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

We present a cohort of 41 patients with osimertinib resistance biopsies, including 2 with an acquired <i>CCDC6-RET</i> fusion. Although <i>RET</i> fusions have been identified in resistant <i>EGFR</i>-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 <i>RET</i> fusions in an <i>EGFR</i>-mutant cancer, we expressed CCDC6-RET in PC9 (<i>EGFR</i> del19) and MGH134 (<i>EGFR</i> 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 <i>EGFR</i>-mutant NSCLC and <i>RET</i>-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 <i>RET</i> 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 <i>RET</i> fusions in resistant <i>EGFR</i>-mutant cancers is unknown. We report that <i>RET</i> 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.<i>This article is highlighted in the In This Issue feature, p. 1494</i>.