Treating patients with EGFR-sensitizing mutations: first line or second line--is there a difference?

First-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) is a standard treatment for patients with activating EGFR mutations. Six randomized studies have demonstrated consistent improvement in tumor response rate and progression-free survival over platinum-based combination chemotherapy. The only reason to consider EGFR TKI as second-line therapy is that none of the six comparative studies has shown improvement in overall survival, which can be explained by the high proportion of patients from the chemotherapy arm crossing over to the EGFR TKI arm on progression. It is true that patients with EGFR mutations may benefit from second-line EGFR TKI therapy, but we cannot conclude that the benefit is either equal to or inferior to first-line EGFR TKI therapy. To date, there are no direct comparative data between first- and second-line EGFR TKI in patients with activating EGFR mutations. Tumor response rates to second-line EGFR TKI have been inconsistent, which could potentially be explained by the impact of first-line chemotherapy on the abundance of tumor cells with activating EGFR mutations. However, numerous arguments, including assurance on drug exposure, improvement in quality of life, better tolerance by patients with poor performance status, and deferral of whole-brain radiation therapy for patients with brain metastasis, support the general application of first-line EGFR TKI.