The EGFR Exon 19 Mutant L747-A750>P Exhibits Distinct Sensitivity to Tyrosine Kinase Inhibitors in Lung Adenocarcinoma

Purpose: EGFR exon 19 deletion (Ex19Del) mutations account for approximately 60% of lung cancer-associated EGFR mutations and include a heterogeneous group of mutations. Although they are associated with benefit from tyrosine kinase inhibitors (TKI), the relative inhibitor sensitivity of individual Ex19Del mutations is unknown. Experimental Design: We studied the TKI sensitivity and structural features of common Ex19Del mutations and the consequences for patient outcomes on TKI treatment. Results: We found that the L747-A750>P mutation, which represents about 4% of all Ex19Del mutations, displays unique inhibitor selectivity. L747-A750>P differs from other Ex19Del mutations in not being suppressed completely by erlotinib or osimertinib, yet is completely inhibited by low doses of afatinib. The HCC4006 cell line (with the L747-A750>P mutation) exhibited increased sensitivity to afatinib over erlotinib and osimertinib, and computational modeling suggests explanations for this sensitivity pattern. Clinically, patients with EGFR L747-A750>P mutant tumors showed inferior outcomes when treated with erlotinib than patients with E746-A750 mutant tumors. Conclusions: These results highlight important differences between specific Ex19Del mutations that may be relevant for optimizing TKI choice for patients.