Optimizing treatment and sequencing strategies for maximal survival and net health benefits in ALK-positive NSCLC: a systematic review and reconstructed individual patient data meta-analysis.

OBJECTIVES: To identify optimal treatments and sequencing strategies that maximize efficacy, safety, and net health benefits (NHB, a comprehensive measure of safety and efficacy) for ALK-positive non-small-cell lung-cancer (NSCLC). METHODS: Related data from phase Ⅱ-Ш clinical trials targeting ALK-positive NSCLC was identified through a systematic search of PubMed, EMBASE, the Cochrane Library, and ClinicalTrials.gov. Progression-free survival (PFS) and overall survival (OS) estimates were derived from Kaplan-Meier curves using individual participant data. Life-year gained (LYG) was the main efficacy outcome. Safety was evaluated by all-cause grade 3 + adverse events. Survival outcomes across treatment sequences were projected using a clock-reset semi-Markov model. Quality-adjusted life year (QALY) was used as the metric for NHB to evaluate the comprehensive value of treatment effectiveness and safety. Sensitivity and scenario analyses were conducted to validate our findings. RESULTS: A total of 27 studies were included. Lorlatinib maximized LYG and NHB as both first-line and post-crizotinib second-line therapy. Alectinib led LYG and NHB after chemotherapy resistance, while brigatinib topped after alectinib resistance. Chemotherapy followed by alectinib or brigatinib, resulted in the highest LYG for first-line to second-line PFS, with the alectinib-brigatinib sequence delivering the highest NHB. For first-line to third-line PFS, the chemotherapy-alectinib-brigatinib sequence maximized survival, while alectinib-brigatinib-lorlatinib was optimal for NHB. Frontline second-generation ALK-TKI enhanced boost survival and NHB, using first-generation ALK-TKI before chemotherapy had little impact on survival but improved initial NHB. Safety profiles emphasized alectinib as the safest first-line option, with iruplinalkib being the most favorable option after crizotinib resistance. Uncertainty analysis indicated that the findings were robust. CONCLUSIONS: According to current analyses, lorlatinib is an optimal first-line therapy. Alectinib and brigatinib are effective subsequent treatments in cases of non-lorlatinib resistance. First-line ALK-TKIs optimize patient benefits, and carefully sequenced treatments offer substantial survival and NHB across all stages of therapy.