Tumor Analyses Reveal Squamous Transformation and Off-Target Alterations As Early Resistance Mechanisms to First-line Osimertinib in EGFR-Mutant Lung Cancer

Abstract

<div class="section"> <a class="named-anchor" id="S1"> <!-- named anchor --> </a> <h5 class="title" id="d767504e327">Purpose:</h5> <p id="P2">Patterns of resistance to first-line osimertinib are not well-established and have primarily been evaluated using plasma assays which cannot detect histologic transformation and have differential sensitivity for copy number changes and chromosomal rearrangements. </p> </div><div class="section"> <a class="named-anchor" id="S2"> <!-- named anchor --> </a> <h5 class="title" id="d767504e332">Experimental Design:</h5> <p id="P3">To characterize mechanisms of resistance to osimertinib, patients with metastatic <i>EGFR</i>-mutant lung cancers who received osimertinib at Memorial Sloan Kettering and had next-generation sequencing performed on tumor tissue before osimertinib initiation and after progression were identified. </p> </div><div class="section"> <a class="named-anchor" id="S3"> <!-- named anchor --> </a> <h5 class="title" id="d767504e340">Results:</h5> <p id="P4">Among 62 patients who met eligibility critieria, histologic transformation, primarily squamous transformation, was identified in 15% of first-line osimertinib cases and 14% of later-line cases. Nineteen percent (5/27) of patients treated with first-line osimertinib had off-target genetic resistance (2 <i>MET</i> amplification, 1 <i>KRAS</i> mutation, 1 <i>RET</i> fusion, and 1 <i>BRAF</i> fusion) whereas 4% (1/27) had an acquired <i>EGFR</i> mutation ( <i>EGFR</i> G724S). Patients with squamous transformation exhibited considerable genomic complexity; acquired <i>PIK3CA</i> mutation, chromosome 3q amplification and <i>FGF</i> amplification were all seen. Patients with transformation had shorter time on osimertinib and shorter survival compared to patients with on-target resistance. Initial <i>EGFR</i> sensitizing mutation, time on osimertinib treatment and line of therapy also influenced resistance mechanism that emerged. The compound mutation <i>EGFR</i> S768 + V769L and the mutation <i>MET</i> H1094Y were identified and validated as resistance mechanisms with potential treatment options. </p> </div><div class="section"> <a class="named-anchor" id="S4"> <!-- named anchor --> </a> <h5 class="title" id="d767504e379">Conclusion:</h5> <p id="P5">Histologic transformation and other off-target molecular alterations are frequent early emerging resistance mechanisms to osimertinib and are associated with poor clinical outcomes. </p> </div>