A Comparison Between First-, Second- and Third-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients with Non-Small-Cell Lung Cancer and Brain Metastases

Salvatore Caponnetto,Alessio Cortellini,Ornella Cantale,Dario Giuffrida,Alain Gelibter,Sunil Daryanani,Alex Friedlaender,Giuseppe Luigi Banna,Alfredo Addeo,Fabio Gomes

doi:10.3390/jmp2010001

Abstract

Patients with non-small-cell lung cancer (NSCLC), harboring Epidermal Growth Factor Receptor (EGFR) mutations, are more susceptible to brain metastases (BM). Comparisons of the efficacy of different-generation EGFR-tyrosine kinase inhibitors (TKI) on BMs from NSCLC are currently limited. We identified studies comparing different EGFR-TKIs for NSCLC through Pubmed literature search and selected those with neurological outcome data. By two retrospective analyses, Erlotinib showed longer neurological time-to-progression (30 months vs. 15.8 months, P = 0.024) and reduced the risk of central nervous system (CNS) progression (Hazard Ratio (HR) 0.25; 95% CI, 0.08–0.81; P = 0.021) compared to Gefitinib. In a phase 2b randomized trial, 16% of patients with BMs had a similar Progression Free Survival (PFS) (HR 0.76, 95% CI 0.41–1.44) or Overall Survival (OS) (HR 1.16, 95% CI 0.61–2.21) with Afatinib versus Gefitinib; a lower risk of developing subsequent BMs with Afatinib than Gefitinib (HR 0.49; 95% CI 0.34–0.71; P < 0.001) was reported by a retrospective study. A randomized phase 3 trial proved that patients with BMs treated with Osimertinib had longer PFS (HR 0.47, 95% CI 0.30–0.74) and OS (HR 0.79, 95% CI 0.61–1.01) than with Gefitinib, and lower incidence of CNS progression (6% vs. 15%, respectively). Although there is limited evidence, differences in CNS activity may exist between EGFR-TKIs.

Highlights

The second analysis [20] evaluating the risk of central nervous system (CNS) progression and progression-free survival (PFS) in patients treated with either Erlotinib (n = 22) or Gefitinib (n = 55), confirmed a significantly reduced risk of CNS progression in those with pre-existing brain metastases (BMs) treated with Erlotinib as compared to Gefitinib (HR 0.25; 95% CI, 0.08–0.81; P = 0.021), but not in those without BMs (HR 0.25; 95% CI, 0.08–0.81; P = 0.021)
Several analyses compared the efficacy of tyrosine kinase inhibitors (TKI) to chemotherapy or radiotherapy in Epidermal Growth Factor Receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC), but the literature addressing which TKI is the most effective against BMs is currently limited
New-generation EGFR-TKIs are continuously being investigated to counteract the acquired resistance developed by tumors exposed to previous-generation agents

Summary

Introduction

Lung cancer is one of the most lethal cancers worldwide. Around 80 to 90% are non-small-cell lung cancers (NSCLC). In 70% of patients, the disease is diagnosed at a late, metastatic stage (stage IV) [1,2]. Activating mutations in the Epidermal Growth Factor. Receptor (EGFR) kinase domain occur in 10–15% of patients with lung adenocarcinoma in Western countries, and up to 50% in Asian patients [3,4]. EGFR mutations are more frequent in women and never- or light-smokers with adenocarcinoma histology.

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Conclusion