EP1.14-07 Efficacy and Safety of ALK Inhibitors in ALK-Rearranged Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis

Abstract

First and second generation ALK inhibitors were shown to delay disease progression and improve tumour response in ALK-rearranged advanced non-small cell lung cancer (NSCLC) patients. While a significant progression free survival (PFS) improvement has been consistently reported, no overall survival (OS) benefit was shown in randomized trials. We conducted a systematic review and meta-analysis to assess the efficacy and safety of ALK inhibitors compared to chemotherapy (ALK vs. chemo) and 2nd generation ALK inhibitors compared to 1st generation ALK inhibitors (ALK 2G vs. ALK 1G). The electronic databases PubMed and EMBASE, were searched for relevant randomized trials. Pooled hazard ratios (HR) for overall survival (OS) and progression free survival (PFS), and pooled risk ratios for objective response rates (ORR) and grade 3 or higher 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. Six trials were included in the analysis of ALK vs. chemo and four in the analysis of ALK 2G vs. ALK 1G. 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 2G vs. ALK 1G without reaching statistical significance (HR: 0.64, 95%CI 0.36-1.16). PFS was improved with ALK vs. chemo and ALK 2G vs. ALK 1G (HR: 0.44, 95%CI 0.35-0.44 and HR: 0.38, 95%CI-0.29-0.51, respectively). Similarly, ORR was improved with ALK vs. chemo and ALK 2G vs. ALK 1G (RR: 2.68, 95%CI 1.89-3.81 and RR: 1.16, 95%CI 1.08-1.24, respectively). The risk of grade 3 or higher toxicity did not differ between treatments (RR 1.08, 95%CI 0.88-1.33 and RR 0.77, 95%CI 0.56-1.06, respectively). Overall the PFS benefit of ALK vs. chemo and ALK 2G vs. ALK 1G was homogenous across all subgroups with a greater degree of benefit within never-smokers when treated with ALK vs. chemo (p for subgroup differences=0.03). This meta-analysis is the first, to our knowledge, to report an OS improvement with the use of ALK vs. chemo. A trend toward a better OS was also seen with ALK 2G vs. ALK 1G 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 2nd generation ALK inhibitors as initial therapy.