects (often dose-manageable).

Evidence: CROWN

• Progression → Platinum-pemetrexed chemotherapy ± bevacizumab

2L: Lorlatinib

For progression after a second-generation TKI. Repeat biopsy or ctDNA to identify resistance mutations (e.g., G1202R) that inform sequencing; lorlatinib retains activity against most.

• Progression → Platinum-pemetrexed chemotherapy ± bevacizumab

3L+: Platinum-pemetrexed chemotherapy ± bevacizumab

After exhaustion of ALK-directed options. Platinum-pemetrexed is standard; single-agent immunotherapy is not recommended in ALK-driven disease. Prioritize a clinical trial for emerging resistance-directed agents.