Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX)

an open-label, randomised phase 3 trial

Toyoaki Hida, Hiroshi Nokihara, Masashi Kondo, Young Hak Kim, Koichi Azuma, Takashi Seto, Yuichi Takiguchi, Makoto Nishio, Hiroshige Yoshioka, Fumio Imamura, Katsuyuki Hotta, Satoshi Watanabe, Koichi Goto, Miyako Satouchi, Toshiyuki Kozuki, Takehito Shukuya, Kazuhiko Nakagawa, Tetsuya Mitsudomi, Nobuyuki Yamamoto, Takashi Asakawa & 3 others Ryoichi Asabe, Tomohiro Tanaka, Tomohide Tamura

Research output: Contribution to journalArticle

233 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)29-39
Number of pages11
JournalThe Lancet
Volume390
Issue number10089
DOIs
Publication statusPublished - 01-07-2017

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Non-Small Cell Lung Carcinoma
Japan
Disease-Free Survival
crizotinib
CH5424802
anaplastic lymphoma kinase
Furylfuramide
Clinical Trials Data Monitoring Committees
Pharmaceutical Preparations
Safety
Information Centers
Drug Therapy
Fatal Outcome
Therapeutics
Standard of Care
Drug-Related Side Effects and Adverse Reactions
Patient Selection

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Hida, Toyoaki ; Nokihara, Hiroshi ; Kondo, Masashi ; Kim, Young Hak ; Azuma, Koichi ; Seto, Takashi ; Takiguchi, Yuichi ; Nishio, Makoto ; Yoshioka, Hiroshige ; Imamura, Fumio ; Hotta, Katsuyuki ; Watanabe, Satoshi ; Goto, Koichi ; Satouchi, Miyako ; Kozuki, Toshiyuki ; Shukuya, Takehito ; Nakagawa, Kazuhiko ; Mitsudomi, Tetsuya ; Yamamoto, Nobuyuki ; Asakawa, Takashi ; Asabe, Ryoichi ; Tanaka, Tomohiro ; Tamura, Tomohide. / Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX) : an open-label, randomised phase 3 trial. In: The Lancet. 2017 ; Vol. 390, No. 10089. pp. 29-39.
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abstract = "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.",
author = "Toyoaki Hida and Hiroshi Nokihara and Masashi Kondo and Kim, {Young Hak} and Koichi Azuma and Takashi Seto and Yuichi Takiguchi and Makoto Nishio and Hiroshige Yoshioka and Fumio Imamura and Katsuyuki Hotta and Satoshi Watanabe and Koichi Goto and Miyako Satouchi and Toshiyuki Kozuki and Takehito Shukuya and Kazuhiko Nakagawa and Tetsuya Mitsudomi and Nobuyuki Yamamoto and Takashi Asakawa and Ryoichi Asabe and Tomohiro Tanaka and Tomohide Tamura",
year = "2017",
month = "7",
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doi = "10.1016/S0140-6736(17)30565-2",
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volume = "390",
pages = "29--39",
journal = "The Lancet",
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Hida, T, Nokihara, H, Kondo, M, Kim, YH, Azuma, K, Seto, T, Takiguchi, Y, Nishio, M, Yoshioka, H, Imamura, F, Hotta, K, Watanabe, S, Goto, K, Satouchi, M, Kozuki, T, Shukuya, T, Nakagawa, K, Mitsudomi, T, Yamamoto, N, Asakawa, T, Asabe, R, Tanaka, T & Tamura, T 2017, 'Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial', The Lancet, vol. 390, no. 10089, pp. 29-39. https://doi.org/10.1016/S0140-6736(17)30565-2

Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX) : an open-label, randomised phase 3 trial. / Hida, Toyoaki; Nokihara, Hiroshi; Kondo, Masashi; Kim, Young Hak; Azuma, Koichi; Seto, Takashi; Takiguchi, Yuichi; Nishio, Makoto; Yoshioka, Hiroshige; Imamura, Fumio; Hotta, Katsuyuki; Watanabe, Satoshi; Goto, Koichi; Satouchi, Miyako; Kozuki, Toshiyuki; Shukuya, Takehito; Nakagawa, Kazuhiko; Mitsudomi, Tetsuya; Yamamoto, Nobuyuki; Asakawa, Takashi; Asabe, Ryoichi; Tanaka, Tomohiro; Tamura, Tomohide.

In: The Lancet, Vol. 390, No. 10089, 01.07.2017, p. 29-39.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX)

T2 - an open-label, randomised phase 3 trial

AU - Hida, Toyoaki

AU - Nokihara, Hiroshi

AU - Kondo, Masashi

AU - Kim, Young Hak

AU - Azuma, Koichi

AU - Seto, Takashi

AU - Takiguchi, Yuichi

AU - Nishio, Makoto

AU - Yoshioka, Hiroshige

AU - Imamura, Fumio

AU - Hotta, Katsuyuki

AU - Watanabe, Satoshi

AU - Goto, Koichi

AU - Satouchi, Miyako

AU - Kozuki, Toshiyuki

AU - Shukuya, Takehito

AU - Nakagawa, Kazuhiko

AU - Mitsudomi, Tetsuya

AU - Yamamoto, Nobuyuki

AU - Asakawa, Takashi

AU - Asabe, Ryoichi

AU - Tanaka, Tomohiro

AU - Tamura, Tomohide

PY - 2017/7/1

Y1 - 2017/7/1

N2 - 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.

AB - 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.

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