Receptor Tyrosine Kinase Fusions as an Actionable Resistance Mechanism to EGFR TKIs in EGFR-Mutant Non-Small-Cell Lung Cancer

Tumor resistance to EGFR tyrosine kinase inhibitors (TKIs) occurs invariably, and receptor tyrosine kinase (RTK) fusions have emerged as rare but actionable resistance mechanisms. In 2015, the detection of RTK fusions as acquired resistance (AR) in two cases was first reported. Subsequently, a survey of FGFR3-TACC3 fusion and other RTK fusions from a large commercial genomic sequencing company database was published, followed by large-scale clinical trials of EGFR TKIs demonstrating the emergence of RTK fusions in AR. However, detailed examination of the AR RTK fusion landscape in non-small-cell lung cancer is lacking. Hence, we conducted a comprehensive review to categorize these fusion events by the generation of EGFR TKIs, the specific RTK fusions and their fusion partners, the founder EGFR mutations, and their methods of detection. To support the actionability and clinical significance of AR RTK fusions we present all available data demonstrating clinical benefit of concurrent dual blockade of the AR RTKfusion and the original EGFR mutation.