title: Clinical outcomes with pemetrexed-based systemic therapies in RET-rearranged lung cancers.
abstract: RET rearrangements are targetable, oncogenic lung cancer drivers. While previous series have shown durable clinical benefit with pemetrexed-based therapies in ALK- and ROS1-rearranged lung cancers, the benefits of pemetrexed-based treatments in patients with RET-rearranged lung cancers relative to other genomic subsets have not previously been explored.
  
  
  
  A retrospective review of patients with pathologically confirmed stage IIIB/IV lung adenocarcinomas and evidence of a RET, ROS1, or ALK rearrangement, or a KRAS mutation was conducted. Patients were eligible if they received treatment with pemetrexed alone or in combination. The primary outcome of progression-free survival (PFS), and secondary outcomes of overall response rate (ORR, RECIST v1.1), time to progression (TTP), and time to treatment discontinuation were compared between RET-rearranged and groups of ROS1-rearranged, ALK-rearranged, and KRAS-mutant lung cancers.
  
  
  
  We evaluated 104 patients. Patients with RET-rearranged lung cancers (n = 18) had a median PFS of 19 months [95% confidence interval (CI) 12-not reached (NR)] that was comparable with patients with ROS1- (23 months, 95% CI 14-NR, n = 10) and ALK-rearranged (19 months, 95% CI 15-36, n = 36) lung cancers, and significantly improved compared with patients with KRAS-mutant lung cancers (6 months, 95% CI 5-9, P < 0.001, n = 40). ORR (45%), median TTP (20 months, 95% CI 17-NR), and median time to treatment discontinuation (21 months, 95% CI 6-NR) in patients with RET-rearranged lung cancers were not significantly different compared with patients with ALK- and ROS1-rearranged lung cancers, and improved compared with patients with KRAS-mutant lung cancers.
  
  
  
  Durable benefits with pemetrexed-based therapies in RET-rearranged lung cancers are comparable with ALK- and ROS1-rearranged lung cancers. When selecting therapies for patients with RET-rearranged lung cancers, pemetrexed-containing regimens should be considered.
authors.affiliation: Department of Medicine drilona@mskcc.org.
authors.forename: A
authors.initials: A
authors.lastname: Drilon
authors.affiliation: Department of Medicine.
authors.forename: I
authors.initials: I
authors.lastname: Bergagnini
authors.affiliation: Department of Medicine.
authors.forename: L
authors.initials: L
authors.lastname: Delasos
authors.affiliation: Department of Medicine.
authors.forename: J
authors.initials: J
authors.lastname: Sabari
authors.affiliation: Department of Epidemiology/Biostatistics.
authors.forename: K M
authors.initials: KM
authors.lastname: Woo
authors.affiliation: Department of Radiology.
authors.forename: A
authors.initials: A
authors.lastname: Plodkowski
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Medicine.
authors.forename: M D
authors.initials: MD
authors.lastname: Hellmann
authors.affiliation: Department of Pathology, Université Laval, Québec, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Joubert
authors.affiliation: Department of Epidemiology/Biostatistics.
authors.forename: C S
authors.initials: CS
authors.lastname: Sima
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: R
authors.initials: R
authors.lastname: Smith
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: R
authors.initials: R
authors.lastname: Somwar
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: N
authors.initials: N
authors.lastname: Rekhtman
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: M
authors.initials: M
authors.lastname: Ladanyi
authors.affiliation: Department of Medicine.
authors.forename: G J
authors.initials: GJ
authors.lastname: Riely
authors.affiliation: Department of Medicine.
authors.forename: M G
authors.initials: MG
authors.lastname: Kris
mesh_terms: D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D000068437:Pemetrexed / Q000008:administration & dosage / Q000009:adverse effects; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D000068437:Pemetrexed; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D051096:Proto-Oncogene Proteins c-ret; C062333:ROS1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D016283:Proto-Oncogene Proteins p21(ras)
keywords: RET rearrangement; non-small-cell lung cancer; pemetrexed