Summary

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• This summary is based on the review of 25 systematic review(s)/meta-analysis(es). ^[1-25]
• Lorlatinib demonstrated superior progression-free survival (PFS) and high probabilities of better PFS across all efficacy endpoints compared to crizotinib, alectinib, and brigatinib, with particularly strong outcomes in patients with brain metastases. Lorlatinib also showed the best intracranial PFS and objective response rate (ORR), making it highly effective for central nervous system (CNS) progression.
• Alectinib had the longest overall survival (OS) among ALK inhibitors, significantly outperforming crizotinib. However, there were no significant OS differences between lorlatinib, brigatinib, and alectinib.
• Lorlatinib and brigatinib had the lowest number needed to treat (NNT) for intracranial outcomes, with lorlatinib excelling in PFS for patients with baseline brain metastases.
• Lorlatinib was associated with higher frequencies of neurocognitive adverse events (NAEs), including cognitive (14.57%), mood (11.17%), speech (7.24%), and psychotic effects (4.97%), compared to other ALK inhibitors like alectinib and brigatinib, which had fewer neurocognitive issues.
• Alectinib demonstrated a better safety profile with a lower incidence of grade 3-4 adverse events (AEs) and fewer treatment discontinuations due to AEs compared to lorlatinib and brigatinib. Brigatinib showed higher rates of laboratory anomalies and hypertension.
• Crizotinib was associated with gastrointestinal toxicity, including visual disorders and elevated liver enzymes, while ensartinib primarily caused skin-related side effects, such as pruritus and rash.
• Patients with brain metastases benefited most from lorlatinib and brigatinib, with lorlatinib showing the best intracranial PFS and ORR. Asian patients had better PFS with iruplinalkib and alectinib compared to other ALK inhibitors. Smoking status also impacted outcomes, with low-dose alectinib performing better among smokers, while lorlatinib was more effective for never-smokers.