Updated Efficacy and Safety Data and Impact of the EML4-ALK Fusion Variant on the Efficacy of Alectinib in Untreated ALK-Positive Advanced Non–Small Cell Lung Cancer in the Global Phase III ALEX Study

D. Ross Camidge, Rafal Dziadziuszko, Solange Peters, Tony Mok, Johannes Noe, Malgorzata Nowicka, Shirish M. Gadgeel, Parneet Cheema, Nick Pavlakis, Filippo de Marinis, Byoung Chul Cho, Li Zhang, Denis Moro-Sibilot, Ting Liu, Walter Bordogna, Bogdana Balas, Barbara Müller, Alice T. Shaw

Research output: Contribution to journalArticlepeer-review

105 Citations (Scopus)


Introduction: At the prior data cutoff (February 9, 2017) the ALEX trial showed superior investigator-assessed progression-free survival (PFS) for alectinib versus crizotinib in untreated, anaplastic lymphoma kinase (ALK)-positive, advanced NSCLC (hazard ratio = 0.47, 95% confidence interval: 0.34–0.65, p < 0.001). The median PFS in the alectinib arm was not reached versus 11.1 months with crizotinib. Retrospective analyses suggest that the echinoderm microtubule-associated protein-like 4 gene-ALK variant (EML4-ALK) may influence ALK-inhibitor treatment benefit. We present updated analyses, including exploratory subgroup analysis by EML4-ALK variant, after an additional 10 months’ follow-up (cutoff December 1, 2017). Methods: Patients were randomized to receive twice-daily alectinib, 600 mg, or crizotinib, 250 mg, until disease progression, toxicity, death, or withdrawal. PFS was determined by the investigators. Baseline plasma and tissue biomarker samples were analyzed by using hybrid-capture, next-generation sequencing to determine EML4-ALK variant. Results: Baseline characteristics were balanced. Investigator-assessed PFS was prolonged with alectinib (stratified hazard ratio = 0.43, 95% confidence interval: 0.32–0.58). The median PFS times were 34.8 months with alectinib and 10.9 months with crizotinib. EML4-ALK fusions were detectable in 129 patient plasma samples and 124 tissue samples; variants 1, 2, and 3/ab did not affect PFS, objective response rate, or duration of response. Investigator-assessed PFS was longer for alectinib than for crizotinib across EML4-ALK variants 1, 2, and 3a/b in plasma and tissue. Despite longer treatment duration (27.0 months in the case of alectinib versus 10.8 months in the case of crizotinib), the safety of alectinib compared favorably with that of crizotinib. Conclusion: Alectinib continues to demonstrate superior investigator-assessed PFS versus crizotinib in untreated ALK-positive NSCLC, irrespective of EML4-ALK variant.

Original languageEnglish
Pages (from-to)1233-1243
Number of pages11
JournalJournal of Thoracic Oncology
Issue number7
Publication statusPublished - 2019 Jul

