title: Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis.
abstract: BACKGROUND
  ALK gene rearrangement defines a new molecular subtype of non-small-cell lung cancer (NSCLC). In a recent phase 1 clinical trial, the ALK tyrosine-kinase inhibitor (TKI) crizotinib showed marked antitumour activity in patients with advanced, ALK-positive NSCLC. To assess whether crizotinib affects overall survival in these patients, we did a retrospective study comparing survival outcomes in crizotinib-treated patients in the trial and crizotinib-naive controls screened during the same time period.
  
  
  METHODS
  We examined overall survival in patients with advanced, ALK-positive NSCLC who enrolled in the phase 1 clinical trial of crizotinib, focusing on the cohort of 82 patients who had enrolled through Feb 10, 2010. For comparators, we identified 36 ALK-positive patients from trial sites who were not given crizotinib (ALK-positive controls), 67 patients without ALK rearrangement but positive for EGFR mutation, and 253 wild-type patients lacking either ALK rearrangement or EGFR mutation. To assess differences in overall survival, we assessed subsets of clinically comparable ALK-positive and ALK-negative patients.
  
  
  RESULTS
  Among 82 ALK-positive patients who were given crizotinib, median overall survival from initiation of crizotinib has not been reached (95% CI 17 months to not reached); 1-year overall survival was 74% (95% CI 63-82), and 2-year overall survival was 54% (40-66). Overall survival did not differ based on age, sex, smoking history, or ethnic origin. Survival in 30 ALK-positive patients who were given crizotinib in the second-line or third-line setting was significantly longer than in 23 ALK-positive controls given any second-line therapy (median overall survival not reached [95% CI 14 months to not reached] vs 6 months [4-17], 1-year overall survival 70% [95% CI 50-83] vs 44% [23-64], and 2-year overall survival 55% [33-72] vs 12% [2-30]; hazard ratio 0·36, 95% CI 0·17-0·75; p=0·004). Survival in 56 crizotinib-treated, ALK-positive patients was similar to that in 63 ALK-negative, EGFR-positive patients given EGFR TKI therapy (median overall survival not reached [95% CI 17 months to not reached] vs 24 months [15-34], 1-year overall survival 71% [95% CI 58-81] vs 74% [61-83], and 2-year overall survival 57% [40-71] vs 52% [38-65]; p=0·786), whereas survival in 36 crizotinib-naive, ALK-positive controls was similar to that in 253 wild-type controls (median overall survival 20 months [95% CI 13-26] vs 15 months [13-17]; p=0·244).
  
  
  CONCLUSIONS
  In patients with advanced, ALK-positive NSCLC, crizotinib therapy is associated with improved survival compared with that of crizotinib-naive controls. ALK rearrangement is not a favourable prognostic factor in advanced NSCLC.
  
  
  BACKGROUND
  Pfizer Inc, V Foundation for Cancer Research.
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA, USA. ashaw1@partners.org
authors.forename: Alice T
authors.initials: AT
authors.lastname: Shaw
authors.forename: Beow Y
authors.initials: BY
authors.lastname: Yeap
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Solomon
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Riely
authors.forename: Justin
authors.initials: J
authors.lastname: Gainor
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Costa
authors.forename: Sai-Hong I
authors.initials: SH
authors.lastname: Ou
authors.forename: Mohit
authors.initials: M
authors.lastname: Butaney
authors.forename: Ravi
authors.initials: R
authors.lastname: Salgia
authors.forename: Robert G
authors.initials: RG
authors.lastname: Maki
authors.forename: Marileila
authors.initials: M
authors.lastname: Varella-Garcia
authors.forename: Robert C
authors.initials: RC
authors.lastname: Doebele
authors.forename: Yung-Jue
authors.initials: YJ
authors.lastname: Bang
authors.forename: Kimary
authors.initials: K
authors.lastname: Kulig
authors.forename: Paulina
authors.initials: P
authors.lastname: Selaru
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Tang
authors.forename: Keith D
authors.initials: KD
authors.lastname: Wilner
authors.forename: Eunice L
authors.initials: EL
authors.lastname: Kwak
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Clark
authors.forename: A John
authors.initials: AJ
authors.lastname: Iafrate
authors.forename: D Ross
authors.initials: DR
authors.lastname: Camidge
mesh_terms: D000328:Adult; D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001315:Australia; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D017321:Clinical Trials, Phase I as Topic; D000077547:Crizotinib; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D018579:Patient Selection; D016016:Proportional Hazards Models; 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* / Q000235:genetics; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D015996:Survival Rate; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases