title: Erlotinib and gefitinib for treating non-small cell lung cancer that has progressed following prior chemotherapy (review of NICE technology appraisals 162 and 175): a systematic review and economic evaluation.
abstract: BACKGROUND
  Lung cancer is the second most diagnosed cancer in the UK. Over 70% of lung cancers are non-small cell lung cancers (NSCLCs). Patients with stage III or IV NSCLC may be offered treatment to improve survival, disease control and quality of life. One-third of these patients receive further treatment following disease progression; these treatments are the focus of this systematic review.
  
  
  OBJECTIVE
  To appraise the clinical effectiveness and cost-effectiveness of erlotinib [Tarceva(®), Roche (UK) Ltd] and gefitinib (IRESSA(®), AstraZeneca) compared with each other, docetaxel or best supportive care (BSC) for the treatment of NSCLC after disease progression following prior chemotherapy. The effectiveness of treatment with gefitinib was considered only for patients with epidermal growth factor mutation-positive (EGFR M+) disease.
  
  
  METHODS
  Four electronic databases (EMBASE, MEDLINE, The Cochrane Library, PubMed) were searched for randomised controlled trials (RCTs) and economic evaluations. Manufacturers' evidence submissions to the National Institute for Health and Care Excellence were also considered.
  
  
  METHODS
  Outcomes for three distinct patient groups based on EGFR mutation status [EGFR M+, epidermal growth factor mutation negative (EGFR M-) and epidermal growth factor mutation status unknown (EGFR unknown)] were considered. Heterogeneity of the data precluded statistical analysis. A de novo economic model was developed to compare treatments (incremental cost per quality-adjusted life-year gained).
  
  
  RESULTS
  Twelve trials were included in the review. The use of gefitinib was compared with chemotherapy (n = 6) or BSC (n = 1), and the use of erlotinib was compared with chemotherapy (n = 3) or BSC (n = 1). One trial compared the use of gefitinib with the use of erlotinib. No trials included solely EGFR M+ patients; all data were derived from retrospective subgroup analyses from six RCTs [Kim ST, Uhm JE, Lee J, Sun JM, Sohn I, Kim SW, et al. Randomized phase II study of gefitinib versus erlotinib in patients with advanced non-small cell lung cancer who failed previous chemotherapy. Lung Cancer 2012;75:82-8, V-15-32, Tarceva In Treatment of Advanced NSCLC (TITAN), BR.21, IRESSA Survival Evaluation in Lung cancer (ISEL) and IRESSA NSCLC Trial Evaluating REsponse and Survival versus Taxotere (INTEREST)]. These limited data precluded conclusions regarding the clinical effectiveness of any treatment for EGFR M+ patients. For EGFR M- patients, data were derived from the TArceva Italian Lung Optimization tRial (TAILOR) trial and Docetaxel and Erlotinib Lung Cancer Trial (DELTA). Retrospective data were also derived from subgroup analyses of BR.21, Kim et al., TITAN, INTEREST and ISEL. The only statistically significant reported results were for progression-free survival (PFS) for TAILOR and DELTA, and favoured docetaxel over erlotinib [TAILOR hazard ratio (HR) 1.39, 95% confidence interval (CI) 1.06 to 1.82; DELTA HR 1.44, 95% CI 1.08 to 1.92]. In EGFR unknown patients, nine trials (INTEREST, IRESSA as Second-line Therapy in Advanced NSCLC - KoreA, Li, Second-line Indication of Gefitinib in NSCLC, V-15-32, ISEL, DELTA, TITAN and BR.21) reported overall survival data and only one (BR.21) reported a statistically significant result favouring the use of erlotinib over BSC (HR 0.7, 95% CI 0.58 to 0.85). For PFS, BR.21 favoured the use of erlotinib when compared with BSC (HR 0.61, 95% CI 0.51 to 0.74) and the use of gefitinib was favoured when compared with BSC (HR 0.82, 95% CI 0.73 to 0.92) in ISEL. Limitations in the clinical data precluded assessment of cost-effectiveness of treatments for an EGFR M+ population by the Assessment Group (AG). The AG's economic model suggested that for the EGFR M- population, the use of erlotinib was not cost-effective compared with the use of docetaxel and compared with BSC. For EGFR unknown patients, the use of erlotinib was not cost-effective when compared with BSC.
  The lack of clinical data available for distinct patient populations limited the conclusions of the assessment. Future trials should distinguish between patients with EGFR M+ and EGFR M- disease.
  
  
  BACKGROUND
  The National Institute for Health Research Health Technology Assessment programme.
authors.affiliation: Liverpool Reviews and Implementation Group, University of Liverpool, Liverpool, UK.
authors.forename: Janette
authors.initials: J
authors.lastname: Greenhalgh
authors.affiliation: Liverpool Reviews and Implementation Group, University of Liverpool, Liverpool, UK.
authors.forename: Adrian
authors.initials: A
authors.lastname: Bagust
authors.affiliation: Liverpool Reviews and Implementation Group, University of Liverpool, Liverpool, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Boland
authors.affiliation: Liverpool Reviews and Implementation Group, University of Liverpool, Liverpool, UK.
authors.forename: Kerry
authors.initials: K
authors.lastname: Dwan
authors.affiliation: Liverpool Reviews and Implementation Group, University of Liverpool, Liverpool, UK.
authors.forename: Sophie
authors.initials: S
authors.lastname: Beale
authors.affiliation: Liverpool Reviews and Implementation Group, University of Liverpool, Liverpool, UK.
authors.forename: Juliet
authors.initials: J
authors.lastname: Hockenhull
authors.affiliation: North West Medicines Information Centre, Pharmacy Practice Unit, Liverpool, UK.
authors.forename: Christine
authors.initials: C
authors.lastname: Proudlove
authors.affiliation: Liverpool Reviews and Implementation Group, University of Liverpool, Liverpool, UK.
authors.forename: Yenal
authors.initials: Y
authors.lastname: Dundar
authors.affiliation: Liverpool Reviews and Implementation Group, University of Liverpool, Liverpool, UK.
authors.forename: Marty
authors.initials: M
authors.lastname: Richardson
authors.affiliation: Liverpool Reviews and Implementation Group, University of Liverpool, Liverpool, UK.
authors.forename: Rumona
authors.initials: R
authors.lastname: Dickson
authors.affiliation: The Clatterbridge Centre NHS Foundation Trust, Liverpool, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Mullard
authors.affiliation: The Clatterbridge Centre NHS Foundation Trust, Liverpool, UK.
authors.forename: Ernie
authors.initials: E
authors.lastname: Marshall
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D003362:Cost-Benefit Analysis; D018572:Disease-Free Survival; D000069347:Erlotinib Hydrochloride / Q000009:adverse effects / Q000191:economics* / Q000627:therapeutic use*; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011788:Quality of Life; D019057:Quality-Adjusted Life Years; D011799:Quinazolines / Q000009:adverse effects / Q000191:economics* / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib