Intercalated combination of chemotherapy and epidermal growth factor receptor inhibitors for patients with advanced non-small-cell lung cancer: A systematic review and meta-analysis

Abstract

Background: Trials investigating the efficacy of EGFR-tyrosine kinase inhibitors (TKIs) in combination with chemotherapy in unselected patients with advanced non-small-cell lung cancer (NSCLC) showed negative results. Preclinical data suggest that the intercalated administration could be effective. The aim of our study was to perform a systematic review and meta-analysis of randomized trials (RCTs) testing the addition of intercalated EGFR-TKIs to chemotherapy in patients with advanced NSCLC. Methods: A systematic review of articles published or presented at major meetings was performed in December 2015. RCTs comparing CT + intercalated EGFR TKI vs. CT alone in pts with advanced NSCLC were included. The primary outcome measure was overall survival (OS); secondary outcomes were progression-free survival (PFS), objective response rate (ORR) and toxicity. Results: 9 RCTs were eligible (5 with erlotinib, 4 with gefitinib): 37% of patients had known EGFR mutational status, and 46% were EGFR mutation-positive. Intercalated combination was associated with a significant improvement in OS (Hazard Ratio [HR] 0.83, 95%CI 0.72-0.97, p = 0.02), PFS (HR 0.60, 95%CI 0.53-0.68, p < 0.00001) and ORR (Odds Ratio [OR] 2.69, 95%CI 2.07-3.50, p < 0.00001). Addition of EGFR-TKI produced a significant increase in skin rash (OR 4.60, 95%CI 3.46-6.11, p < 0.0001) and diarrhea (OR 2.73, 95%CI 1.93-3.87, p < 0.0001). Considering only first-line trials, similar differences were shown in OS (HR 0.85, 95%CI 0.72-1.00, p = 0.05), PFS (HR 0.63, 95%CI 0.55-0.73, p < 0.00001), ORR (OR 2.21, 95%CI 1.65-2.95, p < 0.00001). In EGFR mutated patients, addition of intercalated EGFR-TKI produced a significant benefit in PFS (HR 0.24, 95%CI 0.16-0.37, p < 0.00001) and ORR (OR 11.59, 95%CI 5.54-24.25, p < 0.00001). Conclusions: The addition of intercalated EGFR-TKI to chemotherapy is associated with a significant benefit in OS, PFS and objective response rate in patients with advanced NSCLC, although a definitive interpretation is jeopardized by the variable proportion of patients with EGFR mutation-positive tumors included.