Improvement in Overall Survival in a Randomized Study That Compared Dacomitinib With Gefitinib in Patients With Advanced Non-Small-Cell Lung Cancer and EGFR-Activating Mutations.

Purpose ARCHER 1050, a randomized, open-label, phase III study of dacomitinib versus gefitinib in treatment-naïve patients with advanced non-small-cell lung cancer (NSCLC) and activating mutations in EGFR, reported significant improvement in progression-free survival with dacomitinib. The mature overall survival (OS) analysis for the intention-to-treat population is presented here. Patients and Methods In this multinational, multicenter study, patients age 18 years or older (≥ 20 years in Japan and Korea) who had an Eastern Cooperative Oncology Group performance status of 0 or 1 and newly diagnosed NSCLC with activating mutations in EGFR (exon 19 deletion or exon 21 L858R) were enrolled and randomly assigned in a 1:1 manner to dacomitinib (n = 227) or gefitinib (n = 225). Random assignment was stratified by race (Japanese, Chinese, other East Asian, or non-Asian) and EGFR mutation type. The final OS analysis was conducted with a data cutoff date of February 17, 2017; at that time 220 deaths (48.7%) were observed. Results During a median follow-up time of 31.3 months, 103 (45.4%) and 117 (52.0%) deaths occurred in the dacomitinib and gefitinib arms, respectively. The estimated hazard ratio for OS was 0.760 (95% CI, 0.582 to 0.993; two-sided P = .044). The median OS was 34.1 months with dacomitinib versus 26.8 months with gefitinib. The OS probabilities at 30 months were 56.2% and 46.3% with dacomitinib and gefitinib, respectively. Preliminary subgroup analyses for OS that are based on baseline characteristics were consistent with the primary OS analysis. Conclusion In patients with advanced NSCLC and EGFR activating mutations, dacomitinib is the first second-generation epidermal growth factor receptor tyrosine kinase inhibitor (TKI) to show significant improvement in OS in a phase III randomized study compared with a standard-of-care TKI. Dacomitinib should be considered one of the standard treatment options for these patients.

[1]  A. Gemma,et al.  F1000 highlights , 2010 .

[2]  K. O'Byrne,et al.  Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial. , 2017, Annals of oncology : official journal of the European Society for Medical Oncology.

[3]  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.

[4]  R. Doebele,et al.  Exploratory analysis of the association of depth of response and survival in patients with metastatic non-small-cell lung cancer treated with a targeted therapy or immunotherapy. , 2017, Annals of oncology : official journal of the European Society for Medical Oncology.

[5]  K. O'Byrne,et al.  Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial , 2016, Annals of oncology : official journal of the European Society for Medical Oncology.

[6]  Ying Cheng,et al.  Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. , 2017, The Lancet. Oncology.

[7]  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.

[8]  P. Jänne,et al.  AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. , 2015, The New England journal of medicine.

[9]  Yi-long Wu,et al.  A phase III randomised controlled trial of erlotinib vs gefitinib in advanced non-small cell lung cancer with EGFR mutations , 2017, British Journal of Cancer.

[10]  R. Doebele,et al.  Exploratory analysis of the association of depth of response and survival in patients with metastatic non-small-cell lung cancer treated with a targeted therapy or immunotherapy. , 2019, Annals of oncology : official journal of the European Society for Medical Oncology.

[11]  Ying Cheng,et al.  Osimertinib in Untreated EGFR‐Mutated Advanced Non–Small‐Cell Lung Cancer , 2018, The New England journal of medicine.

[12]  M. Meyerson,et al.  PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. , 2007, Cancer research.

[13]  C. Paweletz,et al.  Dacomitinib as first-line treatment in patients with clinically or molecularly selected advanced non-small-cell lung cancer: a multicentre, open-label, phase 2 trial. , 2014, The Lancet. Oncology.

[14]  William Pao,et al.  Analysis of Tumor Specimens at the Time of Acquired Resistance to EGFR-TKI Therapy in 155 Patients with EGFR-Mutant Lung Cancers , 2013, Clinical Cancer Research.

[15]  A. Gemma,et al.  Low-Dose Gefitinib Treatment for Patients with Advanced Non-small Cell Lung Cancer Harboring Sensitive Epidermal Growth Factor Receptor Mutations , 2011, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[16]  L. Sequist,et al.  Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. , 2015, The Lancet. Oncology.

[17]  Sean Khozin,et al.  Overall response rate, progression-free survival, and overall survival with targeted and standard therapies in advanced non-small-cell lung cancer: US Food and Drug Administration trial-level and patient-level analyses. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  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.

[19]  T. Mok,et al.  Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. , 2009, The New England journal of medicine.

[20]  K. O'Byrne,et al.  Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. , 2016, The Lancet. Oncology.

[21]  William Pao,et al.  Acquired Resistance to EGFR Tyrosine Kinase Inhibitors in EGFR-Mutant Lung Cancer: Distinct Natural History of Patients with Tumors Harboring the T790M Mutation , 2010, Clinical Cancer Research.