title: Randomized Phase II Trial of Erlotinib Beyond Progression in Advanced Erlotinib-Responsive Non-Small Cell Lung Cancer.
abstract: BACKGROUND
  Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy is clearly beneficial in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). However, acquired resistance develops uniformly and the benefit of continuation of EGFR TKI therapy beyond progression remains unclear.
  
  
  METHODS
  This was a randomized phase II study of chemotherapy (arm A: pemetrexed or docetaxel) versus chemotherapy plus erlotinib (ERL) (arm B) in patients with progressive NSCLC following clinical benefit from erlotinib. In arm B, chemotherapy was given with erlotinib at an oral daily dose of 150 mg on days 2-19 of each cycle to minimize negative pharmacodynamic interactions. The primary endpoint was that continuation of erlotinib in this patient population could extend progression-free survival (PFS) by 50%.
  
  
  RESULTS
  A total of 46 patients were randomized (arm A: 24; arm B: 22). Patient characteristics were well balanced except there were more female patients in arm A (p = .075). The median PFS of patients in arm A was 5.5 months and for those in arm B, 4.4 months (p = .699). The response rates were 13% and 16% in arms A and B, respectively (p = .79). EGFR status data were available for 39 of the 46 patients and no significant difference in PFS was seen for continuing ERL beyond progression in mutation-positive patients. Substantially more toxicity was seen in arm B than arm A.
  
  
  CONCLUSIONS
  There was added toxicity but no benefit with the continuation of ERL beyond progression along with chemotherapy as compared with chemotherapy alone.
  
  
  CONCLUSIONS
  The benefits of continuing erlotinib upon progression alongside conventional chemotherapy are unclear. This randomized phase II study, initiated prior to the establishment of routine epidermal growth factor receptor (EGFR) mutation testing, addressed this clinically relevant issue through randomizing patients with prior clinical benefit from erlotinib (thereby enriching for EGFR-mutated tumors) upon progression in the second- or third-line setting to conventional chemotherapy (single-agent pemetrexed or docetaxel) with or without continued erlotinib. The results showed no benefit to continuing erlotinib beyond progression, while significantly more side effects were noted in the combination arm. Along with other recently presented study findings, these results argue against the routine practice of continuing erlotinib in this setting.
authors: Division of Hematology/Oncology, Herbert Irving Comprehensive Cancer Center, New York Presbyterian Hospital-Columbia University Medical Center, New York, New York, USA axd44@case.edu bahalmos@montefiore.org.
authors: Balazs
authors: B
authors: Halmos
authors: Cleveland Clinic Foundation, Taussig Cancer Center, Cleveland, Ohio, USA.
authors: Nathan A
authors: NA
authors: Pennell
authors: Case Western Reserve University, Cleveland, Ohio, USA.
authors: Pingfu
authors: P
authors: Fu
authors: Columbia University Medical Center, New York, New York, USA.
authors: Shumaila
authors: S
authors: Saad
authors: Wayne State University, Detroit, Michigan, USA.
authors: Shirish
authors: S
authors: Gadgeel
authors: Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.
authors: Gregory A
authors: GA
authors: Otterson
authors: Florida Hospital Cancer Institute, Orlando, Florida, USA.
authors: Tarek
authors: T
authors: Mekhail
authors: Department of Oncology, Metrohealth Medical Center, Cleveland, Ohio, USA.
authors: Michael
authors: M
authors: Snell
authors: Riverside Methodist Hospital, Columbus, Ohio, USA.
authors: J Philip
authors: JP
authors: Kuebler
authors: Case Medical Center, Cleveland, Ohio, USA.
authors: Neelesh
authors: N
authors: Sharma
authors: Case Medical Center, Cleveland, Ohio, USA axd44@case.edu bahalmos@montefiore.org.
authors: Afshin
authors: A
authors: Dowlati
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000068437:Pemetrexed / Q000008:administration & dosage; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D043823:Taxoids / Q000008:administration & dosage
chemical_list: D047428:Protein Kinase Inhibitors; D043823:Taxoids; D000068437:Pemetrexed; D000077143:Docetaxel; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Epidermal growth factor receptor; Erlotinib; Non-small cell lung cancer; Tyrosine kinase inhibitor