ALK Inhibitors in ALK-rearranged Non-small Cell Lung Cancer with and Without Brain Metastases: Systematic Review and Network Meta-analysis

Objectives: To systematically evaluate the efficacy and safety of anaplastic lymphoma kinase (ALK) inhibitors in ALK-rearranged positive non-small cell lung cancer (NSCLC) with brain metastases, and update the overall survival (OS) outcomes of the second-generation and third-generation ALK (ALK-2G/3G) inhibitors versus first-generation (ALK-1G) inhibitors.

Design: The study is in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis guidelines. Randomised controlled trials (RCTs) published up to 3 November 2021 were retrieved from PubMed, EMBASE, Cochrane Library and ClinicalTrials.gov.

Setting: RCTs from any country and healthcare setting.

Participants: Patients with advanced ALK-positive NSCLC with or without brain metastases.

Interventions And Comparisons: The interventions were ALK-2G/3G; the control arm was ALK-1G or crizotinib.

Primary And Secondary Outcome Measures: Primary outcomes included median progression-free survival and median OS. Secondary outcomes included systemic objective response rate, intracranial response rate and rate of grade ≥3 adverse events (AEs).

Results: A total of 12 RCTs involving 3156 patients were analysed. Compared with ALK-1G (crizotinib), ALK-2G (alectinib, brigatinib, ceritinib and ensartinib) significantly improved the OS (HR: 0.72, 95% CI: 0.57 to 0.90, p=0.004) and intracranial response of patients with any brain metastases, especially with measurable (diameter ≥10 mm) brain metastases. Network meta-analysis demonstrated that ALK-3G (lorlatinib) had superior efficacy for patients with brain lesions, but performed a distinct side-effect profile. Moreover, alectinib showed superior efficacy and lower toxicity in ALK-positive NSCLC.

Conclusion: Treatment with ALK-2G inhibitors significantly improved OS compared with crizotinib, and alectinib has less severe AEs than any other ALK inhibitors with moderate-high efficacy. The limited OS follow-up and inadequate sample sizes might contribute to having no statistically significant difference in OS of lorlatinib versus crizotinib. More high-quality and longer follow-up RCTs are warranted to prove our findings.

Prospero Registration Number: CRD42021292245.