title: Intercalated Chemotherapy and Epidermal Growth Factor Receptor Inhibitors for Patients With Advanced Non-Small-cell Lung Cancer: A Systematic Review and Meta-analysis.
abstract: Randomized clinical trials (RCTs) of concurrent epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) plus chemotherapy for unselected patients with advanced non-small-cell lung cancer (NSCLC) produced negative results. Intercalated administration could avoid the reduction of chemotherapy activity due to G1cell-cycle arrest from EGFR-TKIs. A PubMed search was performed in December 2015 and updated in February 2016. The references from the selected studies were also checked to identify additional eligible trials. Furthermore, the proceedings of the main international meetings were searched from 2010 onward. We included RCTs comparing chemotherapy intercalated with an EGFR-TKI versus chemotherapy alone for patients with advanced NSCLC. Ten RCTs were eligible (6 with erlotinib, 4 with gefitinib): 39% of patients had a known EGFR mutational status, 43% of whom EGFR mutation positive. The intercalated combination was associated with a significant improvement in overall survival (OS; hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.71-0.95; P = .01), progression-free survival (PFS; HR, 0.60; 95% CI, 0.53-0.68; P < .00001), and objective response rate (ORR; odds ratio [OR], 2.70; 95% CI, 2.08-3.49; P < .00001). Considering only first-line trials, similar differences were found in OS (HR, 0.85; 95% CI, 0.72-1.00; P = .05), PFS (HR, 0.63; 95% CI, 0.55-0.73; P < .00001), and ORR (OR, 2.21; 95% CI, 1.65-2.95; P < .00001). In EGFR mutation-positive patients, the addition of an intercalated EGFR-TKI produced a significant benefit in PFS (129 patients; HR, 0.24; 95% CI, 0.16-0.37; P < .00001) and ORR (168 patients; OR, 11.59; 95% CI, 5.54-24.25; P < .00001). In patients with advanced NSCLC, chemotherapy plus intercalated EGFR-TKIs was superior to chemotherapy alone, although a definitive interpretation was jeopardized by the variable proportion of patients with EGFR mutation-positive tumors included.
authors.affiliation: Department of Oncology, University of Turin, "San Luigi Gonzaga" Hospital, Orbassano, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: La Salvia
authors.affiliation: Division of Medical Oncology, "S. G. Moscati" Hospital, Avellino, Italy. Electronic address: arossi_it@yahoo.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rossi
authors.affiliation: Medical Oncology Department, Clinical Cancer Center Giovanni Paolo II, Bari, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Galetta
authors.affiliation: Department of Oncology, University of Turin, "San Luigi Gonzaga" Hospital, Orbassano, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Gobbini
authors.affiliation: Department of Oncology, University of Turin, "San Luigi Gonzaga" Hospital, Orbassano, Italy.
authors.forename: Emmanuele
authors.initials: E
authors.lastname: De Luca
authors.affiliation: Department of Oncology, University of Turin, "San Luigi Gonzaga" Hospital, Orbassano, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Novello
authors.affiliation: Department of Oncology, University of Turin, "San Luigi Gonzaga" Hospital, Orbassano, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Di Maio
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D011379:Prognosis; D047428:Protein Kinase Inhibitors
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Afatinib; Erlotinib; Gefitinib; Mutation; NSCLC