Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations.

PURPOSE The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and ErbB4 and has wide-spectrum preclinical activity against EGFR mutations. A phase II study of afatinib in EGFR mutation-positive lung adenocarcinoma demonstrated high response rates and progression-free survival (PFS). PATIENTS AND METHODS In this phase III study, eligible patients with stage IIIB/IV lung adenocarcinoma were screened for EGFR mutations. Mutation-positive patients were stratified by mutation type (exon 19 deletion, L858R, or other) and race (Asian or non-Asian) before two-to-one random assignment to 40 mg afatinib per day or up to six cycles of cisplatin plus pemetrexed chemotherapy at standard doses every 21 days. The primary end point was PFS by independent review. Secondary end points included tumor response, overall survival, adverse events, and patient-reported outcomes (PROs). RESULTS A total of 1,269 patients were screened, and 345 were randomly assigned to treatment. Median PFS was 11.1 months for afatinib and 6.9 months for chemotherapy (hazard ratio [HR], 0.58; 95% CI, 0.43 to 0.78; P = .001). Median PFS among those with exon 19 deletions and L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = .001). The most common treatment-related adverse events were diarrhea, rash/acne, and stomatitis for afatinib and nausea, fatigue, and decreased appetite for chemotherapy. PROs favored afatinib, with better control of cough, dyspnea, and pain. CONCLUSION Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations.

[1]  Ross Camidge,et al.  The European Organisation for Research and Treatment of Cancer , 2002 .

[2]  C. Klein,et al.  Target Binding Properties and Cellular Activity of Afatinib (BIBW 2992), an Irreversible ErbB Family Blocker , 2012, Journal of Pharmacology and Experimental Therapeutics.

[3]  D. Osoba,et al.  Interpreting the significance of changes in health-related quality-of-life scores. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  L. Tanoue,et al.  Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma , 2010 .

[5]  M. Meyerson,et al.  EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. , 2005, The New England journal of medicine.

[6]  Yi-long Wu,et al.  Relative abundance of EGFR mutations predicts benefit from gefitinib treatment for advanced non-small-cell lung cancer. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  Jun Ma,et al.  Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. , 2011, The Lancet. Oncology.

[8]  S. Kaasa,et al.  The EORTC QLQ-LC13: a modular supplement to the EORTC Core Quality of Life Questionnaire (QLQ-C30) for use in lung cancer clinical trials. EORTC Study Group on Quality of Life. , 1994, European journal of cancer.

[9]  K Al-Saleh,et al.  Role of pemetrexed in advanced non-small-cell lung cancer: meta-analysis of randomized controlled trials, with histology subgroup analysis. , 2012, Current oncology.

[10]  E. McFadden,et al.  Toxicity and response criteria of the Eastern Cooperative Oncology Group , 1982, American journal of clinical oncology.

[11]  Daniel A. Haber,et al.  Epidermal growth factor receptor mutations in lung cancer , 2007, Nature Reviews Cancer.

[12]  Miklos Pless,et al.  Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  Johan Vansteenkiste,et al.  Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  S. Toyooka,et al.  Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. , 2010, The Lancet. Oncology.

[15]  G. Scagliotti,et al.  The differential efficacy of pemetrexed according to NSCLC histology: a review of two Phase III studies. , 2009, The oncologist.

[16]  S. Digumarthy,et al.  Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors , 2011, Science Translational Medicine.

[17]  L. Tanoue,et al.  Erlotinib in Previously Treated Non-Small-Cell Lung Cancer , 2007 .

[18]  L. Tanoue Gefitinib or Chemotherapy for Non–Small-Cell Lung Cancer with Mutated EGFR , 2011 .

[19]  L. Tanoue,et al.  Detection of Mutations in EGFR in Circulating Lung-Cancer Cells , 2010 .

[20]  C. Gridelli,et al.  Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. , 2012, The Lancet. Oncology.

[21]  H. Varmus,et al.  Acquired Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib Is Associated with a Second Mutation in the EGFR Kinase Domain , 2005, PLoS medicine.

[22]  Andrew Bottomley,et al.  EORTC QLQ-C30 Scoring Manual , 1995 .

[23]  L. Sequist,et al.  Symptom control and quality of life in LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  A. Gazdar,et al.  Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors , 2009, Oncogene.

[25]  Anne Fleissig,et al.  The value of progression-free survival to patients with advanced-stage cancer , 2012, Nature Reviews Clinical Oncology.

[26]  Robert Gray,et al.  Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. , 2006, The New England journal of medicine.

[27]  J. Shih,et al.  Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. , 2012, The Lancet. Oncology.

[28]  E. Felip,et al.  Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. , 2012, The Lancet. Oncology.

[29]  M. Okada,et al.  [New response evaluation criteria in solid tumours-revised RECIST guideline (version 1.1)]. , 2009, Gan to kagaku ryoho. Cancer & chemotherapy.

[30]  J. Mate,et al.  Pretreatment EGFR T790M Mutation and BRCA1 mRNA Expression in Erlotinib-Treated Advanced Non–Small-Cell Lung Cancer Patients with EGFR Mutations , 2011, Clinical Cancer Research.

[31]  Yan Sun,et al.  Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. , 2012, The Lancet. Oncology.

[32]  Kevin Carroll,et al.  Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer) , 2005, The Lancet.

[33]  Sung-Liang Yu,et al.  Pretreatment epidermal growth factor receptor (EGFR) T790M mutation predicts shorter EGFR tyrosine kinase inhibitor response duration in patients with non-small-cell lung cancer. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[34]  M. Meyerson,et al.  BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models , 2008, Oncogene.

[35]  M. Ladanyi,et al.  Integration of Molecular Profiling into the Lung Cancer Clinic , 2009, Clinical Cancer Research.