Non-small-cell lung cancer with anaplastic lymphoma kinase fusion gene-rearrangement (ALK positive) is a distinct subset of lung cancer in approximately 5% of patients with advanced adenocarcinoma.1, 2, 3 ALK fusion proteins promote tumour cell growth and survival through the aberrant activation of intracellular signalling.4, 5 Lung cancers harbouring ALK fusion proteins are highly sensitive to ALK tyrosine kinase inhibitors, which efficiently induce apoptosis.6, 7
The first approved ALK inhibitor, crizotinib, significantly prolonged progression-free survival compared with chemotherapy in patients with untreated and chemotherapy-treated advanced ALK-positive non-small-cell lung cancer.8, 9 Crizotinib is approved in Japan (since March, 2012) and the USA (since August, 2011) in any line of treatment, and was approved in the European Union in October, 2012, in the first-line setting.10, 11, 12 However, emergence of resistance to crizotinib is almost inevitable after a median of 10·9 months.8 This resistance could be due to secondary mutations or amplification of ALK, activation of downstream molecules, or poor penetration to the CNS, which is the most common site of progressive disease.9, 13
Research in context
Evidence before this study
The selective anaplastic lymphoma kinase tyrosine kinase inhibitor, alectinib, has shown both systemic and CNS efficacy in patients with ALK-positive non-small-cell lung cancer. Alectinib showed high activity in patients with chemotherapy-pretreated, ALK-positive non-small-cell lung cancer in the phase 1/2 Japanese AF-001JP study, and in crizotinib-refractory patients with ALK-positive non-small-cell lung cancer, in two pivotal single-arm phase 2 trials, the global NP28673 study and the North American NP28761 study. No randomised phase 3 trials had been initiated at the design stage of this study. We searched PubMed for English language articles published up to Oct 1, 2016, using the search terms “alectinib”, “NSCLC”, “ALK-rearranged”, and “ALK-positive”, but found no evidence of phase 3 trials reporting clinical data for alectinib.
Added value of this study
This is the first trial, to our knowledge, to directly compare two ALK inhibitors in a predominantly first-line treatment setting, resulting in a favourable progression-free survival for alectinib versus crizotinib. Results of this phase 3 randomised trial showed that alectinib has greater clinical efficacy and better tolerability than the current standard of care, crizotinib, in ALK inhibitor-naive patients with ALK-positive non-small-cell lung cancer.
Implications of all the available evidence
Results of this study provide the first head-to-head comparison of alectinib and crizotinib and have the potential to change the standard first-line treatment of ALK-positive non-small-cell lung cancer. ALK positivity was confirmed in this study using immunohistochemistry and fluorescence in-situ hybridisation (FISH), or by RT-PCR. Previous studies suggest that concordance between the immunohistochemistry and FISH ALK test is high, thus the results of this study might generalise to patients with ALK positivity confirmed by only immunohistochemistry. The use of immunohistochemistry as a sole diagnostic test will be assessed in the ongoing ALEX study, which will compare the efficacy and safety of alectinib with crizotinib in patients with treatment-naive ALK-positive non-small-cell lung cancer.
Alectinib is a selective ALK inhibitor with high CNS penetration;14, 15 it is active against several secondary mutations that confer acquired resistance to crizotinib such as Thr1151_Leu1152insThr, Leu1196Met, Cys1156Tyr, Phe1174Leu, and Gly1269Ala. In a Japanese single-arm, open-label, phase 1/2 study (AF-001JP),16 alectinib showed high activity in chemotherapy-pretreated, ALK tyrosine kinase inhibitor-naive patients with ALK-positive non-small-cell lung cancer. The proportion of patients who achieved an objective response was 93·5% (95% CI 82·1–98·6) with 43 of 46 evaluable patients responding to treatment; the median progression-free survival has not yet been reached, but is anticipated to be longer than 29 months.16, 17 These findings led to the approval of alectinib in Japan in July, 2014.18 In the USA, alectinib received accelerated approval by the US Food and Drug Administration in 2015 following results from two pivotal single-arm phase 2 trials (the global NP2867319 and the North American NP2876120 studies) in patients with disease progression while on crizotinib.19, 20
Given the promising efficacy and tolerability of alectinib in the AF-001JP study, we did a phase 3 trial (J-ALEX) to directly compare the efficacy and safety of alectinib and crizotinib in Japanese patients with advanced ALK-positive non-small-cell lung cancer.