4.1. Search Strategy

The search for relevant articles was conducted by querying PubMed/MEDLINE and Embase, according to the PRISMA guidelines. Articles published since inception until 31 May 2019 were evaluated for inclusion in the systematic review. Abstracts and presentations from ASCO (American Society of Clinical Oncology) and ESMO (European Society of Medical Oncology) from 2010 until 2019 were also reviewed.

The search terms included the following keywords: “EGFR-TKI”, “epidermal growth factor receptor-tyrosine kinase inhibitor”, “gefitinib”, “erlotinib”, “icotinib”, “dacomitinib”, “osimertinib”, “afatinib”.

We also reviewed the references of articles finally included in this meta-analysis. When duplicate publications were found, the most updated data were considered.

We included all articles reporting about phase II and III randomized control clinical trials conducted in patients with non-small cell lung cancer randomized to EGFR-TKI vs. any other treatment. Eligible articles were required to report subgroup analysis in EGFR-mutated patients of progression-free survival (PFS) (or disease-free survival (DFS) in trials conducted in the adjuvant setting) and/or overall survival (OS) by at least one of the following seven variables categorized as specified here: gender (male vs. female), age (<65 vs. ≥65 years old), ethnicity (Asian vs. non-Asian), smoking habit (current vs. never smoker), brain metastasis (presence vs. absence), type of EGFR mutation (exon 19 mutation vs. L858R mutation), ECOG PS (0 vs. 1). We also included trials comparing third-generation (osimertinib) and second-generation (dacomitinib, afatinib) EGFR-TKIs vs. first-generation EGFR-TKIs (erlotinib, gefitinib, icotinib).

Subgroups of RCTs were identified by considering the EGFR-TKI generation of the interventional arm (first vs. second vs. third EGFR-TKI generation), type of control arm (first-generation EGFR-TKI vs. other), setting (adjuvant vs. first line vs. second/later lines of therapy).