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Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Front-line treatment for advanced non-small-cell lung cancer and ALK fusion: a network meta-analysis
Yaokai Wen1, Tao Jiang1, Xiangrong Wu2
1Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.
Background:
It remains unknown what is the optimal front-line choice for advanced non-small-cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) fusion.
Methods:
We conducted a systematic review and network meta-analysis of randomized phase III clinical trials comparing two or more treatments as the front-line setting for patients with advanced ALK-positive NSCLC.
Results:
Nine phase III randomized clinical trials with 2367 patients were included. As to efficacy, lorlatinib had the most favorable progression-free survival [PFS; surface under the cumulative ranking curve (SUCRA) = 98.4%] in the first-line setting, with noticeable outcome benefits versus chemotherapy [hazard ratio (HR): 0.12; 95% confidence interval (CI): 0.08-0.19], crizotinib (HR: 0.28; 95% CI: 0.19-0.41), ceritinib (HR: 0.22; 95% CI: 0.13-0.37), and brigatinib (HR: 0.58; 95% CI: 0.35-0.96), as well as beneficial trends when compared with alectinib (HR: 0.66; 95% CI: 0.41-1.04) and ensartinib (HR: 0.62; 95% CI: 0.36-1.08). Meanwhile, alectinib showed the optimal overall survival (OS; SUCRA = 91.2%), with significant improvements over chemotherapy (HR: 0.47; 95% CI: 0.30-0.72) and crizotinib (HR: 0.58; 95% CI: 0.41-0.82). Similarly, brigatinib also displayed prolonged OS compared with crizotinib after adjustment for crossover by the marginal structural model (HR: 0.54; 95% CI: 0.31-0.92). In terms of safety, alectinib had the fewest grade 3-5 adverse events (SUCRA = 98.9%), with marked advantages versus crizotinib [odds ratio (OR): 0.67; 95% CI: 0.46-0.97], ceritinib (OR: 0.21; 95% CI: 0.10-0.43), brigatinib (OR: 0.37; 95% CI: 0.20-0.69), ensartinib (OR: 0.48; 95% CI: 0.27-0.89), and lorlatinib (OR: 0.30; 95% CI: 0.16-0.54).
Conclusions:
Lorlatinib may have advantageous PFS compared with other agents but a greater risk of severe toxicity. Second-generation inhibitors, including alectinib, brigatinib, and ensartinib, provide major efficacy with less toxicity and remain appropriate regimens in the front-line setting.
Insights
Lorlatinib offers superior progression-free survival (PFS) for advanced anaplastic lymphoma kinase (ALK) fusion non-small-cell lung cancer (NSCLC) but with higher toxicity. Second-generation inhibitors provide a balance of efficacy and safety for first-line treatment.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Optimal first-line therapy for advanced non-small-cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) fusion remains undetermined.
- ALK-positive NSCLC represents a distinct molecular subtype requiring targeted treatment strategies.
Purpose of the Study:
- To systematically compare the efficacy and safety of various first-line treatments for advanced ALK-positive NSCLC.
- To identify the optimal treatment regimen based on progression-free survival (PFS), overall survival (OS), and toxicity profiles.
Main Methods:
- A systematic review and network meta-analysis of nine phase III randomized clinical trials.
- Inclusion of 2367 patients with advanced ALK-positive NSCLC.
- Comparative analysis of treatments including lorlatinib, alectinib, brigatinib, ensartinib, crizotinib, and ceritinib.
Main Results:
- Lorlatinib demonstrated the most favorable PFS (SUCRA=98.4%) compared to chemotherapy, crizotinib, ceritinib, and brigatinib.
- Alectinib showed the optimal OS (SUCRA=91.2%) and the fewest grade 3-5 adverse events (SUCRA=98.9%).
- Brigatinib also showed prolonged OS compared to crizotinib.
Conclusions:
- Lorlatinib offers superior PFS but carries a higher risk of severe toxicity.
- Second-generation inhibitors like alectinib, brigatinib, and ensartinib provide a favorable balance of efficacy and safety for first-line treatment of ALK-positive NSCLC.
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