What Next? Options after Progression on EGFR TKIs
Dr Azza Omar, Hospital Raja Perempuan Zainab II

The 21st century is the era of targeted cancer treatment with a dramatic change in the management of EGFR-mutant non-small cell lung cancer (NSCLC) and other several promising options for lung adenocarcinoma patients. While the choice of second- or third-generation EGFR tyrosine kinase inhibitors (TKIs) is preferred over first-generation EGFR-TKIs, choosing the ideal agent depends on multiple factors (drug availability, financial funding, physician comfort, specific EGFR mutation, presence of brain metastasis, etc.). Unfortunately, the median response duration of TKIs as a first-line treatment for EGFR mutant tumors ranges from 11 to 14 months.

It has been demonstrated that tumors become increasingly molecularly heterogeneous following targeted therapy as acquired resistance to EGFR-TKIs is inevitable. This is due to various mechanisms, such as T790M, c-Met amplification, activation of alternative pathways (IGF-1, HGF, PI3CA, AXL), transformation to mesenchymal cell or small cell features, and tumor heterogeneity.  This problem of drug resistance inevitably leads to disease progression.

Strategies to overcome these intrinsic and acquired resistance mechanisms are complex. With the development of the precision medicine for advanced NSCLC, available systemic and local treatment options have expanded, requiring new clinical algorithms that take into account resistance mechanism. The aim is to target or bypass the mechanisms of resistance, including MET-, HER2-, and HER3-directed therapies. In patients with acquired TKI resistance, molecular profiling at the time of initial progression may help identify relevant mechanisms of resistance.