Alexa B Schrock1, Viola W Zhu2, Wen-Son Hsieh3, Russell Madison1, Benjamin Creelan4, Jeffrey Silberberg5, Dan Costin6, Anjali Bharne7, Ioana Bonta8, Thangavijayan Bosemani9, Petros Nikolinakos10, Jeffrey S Ross11, Vincent A Miller1, Siraj M Ali1, Samuel J Klempner12, Sai-Hong Ignatius Ou13. 1. Foundation Medicine, Inc., Cambridge, Massachusetts. 2. University of California Irvine School of Medicine, Chao Family Comprehensive Cancer Center, Orange, California. 3. Icon Singapore Oncology Consultants, Farrer Park Medical Clinic, Connexion, Singapore. 4. H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. 5. Regional Cancer Care Associates, Freehold, New Jersey. 6. White Plains Hospital Center for Cancer Care, White Plains, New York. 7. University of California San Diego Health, Encinitas, California. 8. Cancer Treatment Centers of America, Newnan, Georgia. 9. University of California Irvine School of Medicine, Department of Radiological Sciences, Orange, California. 10. University Cancer and Blood Center, Athens, Georgia. 11. Foundation Medicine, Inc., Cambridge, Massachusetts; SUNY Upstate Medical University, Syracuse, New York. 12. The Angeles Clinic and Research Institute, Los Angeles, California. 13. University of California Irvine School of Medicine, Chao Family Comprehensive Cancer Center, Orange, California. Electronic address: Ignatius.ou@uci.edu.
Abstract
INTRODUCTION: We analyzed a large set of EGFR-mutated (EGFR+) NSCLC to identify and characterize cases with co-occurring kinase fusions as potential resistance mechanisms to EGFR tyrosine kinase inhibitors (TKIs). METHODS: EGFR+ (del 19, L858R, G719X, S768I, L851Q) NSCLC clinical samples (formalin-fixed paraffin-embedded tumor and blood) were analyzed for the presence of receptor tyrosine kinase (RTK) and BRAF fusions. Treatment history and response were obtained from provided pathology reports and treating clinicians. RESULTS: Clinical samples from 3505 unique EGFR+ NSCLCs were identified from June 2012 to October 2017. A total of 31 EGFR+ cases had concurrent kinase fusions detected: 10 (32%) BRAF, 7 (23%) ALK receptor tyrosine kinase (ALK), 6 (19%) ret proto-oncogene (RET), 6 (19%) fibroblast growth factor receptor 3 (FGFR3), 1 (3.2%) EGFR, and 1 (3.2%) neurotrophic receptor tyrosine kinase 1 (NTRK1), including two novel fusions (SALL2-BRAF and PLEKHA7-ALK). Twenty-seven of 31 patients had either a known history of EGFR+ NSCLC diagnosis or prior treatment with an EGFR TKI before the fusion+ sample was collected. Twelve of the 27 patients had paired pre-treatment samples where the fusion was not present before treatment with an EGFR TKI. Multiple patients treated with combination therapy targeting EGFR and the acquired fusion had clinical benefit, including one patient with osimertinib resistance due to an acquired PLEKHA7-ALK fusion achieving a durable partial response with combination of full-dose osimertinib and alectinib. CONCLUSIONS: RTK and BRAF fusions are rare but potentially druggable resistance mechanisms to EGFR TKIs. Detection of RTK and BRAF fusions should be part of comprehensive profiling panels to determine resistance to EGFR TKIs and direct appropriate combination therapeutic strategies.
INTRODUCTION: We analyzed a large set of EGFR-mutated (EGFR+) NSCLC to identify and characterize cases with co-occurring kinase fusions as potential resistance mechanisms to EGFR tyrosine kinase inhibitors (TKIs). METHODS:EGFR+ (del 19, L858R, G719X, S768I, L851Q) NSCLCclinical samples (formalin-fixed paraffin-embedded tumor and blood) were analyzed for the presence of receptor tyrosine kinase (RTK) and BRAF fusions. Treatment history and response were obtained from provided pathology reports and treating clinicians. RESULTS:Clinical samples from 3505 unique EGFR+ NSCLCs were identified from June 2012 to October 2017. A total of 31 EGFR+ cases had concurrent kinase fusions detected: 10 (32%) BRAF, 7 (23%) ALKreceptor tyrosine kinase (ALK), 6 (19%) ret proto-oncogene (RET), 6 (19%) fibroblast growth factor receptor 3 (FGFR3), 1 (3.2%) EGFR, and 1 (3.2%) neurotrophic receptor tyrosine kinase 1 (NTRK1), including two novel fusions (SALL2-BRAF and PLEKHA7-ALK). Twenty-seven of 31 patients had either a known history of EGFR+ NSCLC diagnosis or prior treatment with an EGFR TKI before the fusion+ sample was collected. Twelve of the 27 patients had paired pre-treatment samples where the fusion was not present before treatment with an EGFR TKI. Multiple patients treated with combination therapy targeting EGFR and the acquired fusion had clinical benefit, including one patient with osimertinib resistance due to an acquired PLEKHA7-ALK fusion achieving a durable partial response with combination of full-dose osimertinib and alectinib. CONCLUSIONS:RTK and BRAF fusions are rare but potentially druggable resistance mechanisms to EGFR TKIs. Detection of RTK and BRAF fusions should be part of comprehensive profiling panels to determine resistance to EGFR TKIs and direct appropriate combination therapeutic strategies.
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