What question did this study set out to answer?

The aim is to find optimal treatment strategies that enhance efficacy, safety, and net health benefits for ALK-positive NSCLC patients.

March 31, 2026Open Access

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

Key Points

The aim is to find optimal treatment strategies that enhance efficacy, safety, and net health benefits for ALK-positive NSCLC patients.
Conducted a systematic review of phase II-III clinical trials on ALK-positive NSCLC.
Utilized individual participant data to derive survival estimates with Kaplan-Meier curves.
Employed a clock-reset semi-Markov model to project survival outcomes across treatment sequences.
Evaluated safety through all-cause grade 3+ adverse events analysis.
Completed sensitivity and scenario analyses to confirm findings.
Lorlatinib was identified as the optimal first-line therapy with maximum life-year gains and net health benefits.
Alectinib and brigatinib were effective treatments after resistance to crizotinib or alectinib, respectively.
Chemotherapy followed by alectinib or brigatinib provided the highest life-year gains for first-line to second-line therapy.
The alectinib-brigatinib sequence yielded the best net health benefits overall.
Safety analysis highlighted alectinib as the safest first-line option.

Abstract

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). 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. 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. 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.

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