Efficacy and safety of ALK inhibitors in ALK-rearranged non-small cell lung cancer: A systematic review and meta-analysis

Objectives: No overall survival (OS) benefit has been reported from a mature randomized trial with the use of ALK inhibitors. We conducted a systematic review and meta-analysis to assess the efficacy of ALK inhibitors compared to chemotherapy (ALK vs. chemo) and 2nd generation ALK inhibitors compared to 1 st generation ALK inhibitors (ALK-2 G vs. ALK-1 G). Methods: The electronic databases Medline (PubMed), EMBASE, and the Cochrane Database of Systematic Reviews were searched for relevant randomized trials. Pooled hazard ratios (HR) for OS and progression free survival (PFS), and pooled risk ratios for objective response rates (ORR) and toxicity were meta-analyzed using the generic inverse variance and the Mantel-Haenszel methods. To account for between-studies heterogeneity, random-effect models were used. Subgroup analyses compared PFS by gender, smoking status, brain metastases, race and age. Results: Six trials were included in the analysis of ALK vs. chemo and four in the analysis of ALK-2 G vs. ALK-1 G. Treatment with ALK inhibitors improved OS compared to chemotherapy (HR: 0.84, 95 %CI 0.72-0.97) while a trend toward a better OS was seen with ALK-2 G vs. ALK-1 G (HR: 0.66, 95 %CI 0.43-1.02). PFS was improved with ALK vs. chemo and ALK-2 G vs. ALK-1 G (HR: 0.44, 95 %CI 0.35-0.54 and HR: 0.38, 95 %CI-0.29-0.51, respectively). ORR was improved with ALK vs. chemo and ALK-2 G vs. ALK-1 G. No difference in toxicity was observed. Conclusions: This meta-analysis is the first, to our knowledge, to report an OS and PFS benefit with the use of ALK inhibitors compared to chemotherapy from randomized trial data. A trend toward a better OS was also seen with ALK-2 G vs. ALK-1 G and this is likely because of crossover effects and limited OS follow-up. Longer follow up and further research are warranted to directly compare ALK inhibitor sequences and to understand the outcomes of second generation ALK inhibitors as initial therapy.