Bibliographical note

Funding Information:
Disclosure: Dr. Camidge has received advisory board/consultation fees (in the past 3 years) from ARIAD, Arrys/Kyn, AstraZeneca , Bio-Thera (DSMB), Blueprint, Bristol-Myers Squibb , Celgene , Clovis, Daichii Sankyo (ILD adjudication committee), F. Hoffmann-La Roche Ltd/ Genentech , G1 Therapeutics (DSMB), Genoptix, Hansoh (SRC), Hengrui, Ignyta, Inivata, Lycera, Mersana Therapeutics, Novartis , Orion, Revolution Med, Ribo, Regeneron, and Takeda and research funding from Takeda (investigator-initiated trial). Dr. Dziadziuszko has received honoraria or consulting fees from Roche, Pfizer, Boehringer Ingelheim, Clovis Oncology, Novartis, AstraZeneca, and Tesaro. Dr. Peters has received honoraria or consultation fees from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Eli Lilly, F. Hoffmann-La Roche Ltd, Janssen, Merck Sharp and Dohme, Merck Serono, Novartis, Pfizer, Regeneron, and Takeda and given a talk in organized public events for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, F. Hoffmann-La Roche Ltd, Merck Sharp and Dohme, Novartis, and Pfizer. Dr. Mok has been compensated for a leadership role with Sanonics Ltd; he is an AstraZeneca board member, and has received honoraria/consulting fees from ACEA Biosciences, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Chimed, Cirina, Fishawack Facilitate, Ignyta, Janssen, Lilly, Merck Serono, Merck Sharp and Dohme, Novartis, OncoGenex, Pfizer, Roche/Genentech, SFJ Pharmaceutical, Takeda, and Vertex and has received research funding from AstraZeneca , Bristol-Myers Squibb , Clovis Oncology, Merck Sharp and Dohme , Novartis , Pfizer , Roche , SFJ Pharmaceutical, and XCovery. Dr. Gadgeel has received honoraria/consultancy fees from Ariad, AstraZeneca, Bristol-Myers Squibb, Pfizer, and Roche/Genentech. Dr. Cheema has participated in advisory boards and received honoraria from AstraZeneca , Boehringer Ingelheim, Bristol-Myers Squibb , F. Hoffmann-La Roche Ltd, Merck , Novartis , Pfizer , and Takeda. Dr. Pavlakis has received advisory board honoraria from Pfizer , Roche , Novartis , AstraZeneca , Amgen , Boehringer Ingelheim, Bristol-Myers Squibb , Merck Sharp and Dohme , Merck KgA , Ipsen, and Takeda and travel assistance from Roche , Bristol-Myers Squibb , and Boehringer Ingelheim. Dr. de Marinis has received honoraria from F. Hoffmann-La Roche Ltd, Bristol-Myers Squibb , AstraZeneca , and Merck . Dr. Cho has received funding from Novartis, AstraZeneca, the MOGAM Institute, Dong-A ST, AbbVie , Janssen, Yuhan, and Champions Oncology and has worked in a consulting role for Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Yuhan, Pfizer, Eli Lilly, Yuhan, and Ono. Dr. Zhang discloses grants from AstraZeneca , Bristol-Myers Squibb , and Pfizer outside of the submitted work. Dr. Moro-Sibilot has received honoraria from F. Hoffmann-La Roche Ltd, Novartis, and Pfizer. Dr. Noe, Dr. Liu, Dr. Nowicka, Dr. Bordogna, Dr. Balas, and Ms. Müller are employees of F. Hoffmann-La Roche Ltd and have received travel, accommodation, or expenses from Roche, and own Roche stocks. Dr. Shaw has served as a compensated consultant or received honoraria from Ariad/Takeda, Bayer, Blueprint Medicines, Chugai, Daiichi-Sankyo, EMD Serono, Foundation Medicine, Genentech/Roche, Guardant, Ignyta, KSQ Therapeutics, LOXO, Natera, Novartis, Pfizer, Taiho Pharmaceuticals, and TP Therapeutics and has received research (institutional) funding from Ariad, Genentech/Roche, Ignyta, Novartis, Pfizer, and TP Therapeutics.

Funding Information:
This work was supported by F. Hoffmann-La Roche Ltd. The authors acknowledge Emmanuel Mitry (formerly of F. Hoffmann-La Roche Ltd) for his contributions to this article. The authors would like to thank the patients, their families, and the participating study centers. Third-party medical writing assistance, under the direction of the authors, was provided by John Bett, PhD, and Nicola Griffin, BSc, of Gardiner-Caldwell Communications and was funded by F. Hoffmann-La Roche Ltd.

Publisher Copyright:
© 2019 International Association for the Study of Lung Cancer

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pulmonary and Respiratory Medicine

Fingerprint Dive into the research topics of 'Updated Efficacy and Safety Data and Impact of the EML4-ALK Fusion Variant on the Efficacy of Alectinib in Untreated ALK-Positive Advanced Non–Small Cell Lung Cancer in the Global Phase III ALEX Study'. Together they form a unique fingerprint.

Cite this