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

Abstract

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. To characterize mechanisms of resistance to osimertinib, patients with metastatic <i>EGFR</i>-mutant lung cancers who received osimertinib at Memorial Sloan Kettering Cancer Center and had next-generation sequencing performed on tumor tissue before osimertinib initiation and after progression were identified. Among 62 patients who met eligibility criteria, 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 with 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. Histologic transformation and other off-target molecular alterations are frequent early emerging resistance mechanisms to osimertinib and are associated with poor clinical outcomes.<i>See related commentary by Piotrowska and Hata, p. 2441</i>.