Optimizing the sequencing of tyrosine kinase inhibitors (TKIs) in epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC)

Abstract

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for 80-85% of cases. Epidermal growth factor receptor (EGFR) mutations are observed in approximately 40% and 20% of patients with NSCLC in Asian and non-Asian populations, respectively. First-generation (gefitinib, erlotinib) and second-generation (afatinib, dacomitinib) EGFR-tyrosine kinase inhibitors (TKIs) have been standard-of-care (SoC) first-line treatment for patients with sensitizing EGFR mutation positive advanced NSCLC following Phase III trials versus platinum-based doublet chemotherapy. However, most patients treated with first-line first- or second-generation EGFR-TKIs develop resistance. Osimertinib, a third-generation, central nervous system active EGFR-TKI which potently and selectively inhibits both EGFR-TKI sensitizing (EGFRm) and the most common EGFR T790 M resistance mutations, has shown superior efficacy versus first-generation EGFR-TKIs (gefitinib / erlotinib). Osimertinib is now a treatment option for patients with advanced NSCLC harboring EGFRm in the first-line setting, and treatment of choice for patients with T790 M positive NSCLC following disease progression on first-line EGFR-TKIs. The second-generation EGFR-TKI dacomitinib has also recently been approved for the first-line treatment of EGFRm positive metastatic NSCLC. There remains a need to determine appropriate sequencing of EGFR-TKIs in this setting, including EGFR-TKIs as monotherapy or in combination with other TKIs / signaling pathway inhibitors. This review considers the evolving role of sequencing treatments to maximize benefits for patients with EGFRm positive advanced NSCLC.

Keywords: Epidermal growth factor receptor; Exon 19 deletion; Exon 21 mutation; Non-small cell lung cancer; Sequencing; Tyrosine kinase inhibitor.

Figure 1.

Median PFS with first-line EGFR-TKI treatment in EGFR mutation-positive NSCLC and the proportion of patients who received subsequent systemic treatment [6-12,19,29,32,33,102,103,138-142] *As a proportion of patients who discontinued EGFR-TKI at data cut-off; treatment presumed systemic when details not provided; however, some references are not clear in this respect. Note, due to the differences in trial designs and patient populations, cross-trial comparisons should be interpreted with caution.

Figure 2.

Approximation of proportion of patients with EGFRm positive advanced NSCLC treated with first- / second-generation EGFR-TKIs and who go on to receive osimertinib as second-line therapy [6-12,19,93,95,98,102,103,111,138-140,143-145] *Based on the proportion of patients who discontinued first-line EGFR-TKIs in randomized-controlled trials and who received subsequent systemic treatment: 47–82% †Based on real-world evidence studies indicating the proportion of patients who received an EGFR T790M test: FLATIRON (30%) and REMEDY (97% of patients with samples collected) ¶Based on a meta-analysis of literature indicating a prevalence of 50% (Wang et al. BMC 2018), and real-world evidence studies indicating a lower than expected T790M positive rate: FLATIRON (28%) and REMEDY (31%) §Based on real-world evidence studies, the vast majority of patients who test positive for T790M receive osimertinib treatment: FLATIRON (96%) and REMEDY (90%) FLATIRON: US Flatiron Electronic Health Record-derived database study REMEDY: A prospective study of molecular testing status in the EGFR mutation positive NSCLC patients with disease progression during EGFR-TKI treatment

Figure 3

A. Resistance mechanisms post ≥second-line osimertinib* [146-152] Composite pie chart (range of data values correspond to the size of each segment) *Resistance mechanism reported may overlap with another ^†Resistance mechanisms in plasma; frequency of MET amplification is expected to be higher in tissue B. Plasma-based resistance mechanisms post first-line osimertinib (FLAURA)* [112] *Resistance mechanism reported may overlap with another †Resistance mechanisms in plasma; frequency of MET amplification is expected to be higher in tissue