title: A Phase 1/1b Study Evaluating Trametinib Plus Docetaxel or Pemetrexed in Patients With Advanced Non-Small Cell Lung Cancer.
abstract: This two-part study evaluated trametinib, a MEK1/2 inhibitor, in combination with anticancer agents. Inhibition of MEK, a downstream effector of KRAS, demonstrated preclinical synergy with chemotherapy in KRAS-mutant NSCLC cell lines. Part 1 of this study identified recommended phase 2 doses of trametinib combinations. Part 2, reported herein, evaluated the safety, tolerability, pharmacokinetics, and efficacy of trametinib combinations in patients with NSCLC with and without KRAS mutations.
  
  
  
  Phase 1b evaluated trametinib plus docetaxel with growth factor support (trametinib, 2.0 mg once daily, and docetaxel, 75 mg/m2every 3 weeks) or pemetrexed (trametinib, 1.5 mg once daily, and pemetrexed, 500 mg/m2every 3 weeks). Eligibility criteria for the expansion cohorts included metastatic NSCLC with measurable disease, known KRAS mutation status, Eastern Cooperative Oncology Group performance status of 1 or lower, and no more than two prior regimens.
  
  
  
  The primary end point of overall response rate (ORR) was met for both combinations. A confirmed partial response (PR) was observed in 10 of the 47 patients with NSCLC who received trametinib plus docetaxel (21%). The ORR was 18% (four PRs in 22 patients) in those with KRAS wild-type NSCLC versus 24% (six PRs in 25 patients) in those with KRAS-mutant NSCLC. Of the 42 patients with NSCLC treated with trametinib plus pemetrexed, six (14%) had a PR; the ORR was 17% (four of 23) in patients with KRAS-mutated NSCLC versus 11% (two of 19) in KRAS wild-type NSCLC. Adverse events-most commonly diarrhea, nausea, and fatigue-were manageable.
  
  
  
  Trametinib-plus-chemotherapy combinations were tolerable. Clinical activity exceeding the ORRs previously reported with docetaxel or pemetrexed alone in KRAS-mutated NSCLC and meeting prespecified criteria was observed.
authors.affiliation: Division of Hematology and Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, California. Electronic address: david.gandara@ucdmc.ucdavis.edu.
authors.forename: David R
authors.initials: DR
authors.lastname: Gandara
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Natasha
authors.initials: N
authors.lastname: Leighl
authors.affiliation: Institut Claudius Regaud, Toulouse, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Delord
authors.affiliation: Aix Marseille University-Assistance Publique Hôpitaux de Marseille, Centre d'Essais Précoces en Cancérologie de Marseille, Marseille, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Barlesi
authors.affiliation: Institut de Cancerologie de l'Ouest, Nantes, France.
authors.forename: Jaafar
authors.initials: J
authors.lastname: Bennouna
authors.affiliation: Caen University Hospital-Clinical Research Hospital, Caen, France.
authors.forename: Gerald
authors.initials: G
authors.lastname: Zalcman
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, Professional Limited Liability Company, Nashville, Tennessee.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.affiliation: Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Reckamp
authors.affiliation: Division of Hematology and Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, California.
authors.forename: Karen
authors.initials: K
authors.lastname: Kelly
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Frances A
authors.initials: FA
authors.lastname: Shepherd
authors.affiliation: Hôpital Larrey Centre Hospitalier Universitaire Toulouse, Toulouse, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Mazieres
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
authors.affiliation: GlaxoSmithKline, Morrisville, North Carolina.
authors.forename: Olivia S
authors.initials: OS
authors.lastname: Gardner
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
authors.forename: Bijoyesh
authors.initials: B
authors.lastname: Mookerjee
authors.affiliation: GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: Yuehui
authors.initials: Y
authors.lastname: Wu
authors.affiliation: GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: Donna S
authors.initials: DS
authors.lastname: Cox
authors.affiliation: GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: Dan
authors.initials: D
authors.lastname: Schramek
authors.affiliation: GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: Vijay
authors.initials: V
authors.lastname: Peddareddigari
authors.affiliation: Novartis Pharmaceuticals Corporation, Wayne, Pennsylvania.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: D'Amelio
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors.forename: George
authors.initials: G
authors.lastname: Blumenschein
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000556:secondary; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018287:Carcinoma, Large Cell / Q000188:drug therapy* / Q000556:secondary; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000556:secondary; D000077143:Docetaxel; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D000068437:Pemetrexed / Q000008:administration & dosage; D011379:Prognosis; D011728:Pyridones / Q000008:administration & dosage; D011744:Pyrimidinones / Q000008:administration & dosage; D015996:Survival Rate; D043823:Taxoids / Q000008:administration & dosage
chemical_list: D011728:Pyridones; D011744:Pyrimidinones; D043823:Taxoids; D000068437:Pemetrexed; D000077143:Docetaxel; C560077:trametinib
keywords: KRAS mutations; MEK inhibitor; NSCLC; Trametinib