title: Differential Crizotinib Response Duration Among ALK Fusion Variants in ALK-Positive Non-Small-Cell Lung Cancer.
abstract: Anaplastic lymphoma kinase (ALK) rearrangement-positive non-small-cell lung cancers can be effectively treated with an ALK tyrosine kinase inhibitor (TKI) such as crizotinib, but the response magnitude and duration are heterogeneous. Several ALK variants have been identified, but few studies have focused on the effects of different ALK variants on the efficacy of crizotinib.
  
  
  
  Among 55 patients treated with crizotinib as the initial ALK-TKI between January 2007 and December 2014, we identified 35 patients with tumor specimens that could be evaluated for ALK variants by reverse transcription polymerase chain reaction. We retrospectively evaluated the efficacy of crizotinib on the basis of the objective response rate and progression-free survival (PFS) according to the ALK variants.
  
  
  
  The most frequent ALK variant was variant 1 in 19 patients (54%), followed by variant 2 in five patients (14%), variant 3a/3b in four patients (12%), and other variants in seven patients (20%). Objective response rate was 69% in all patients, whereas it was 74% and 63% in the variant 1 and non-variant 1 groups, respectively. The median PFS time was significantly longer in patients with variant 1 than in those with non-variant 1 (median PFS, 11.0 months [95% CI, 6.5 to 43.0 months] v 4.2 months [95% CI, 1.6 to 10.2 months], respectively; P < .05). Multivariable analysis identified two significant factors associated with PFS duration, ALK variant 1 (hazard ratio, 0.350; 95% CI, 0.128 to 0.929; P < .05) and advanced stage (hazard ratio, 4.646; 95% CI, 1.381 to 21.750; P < .05).
  
  
  
  Our results indicate the better efficacy of crizotinib in patients with ALK variant 1 versus non-variant 1. The ALK variant status might affect the efficacy of ALK-TKIs.
authors.affiliation: All authors: Aichi Cancer Center Hospital, Aichi, Japan. t.yoshida@aichi-cc.jp.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: All authors: Aichi Cancer Center Hospital, Aichi, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Oya
authors.affiliation: All authors: Aichi Cancer Center Hospital, Aichi, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: All authors: Aichi Cancer Center Hospital, Aichi, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Shimizu
authors.affiliation: All authors: Aichi Cancer Center Hospital, Aichi, Japan.
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Horio
authors.affiliation: All authors: Aichi Cancer Center Hospital, Aichi, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kuroda
authors.affiliation: All authors: Aichi Cancer Center Hospital, Aichi, Japan.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Sakao
authors.affiliation: All authors: Aichi Cancer Center Hospital, Aichi, Japan.
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Hida
authors.affiliation: All authors: Aichi Cancer Center Hospital, Aichi, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yatabe
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D000077547:Crizotinib; D018572:Disease-Free Survival; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D012189:Retrospective Studies
chemical_list: D000970:Antineoplastic Agents; C522504:EML4-ALK fusion protein, human; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases