Overgrowth Of Competing Resistance Mechanisms, Such As An Acquired Kras Mutation, Underlies A Poor Prognosis Subtype Of Acquired Resistance To Osimertinib In T790m-Positive Nsclc

Introduction: Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) which is highly active in EGFR-mutant NSCLC with resistance to prior EGFR TKI. Acquired resistance to osimertinib had been observed clinically; an improved understanding of the molecular mechanisms of resistance is needed. Methods/Results: We initially studied an institutional cohort of 86 patients (pts) treated with osimertinib for advanced T790M-positive NSCLC. 50 pts had progressed on therapy, of whom 25 underwent a resistance biopsy and 17 had NGS results available. 6 pts maintained the T790M mutation at resistance, of whom 3 also acquired an EGFR C797S mutation. The remaining 11 pts had loss of T790M, of whom 5 had evidence of a competing resistance mechanism: 2 with histologic transformation to SCLC, one with BRAF V600E, one with an FGFR3-TACC fusion, and one with KRAS Q61K. For the final case, we confirmed the acquired KRAS Q61K on therapy using serial plasma genotyping. Time to treatment failure (TTF) on osimertinib was 3 months median in pts with loss of T790M and 14 months median in pts with maintained T790M. To test the hypothesis that loss of T790M is a poor prognosis subtype of resistance, we analyzed 127 pts treated for T790M-positive NSCLC on the phase I AURA trial of osimertinib. Plasma drawn after progression was submitted for genotyping using droplet digital PCR. 88 pts had a detectable EGFR driver mutation and were eligible for resistance analysis. 45 pts (51%) had detectable T790M at resistance, 17 (19%) of whom also acquired a C797S mutation; the remaining 43 pts (49%) had loss of T790M and no C797S. Median TTF on osimertinib was 6 months in pts with loss of T790M and 11 months in pts with maintained T790M; among pts with TTF Citation Format: Geoffrey R. Oxnard, Yuebi Hu, Philip Tracy, Nora Feeney, Cloud P. Paweletz, Kenneth S. Thress, Pasi A. Janne. Overgrowth of competing resistance mechanisms, such as an acquired KRAS mutation, underlies a poor prognosis subtype of acquired resistance to osimertinib in T790M-positive NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4112. doi:10.1158/1538-7445.AM2017-4112