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Clin Cancer Res. 2020 Jan 7. pii: clincanres.3563.2019. doi: 10.1158/1078-0432.CCR-19-3563. [Epub ahead of print]

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

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Medicine, Memorial Sloan Kettering Cancer Center.
Department of Orthopedics, Juntendo University.
Pathology, Memorial Sloan Kettering Cancer Center.
Druckenmiller Center for Lung Cancer Research and Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center.
Pathology, Loma Linda University Medical Center and School of Medicine.
Department of Pathology, Memorial Sloan Kettering Cancer Center.
Pediatrics, OHSU.
Biochemistry and Molecular Biology, OHSU.
Program for Computational and Systems Biology, Memorial Sloan Kettering Cancer Center.
Memorial Sloan Kettering Cancer Center.
Medicine, Memorial Sloan Kettering Cancer Center



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 EGFR-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.


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 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 to patients with on-target resistance. Initial EGFR sensitizing mutation, time on osimertinib treatment and line of therapy also influenced resistance mechanism that emerged. The compound mutation EGFR S768 + V769L and the mutation MET 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.

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