Elsevier

The Lancet

Volume 390, Issue 10089, 1–7 July 2017, Pages 29-39
The Lancet

Articles
Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial

https://doi.org/10.1016/S0140-6736(17)30565-2Get rights and content

Summary

Background

Alectinib, a potent, highly selective, CNS-active inhibitor of anaplastic lymphoma kinase (ALK), showed promising efficacy and tolerability in the single-arm phase 1/2 AF-001JP trial in Japanese patients with ALK-positive non-small-cell lung cancer. Given those promising results, we did a phase 3 trial to directly compare the efficacy and safety of alectinib and crizotinib.

Methods

J-ALEX was a randomised, open-label, phase 3 trial that recruited ALK inhibitor-naive Japanese patients with ALK-positive non-small-cell lung cancer, who were chemotherapy-naive or had received one previous chemotherapy regimen, from 41 study sites in Japan. Patients were randomly assigned (1:1) via an interactive web response system using a permuted-block method stratified by Eastern Cooperative Oncology Group performance status, treatment line, and disease stage to receive oral alectinib 300 mg twice daily or crizotinib 250 mg twice daily until progressive disease, unacceptable toxicity, death, or withdrawal. The primary endpoint was progression-free survival assessed by an independent review facility. The efficacy analysis was done in the intention-to-treat population, and safety analyses were done in all patients who received at least one dose of the study drug. The study is ongoing and patient recruitment is closed. This study is registered with the Japan Pharmaceutical Information Center (number JapicCTI-132316).

Findings

Between Nov 18, 2013, and Aug 4, 2015, 207 patients were recruited and assigned to the alectinib (n=103) or crizotinib (n=104) groups. At data cutoff for the second interim analysis, 24 patients in the alectinib group had discontinued treatment compared with 61 in the crizotinib group, mostly due to lack of efficacy or adverse events. At the second interim analysis (data cutoff date Dec 3, 2015), an independent data monitoring committee determined that the primary endpoint of the study had been met (hazard ratio 0·34 [99·7% CI 0·17–0·71], stratified log-rank p<0·0001) and recommended an immediate release of the data. Median progression-free survival had not yet been reached with alectinib (95% CI 20·3–not estimated) and was 10·2 months (8·2–12·0) with crizotinib. Grade 3 or 4 adverse events occurred at a greater frequency with crizotinib (54 [52%] of 104) than alectinib (27 [26%] of 103). Dose interruptions due to adverse events were also more prevalent with crizotinib (77 [74%] of 104) than with alectinib (30 [29%] of 103), and more patients receiving crizotinib (21 [20%]) than alectinib (nine [9%]) discontinued the study drug because of an adverse event. No adverse events with a fatal outcome occurred in either treatment group.

Interpretation

These results provide the first head-to-head comparison of alectinib and crizotinib and have the potential to change the standard of care for the first-line treatment of ALK-positive non-small-cell lung cancer. The dose of alectinib (300 mg twice daily) used in this study is lower than the approved dose in countries other than Japan; however, this limitation is being addressed in the ongoing ALEX study.

Funding

Chugai Pharmaceutical Co, Ltd.

Introduction

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.

Section snippets

Study design and participants

J-ALEX is a multicentre, randomised, open-label trial done at 41 study sites in Japan. The trial enrolled ALK inhibitor-naive Japanese patients with ALK-positive advanced non-small-cell lung cancer, who were chemotherapy-naive or who had received one previous chemotherapy regimen. Although the favourable safety profile of alectinib was shown by the AF-001JP study,16 J-ALEX followed an open-label design to ensure safety in individual patients, for whom the doctors had little clinical experience.

Results

Between Nov 18, 2013, and Aug 4, 2015, 207 patients were enrolled and randomly assigned to receive alectinib (n=103) or crizotinib (n=104; figure 1).

The numbers of patients with measurable disease at baseline, as assessed by the IRF, were 83 (81%) of 103 in the alectinib group and 90 (87%) of 104 in the crizotinib group. Patient characteristics were balanced between the two treatment groups (table 1). The only exception was the proportion of patients with brain metastases at baseline, which was

Discussion

This is the first trial, to our knowledge, to directly compare two ALK inhibitors in a majority first-line treatment setting, resulting in a favourable progression-free survival for alectinib compared with crizotinib. The results show that alectinib has both systemic efficacy and can lead to intracranial disease control in patients with ALK-positive non-small-cell lung cancer and brain metastases. The characteristics of alectinib, including its potent ALK inhibitory activity, high selectivity,

References (28)

  • B Hallberg et al.

    Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology

    Nat Rev Cancer

    (2013)
  • M Soda et al.

    Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer

    Nature

    (2007)
  • U McDermott et al.

    Genomic alterations of anaplastic lymphoma kinase may sensitize tumors to anaplastic lymphoma kinase inhibitors

    Cancer Res

    (2008)
  • K Takezawa et al.

    Role of ERK-BIM and STAT3-survivin signaling pathways in ALK inhibitor-induced apoptosis in EML4-ALK-positive lung cancer

    Clin Cancer Res

    (2011)
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