title: Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed.
abstract: OBJECTIVE
  To explore whether the progression-free survival (PFS) with pemetrexed differs between anaplastic lymphoma kinase (ALK)-positive and other major molecular subtypes of non-small cell lung cancer.
  
  
  METHODS
  In an ALK-enriched population, patients with metastatic non-small cell lung cancer were screened by ALK fluorescence in situ hybridization and for epidermal growth factor receptor (EGFR) and KRAS mutations. Triple-tested, pemetrexed-treated patients (monotherapy or combination therapy) were identified and PFS with pemetrexed captured retrospectively.
  
  
  RESULTS
  Eighty-nine eligible cases were identified (19 ALK fluorescence in situ hybridization positive, 12 EGFR mutant, 21 KRAS mutant, and 37 triple negatives). Eighty-three cases (93%) were adenocarcinomas, two were adenosquamous, one squamous, and three had large cell histology. None of the ALK-positive patients had received crizotinib before pemetrexed. Pemetrexed was first-line therapy in 48% (72% as platinum-based combinations). Median PFS (95% confidence interval) data were EGFR mutant (5.5 months; 1-9), KRAS mutant (7 months; 1.5-10), ALK positive (9 months; 3-12), and triple negative (4 months; 3-5). In a multivariate analysis adjusting for line of therapy, mono- versus platinum and nonplatinum combination therapy, age, sex, histology, and smoking status, the only variable associated with prolonged PFS on pemetrexed was ALK+ (hazard ratio = 0.36 [95% confidence interval: 0.17-0.73], p = 0.0051).
  
  
  CONCLUSIONS
  In this exploratory analysis, ALK-positive patients have a significantly longer PFS on pemetrexed compared with triple-negative patients, whereas EGFR or KRAS mutant patients do not. This information should be considered when sizing randomized studies in ALK-positive patients that involve pemetrexed. Pemetrexed should also be prioritized as a cytotoxic to explore further in patients with known ALK-positive disease.
authors.affiliation: Department of Medical Oncology, University of Colorado Denver, 1665 North Ursula Street, Room 2256, P.O. Box 6510, Mail Stop F-706, Aurora, CO 80045-0508, USA. ross.camidge@ucdenver.edu
authors.forename: D Ross
authors.initials: DR
authors.lastname: Camidge
authors.forename: Scott A
authors.initials: SA
authors.lastname: Kono
authors.forename: Xian
authors.initials: X
authors.lastname: Lu
authors.forename: Sonia
authors.initials: S
authors.lastname: Okuyama
authors.forename: Anna E
authors.initials: AE
authors.lastname: Barón
authors.forename: Ana B
authors.initials: AB
authors.lastname: Oton
authors.forename: Angela M
authors.initials: AM
authors.lastname: Davies
authors.forename: Marileila
authors.initials: M
authors.lastname: Varella-Garcia
authors.forename: Wilbur
authors.initials: W
authors.lastname: Franklin
authors.forename: Robert C
authors.initials: RC
authors.lastname: Doebele
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D000077548:Anaplastic Lymphoma Kinase; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018287:Carcinoma, Large Cell / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D004273:DNA, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D015321:Gene Rearrangement; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000068437:Pemetrexed; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D012189:Retrospective Studies; D015996:Survival Rate; D018631:ras Proteins / Q000235:genetics
chemical_list: D004273:DNA, Neoplasm; D005971:Glutamates; C117307:KRAS protein, human; D009944:Organoplatinum Compounds; D011518:Proto-Oncogene Proteins; D000068437:Pemetrexed; D006147:Guanine; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; C512478:EGFR protein, human; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins