Advanced non-small-cell lung cancer with epidermal growth factor receptor mutations: current evidence and future perspectives

Abstract

The identification of activating mutations in the tyrosine kinase domain of the EGF receptor (EGFR) predictive of response to tyrosine kinase inhibitors (TKIs) led to a therapeutic revolution in the treatment of patients with metastatic non-small-cell lung cancer (NSCLC). To date, eight randomized clinical trials have demonstrated that first-line treatment with TKIs in advanced NSCLC patients harboring activating EGFR mutations is associated with significant improvement in response rate, progression-free survival, quality of life and tolerability, compared with platinum-based chemotherapy. These results prompted the EGFR TKIs as the current standard first-line treatment of patients with advanced NSCLC harboring activating EGFR mutations. However, there are several questions that need to be addressed, including the best choice among different EGFR TKIs, the treatment of resistant disease and of patients with specific clinical conditions. Ongoing and future, well-designed trials should answer all these questions.

Keywords::

• afatinib
• clinical trials
• dacomitinib
• EGFR
• erlotinib
• gefitinib
• neratinib
• NSCLC

Financial & competing interests disclosure

Honoraria: A Morabito, Roche, Astra Zeneca; R Costanzo, Astra Zeneca; M Di Maio, Roche; F Perrone, Roche, Boehringer-Ingelheim. Consultant: N Normanno, Astra Zeneca; M Di Maio, Boehringer-Ingelheim. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • EGF receptor (EGFR) plays a central role in the process of cell growth and tumor progression and its overexpression occurs in many human epithelial tumors, including non-small-cell lung cancer (NSCLC).

• • Activating mutations of EGFR identify a specific subtype of lung cancer, whose growth is dependent on EGFR pathway activation, which represents the leading pathway in inducing cellular transformation in these selected patients.

• • It has been demonstrated that activating EGFR mutations lead to increased affinity of tyrosine kinase inhibitors (TKIs) for the mutant receptor compared with the wild-type one.

• • Several randomized clinical trials have consistently demonstrated the superiority of TKIs over chemotherapy as first-line therapy of EGFR mutated NSCLC, in terms of response rate, progression-free survival (PFS), quality of life and tolerability.

• • However, no improvement in overall survival has been observed, probably in consideration to the high proportion of patients crossing over from first-line chemotherapy to second-line therapy with EGFR TKIs.

• • These results prompted the TKIs of EGFR as the current standard first-line treatment of patients with advanced NSCLC harboring activating EGFR mutations.

• • Currently, there are no direct comparisons between different TKIs: gefitinib was the first EGFR TKI with demonstrated efficacy in the treatment of NSCLC patients with activating mutations of EGFR and it has been considered as the control arm in the ongoing randomized clinical trials that are evaluating the efficacy of different TKIs.