Acquired
epidermal growth factor receptor (EGFR) resistance mutations to
osimertinib are common, including the EGFR C797S that abolishes the covalent binding of
osimertinib to EGFR. Here we report the emergence of novel EGFR
solvent front mutations at Gly796 (G796S/R) in addition to a hinge pocket L792F/H mutations, and C797S/G all in cis with T790M in a single patient on progression on
osimertinib as detected by plasma
circulating tumor DNA (ctDNA) assay in the course of clinical care. A 69-year-old Caucasian female former light-smoker presented with stage IV EGFR L858R positive
adenocarcinoma who developed EGFR T790M mutation after 8 month treatment of
erlotinib. The patient was initiated on
osimertinib with disease shrinkage after 2 months, but
tumor regrowth was observed after 5 months of
osimertinib treatment. Assay of plasma ctDNA at this time revealed these different secondary resistance mutations all in trans with each other including distinct mutations at the same
codon producing different
amino acid changes: G796S/R (mutant allele frequency [MAF]; 14.4%), C797S/G (MAF: 2.26%), L792F/H (MAF: 0.36%), and V802F (MAF: 0.40%), in addition to the pre-existing L858R (MAF:17.9%) and T790M (MAF:18.2%) but all in cis with T790M. The G796S/R mutations are homologous with known reported
solvent front mutations in ALK G1202R, ROS1 G2032R, TrkA G595R and TrkC G623R, all of which are associated with acquired resistance to type I TKIs. In silico modeling revealed mutation at G796 interferes with
osimertinib binding to the EGFR
kinase domain at the phenyl aromatic ring position as this residue forms a narrow "hydrophobic sandwich" with L718, while L792F/H mutation interferes with
osimertinib binding at the methoxyl group on the phenyl ring. Multiple resistance mutations at differing allele frequencies including novel EGFR
solvent front mutations can emerge in a single patient with progression on
osimertinib potentially due to
tumor hetereogeneity and definitely present a significant therapeutic and drug development challenge.