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

作者：Adam J. Schoenfeld, Joseph M. Chan, Daisuke Kubota, Hiroki Sato, Hira Rizvi, Yahya Daneshbod, Jason C. Chang, Paul K. Paik, Michael Offin, Maria E. Arcila, Monika A. Davare, Ujwal Shinde, Dana Pe’er, Natasha Rekhtman, Mark G. Kris, Romel Somwar, Gregory J. Riely, Marc Ladanyi, Helena A. Yu · 发表于：Clinical Cancer Research · 年份：2020 · DOI：10.1158/1078-0432.ccr-19-3563 · 被引用次数：407 · 研究领域：Lung Cancer Treatments and Mutations、Gastric Cancer Management and Outcomes、Cancer Genomics and Diagnostics

Abstract Purpose: 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. Experimental Design: To characterize mechanisms of resistance to osimertinib, patients with metastatic EGFR-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. Results: 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 MET amplification, 1 KRAS mutation, 1 RET fusion, and 1 BRAF fusion) whereas 4% (1/27) had an acquired EGFR mutation (EGFR G724S). Patients with squamous transformation exhibited considerable genomic complexity; acquired PIK3CA mutation, chromosome 3q amplification, and FGF amplification were all seen. Patients with transformation had shorter time on osimertinib and shorter survival compared with patients with on-target resistance. Initial EGFR sensitizing mutation, time on osimertinib treatment, and line of therapy also influenced resistance mechanism that emerged. The comp...