According to GLOBOCAN 2020, lung cancer is the second most common cancer and the leading cause of cancer-related death worldwide [
1]. Non–small cell lung cancer (NSCLC) accounts for nearly 85% of primary lung cancer cases. NSCLC ‘tends to metastasize at early stages so that up to 35% of NSCLC patients present with
de novo brain metastasis [
2]. Brain metastasis is the major cause of morbidity and mortality in NSCLC patients. Treatment of brain metastasis is a great challenge as the blood-brain barrier (BBB) prevents the entry of most chemotherapeutics into the brain.
Recent advances in molecular oncology have improved our understanding of genetic and epigenetic regulations of NSCLC tumorigenesis and cell survival [
3]. Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein receptor with an intracellular tyrosine kinase component implicated in cell proliferation and survival regulations. The current evidence shows the significant involvement of EGFR overexpression in developing several malignancies, including NSCLC [
4]. The frequency of EGFR mutations in NSCLC cases shows substantial ethnic and geographical disparity, with the highest prevalence observed among patients from the Asia-Pacific region (range 20–76%). In Taiwan, the frequency of EGFR mutations was estimated to be as high as 76% amongst NSCLC cases [
5]. Both deletion within exon 19 (ex19del) and leucine to arginine substitution mutation in exon 21 (Leu858Arg) account for nearly 90% of EGFR mutations in NSCLC patients [
6]. These activating EGFR mutations are responsive to small-molecule EGFR tyrosine kinase inhibitors (TKIs) [
6,
7].
Clinical trials and real-world evidence have established the efficacy of afatinib, a second-generation EGFR-TKI, as the first-line treatment of choice for EGFR mut
+ mNSCLC patients [
8]. Afatinib is a second-generation EGFR-TKI that irreversibly blocks the ErbB family of protein-tyrosine kinases. Clinical evidence demonstrated that afatinib can pass the BBB [
9]. Two landmark randomized controlled trials (RCTs) (LUX-Lung 3 and Lux-Lung 6) demonstrated a significant improvement in objective response rate (ORR) and progression-free survival (PFS) with afatinib compared with platinum-based chemotherapy as first-line treatment in EGFR-mutated metastatic NSCLC [
10‐
12]. In Taiwan, afatinib is reimbursed by the National Health Insurance (NHI) as a first-line option for EGFR-mutated metastatic NSCLC [
13]. Unfortunately, data from clinical trials showed that most patients experience tumor progression after 10–14 months [
14]. A combination therapy with other targeted agents is a viable choice to reduce the rates of resistance to EGFR-TKI. In 2009, Naumov et al. demonstrated that the dual inhibition of EGFR and VEGF abrogates the
EGFR resistance in NSCLC models. The authors concluded that
EGFR resistance is a VEGF-mediated process, and combined blockade of the VEGFR and EGFR pathways can overcome EGFR resistance [
15]. Ramucirumab is a fully human IgG1 monoclonal antibody that specifically binds to the extracellular domain of vascular endothelial growth factor receptor 2 (VEGFR-2) with high affinity, preventing the binding of VEGF ligands and inhibiting receptor activation [
16]. The CNS activity of ramucirumab has been demonstrated in clinical studies [
17‐
20]. The groundbreaking phase III double-blind RELAY trial demonstrated that adding ramucirumab to erlotinib improved PFS (19.4 vs.12.4 months) in treatment-naïve EGFR-mutated metastatic NSCLC [
21]. A phase Ib trial, which recruited Japanese patients with advanced EGFR-mutated metastatic NSCLC, showed a tolerable safety profile of afatinib plus ramucirumab and a median PFS of 9.2 months [
22]. Still, the current literature is scarce regarding the benefits of adding ramucirumab to first-line EGFR TKIs, such as afatinib, in patients with treatment-naïve NSCLC. Therefore, we conducted this retrospective study to investigate the survival benefits and safety profile of afatinib plus ramucirumab in patients with treatment-naïve, EGFR-mutated metastatic, NSCLC.