title: Phase 1 study of twice weekly pulse dose and daily low-dose erlotinib as initial treatment for patients with EGFR-mutant lung cancers.
abstract: Patients with EGFR-mutant lung cancers treated with EGFR tyrosine kinase inhibitors (TKIs) develop clinical resistance, most commonly with acquisition of EGFR T790M. Evolutionary modeling suggests that a schedule of twice weekly pulse and daily low-dose erlotinib may delay emergence of EGFR T790M. Pulse dose erlotinib has superior central nervous system (CNS) penetration and may result in superior CNS disease control.
  
  
  
  We evaluated toxicity, pharmacokinetics, and efficacy of twice weekly pulse and daily low-dose erlotinib. We assessed six escalating pulse doses of erlotinib.
  
  
  
  We enrolled 34 patients; 11 patients (32%) had brain metastases at study entry. We observed 3 dose-limiting toxicities in dose escalation: transaminitis, mucositis, and rash. The MTD was erlotinib 1200 mg days 1-2 and 50 mg days 3-7 weekly. The most frequent toxicities (any grade) were rash, diarrhea, nausea, fatigue, and mucositis. 1 complete and 24 partial responses were observed (74%, 95% CI 60-84%). Median progression-free survival was 9.9 months (95% CI 5.8-15.4 months). No patient had progression of an untreated CNS metastasis or developed a new CNS lesion while on study (0%, 95% CI 0-13%). Of the 18 patients with biopsies at progression, EGFR T790M was identified in 78% (95% CI 54-91%).
  
  
  
  This is the first clinical implementation of an anti-cancer TKI regimen combining pulse and daily low-dose administration. This evolutionary modeling-based dosing schedule was well-tolerated but did not improve progression-free survival or prevent emergence of EGFR T790M, likely due to insufficient peak serum concentrations of erlotinib. This dosing schedule prevented progression of untreated or any new central nervous system metastases in all patients.
authors.affiliation: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York.|Weill Cornell Medical College, New York.
authors.forename: H A
authors.initials: HA
authors.lastname: Yu
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York.
authors.forename: C
authors.initials: C
authors.lastname: Sima
authors.affiliation: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York.
authors.forename: D
authors.initials: D
authors.lastname: Feldman
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute.|Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA.
authors.forename: L L
authors.initials: LL
authors.lastname: Liu
authors.affiliation: Donald B. and Catherine C. Marron Cancer Metabolism Center, Sloan Kettering Institute, Sloan Kettering Cancer Center, New York.
authors.forename: B
authors.initials: B
authors.lastname: Vaitheesvaran
authors.affiliation: Donald B. and Catherine C. Marron Cancer Metabolism Center, Sloan Kettering Institute, Sloan Kettering Cancer Center, New York.
authors.forename: J
authors.initials: J
authors.lastname: Cross
authors.affiliation: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York.|Weill Cornell Medical College, New York.
authors.forename: C M
authors.initials: CM
authors.lastname: Rudin
authors.affiliation: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York.|Weill Cornell Medical College, New York.
authors.forename: M G
authors.initials: MG
authors.lastname: Kris
authors.affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, TN.
authors.forename: W
authors.initials: W
authors.lastname: Pao
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute.|Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA.
authors.forename: F
authors.initials: F
authors.lastname: Michor
authors.affiliation: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York.|Weill Cornell Medical College, New York.
authors.forename: G J
authors.initials: GJ
authors.lastname: Riely
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D066246:ErbB Receptors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D020125:Mutation, Missense; D020551:Pulse Therapy, Drug
chemical_list: D000970:Antineoplastic Agents; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: EGFR T790M; EGFR-mutant lung cancer; acquired resistance; evolutionary modeling; pulse dose erlotinib