Landscape of Acquired Resistance to Osimertinib in EGFR -Mutant NSCLC and Clinical Validation of Combined EGFR and RET Inhibition with Osimertinib and BLU-667 for Acquired RET Fusion

We present a cohort of 41 patients with osimertinib resistance biopsies, including 2 with an acquired fusion. Although fusions have been identified in resistant -mutant non-small cell lung cancer (NSCLC), their role in acquired resistance to EGFR inhibitors is not well described. To assess the biolo...

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Bibliographic Details
Published in:	Cancer discovery 2018-12, Vol.8 (12), p.1529-1539
Main Authors:	Piotrowska, Zofia, Isozaki, Hideko, Lennerz, Jochen K, Gainor, Justin F, Lennes, Inga T, Zhu, Viola W, Marcoux, Nicolas, Banwait, Mandeep K, Digumarthy, Subba R, Su, Wenjia, Yoda, Satoshi, Riley, Amanda K, Nangia, Varuna, Lin, Jessica J, Nagy, Rebecca J, Lanman, Richard B, Dias-Santagata, Dora, Mino-Kenudson, Mari, Iafrate, A John, Heist, Rebecca S, Shaw, Alice T, Evans, Erica K, Clifford, Corinne, Ou, Sai-Hong I, Wolf, Beni, Hata, Aaron N, Sequist, Lecia V
Format:	Article
Language:	eng
Subjects:	Acrylamides - pharmacology Acrylamides - therapeutic use Adult Aged Aged, 80 and over Aniline Compounds - pharmacology Aniline Compounds - therapeutic use Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - genetics Carcinoma, Non-Small-Cell Lung - metabolism Cell Line, Tumor Cohort Studies Cytoskeletal Proteins - genetics Cytoskeletal Proteins - metabolism Drug Resistance, Neoplasm - drug effects Drug Resistance, Neoplasm - genetics ErbB Receptors - antagonists & inhibitors ErbB Receptors - genetics ErbB Receptors - metabolism Female Humans Lung Neoplasms - drug therapy Lung Neoplasms - genetics Lung Neoplasms - metabolism Male Middle Aged Mutation Oncogene Proteins, Fusion - genetics Oncogene Proteins, Fusion - metabolism Protein Kinase Inhibitors - pharmacology Protein Kinase Inhibitors - therapeutic use Proto-Oncogene Proteins c-ret - antagonists & inhibitors Proto-Oncogene Proteins c-ret - genetics Proto-Oncogene Proteins c-ret - metabolism
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Summary:	We present a cohort of 41 patients with osimertinib resistance biopsies, including 2 with an acquired fusion. Although fusions have been identified in resistant -mutant non-small cell lung cancer (NSCLC), their role in acquired resistance to EGFR inhibitors is not well described. To assess the biological implications of fusions in an -mutant cancer, we expressed CCDC6-RET in PC9 ( del19) and MGH134 ( L858R/T790M) cells and found that CCDC6-RET was sufficient to confer resistance to EGFR tyrosine kinase inhibitors (TKI). The selective RET inhibitors BLU-667 and cabozantinib resensitized CCDC6-RET-expressing cells to EGFR inhibition. Finally, we treated 2 patients with -mutant NSCLC and -mediated resistance with osimertinib and BLU-667. The combination was well tolerated and led to rapid radiographic response in both patients. This study provides proof of concept that fusions can mediate acquired resistance to EGFR TKIs and that combined EGFR and RET inhibition with osimertinib/BLU-667 may be a well-tolerated and effective treatment strategy for such patients. SIGNIFICANCE: The role of fusions in resistant -mutant cancers is unknown. We report that fusions mediate resistance to EGFR inhibitors and demonstrate that this bypass track can be effectively targeted with a selective RET inhibitor (BLU-667) in the clinic. .
ISSN:	2159-8274 2159-8290