title: Randomized Phase 2 Trial of Pharmacodynamic Separation of Pemetrexed and Intercalated Erlotinib Versus Pemetrexed Alone for Advanced Nonsquamous, Non-small-cell Lung Cancer.
abstract: Pharmacodynamic separation of pemetrexed and erlotinib avoids negative cellular interactions and results in antitumor synergy in erlotinib-resistant non-small-cell lung cancer (NSCLC) cells, independent of EGFR (epidermal growth factor receptor) genotype.
  
  
  
  Patients with platinum-treated metastatic nonsquamous NSCLC were randomly assigned 1:2 to pemetrexed alone (500 mg/m2provided intravenously on day 1) or pemetrexed followed by erlotinib (150 mg provided orally once daily on days 2-17) every 21 days. EGFR genotype was centrally confirmed by Sequenom multiplex oncogenotyping assay. The primary end point was progression-free survival (PFS), which would be considered promising for future study if median PFS was ≥ 4.5 months.
  
  
  
  Of 83 patients enrolled, 79 were randomized to either pemetrexed alone (n = 27) or in combination (n = 52). Fifty-nine (79%) of 75 eligible patients had tumors with confirmed EGFR genotype: 7 with activating mutations and 52 wild type. Median PFS was 4.7 and 2.9 months in the combination and pemetrexed-alone groups, respectively. In patients with EGFR wild-type tumors, median PFS was 5.3 and 3.5 months in the combination and pemetrexed-alone groups, respectively. Objective response rate (29% vs. 10%, P = .17), 6-month PFS (45% vs. 29%, P = .26), and 12-month PFS (23% vs. 10%, P = .28) were all higher in the combination arm. Rash (67% vs. 26%, P = .0007) and diarrhea (44% vs. 11%, P = .003) were significantly more common in the combination arm.
  
  
  
  In patients with unselected or EGFR wild-type advanced nonsquamous NSCLC, pharmacodynamic separation of pemetrexed and intercalated erlotinib had promising antitumor activity without new safety concerns. The combination merits further evaluation as maintenance or second-line therapy against new standards in patients with EGFR wild-type advanced NSCLC.
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, CA; Veterans Affairs Northern California Health Care System, Mather, CA. Electronic address: thli@ucdavis.edu.
authors.forename: Tianhong
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Oncology, Albert Einstein College of Medicine, Bronx, NY.
authors.forename: Bilal
authors.initials: B
authors.lastname: Piperdi
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, University of Massachusetts Medical School-Cancer Center of Excellence, Worcester, MA.
authors.forename: William V
authors.initials: WV
authors.lastname: Walsh
authors.affiliation: Department of Epidemiology, Albert Einstein College of Medicine, Bronx, NY.
authors.forename: Mimi
authors.initials: M
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, CA; Department of Public Health Sciences, University of California, Davis, Davis, CA.
authors.forename: Laurel A
authors.initials: LA
authors.lastname: Beckett
authors.affiliation: Department of Oncology, Albert Einstein College of Medicine, Bronx, NY.
authors.forename: Rasim
authors.initials: R
authors.lastname: Gucalp
authors.affiliation: Department of Oncology, Albert Einstein College of Medicine, Bronx, NY.
authors.forename: Missak
authors.initials: M
authors.lastname: Haigentz
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, University of Massachusetts Medical School-Cancer Center of Excellence, Worcester, MA.
authors.forename: Venu G
authors.initials: VG
authors.lastname: Bathini
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, CA.
authors.forename: Huiyu
authors.initials: H
authors.lastname: Wen
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, CA.
authors.forename: Kaili
authors.initials: K
authors.lastname: Zhou
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, CA.
authors.forename: Patricia B
authors.initials: PB
authors.lastname: Pasquinelli
authors.affiliation: Department of Oncology, Albert Einstein College of Medicine, Bronx, NY.
authors.forename: Srikanth
authors.initials: S
authors.lastname: Gajavelli
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, University of Massachusetts Medical School-Cancer Center of Excellence, Worcester, MA.
authors.forename: Meera
authors.initials: M
authors.lastname: Sreedhara
authors.affiliation: Department of Epidemiology, Albert Einstein College of Medicine, Bronx, NY.
authors.forename: Xianhong
authors.initials: X
authors.lastname: Xie
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, CA.
authors.forename: Primo N
authors.initials: PN
authors.lastname: Lara
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, CA.
authors.forename: David R
authors.initials: DR
authors.lastname: Gandara
authors.affiliation: Department of Oncology, Albert Einstein College of Medicine, Bronx, NY.
authors.forename: Roman
authors.initials: R
authors.lastname: Perez-Soler
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009367:Neoplasm Staging; D000068437:Pemetrexed / Q000008:administration & dosage; D011379:Prognosis; D015996:Survival Rate
chemical_list: D000068437:Pemetrexed; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: EGFR wild type; Multiplex genotyping; Plasma circulating tumor DNA; Randomized phase 2 study; Second line