Abstract
The identification of oncogenic drivers, and the subsequent development of targeted therapies established biomarker-based care for metastatic non-small cell lung cancer (NSCLC). Biomarker testing is standard of care in NSCLC patients with adenocarcinoma because multiple targeted therapies are available. Rearranged during transfection (RET) rearrangements were identified as oncogenic drivers in NSCLC, and are more common among younger patients, adenocarcinoma histology, and patients with a history of never smoking. The prevalence is estimated to be 1-2% among patients with adenocarcinoma histology. The most common rearrangement is between intron 11 of the RET gene and intron 15 of the KIF5B gene, and the next most frequent rearrangement is with the CCDC6 gene. RET rearrangements lead to constitutive activation of the RET tyrosine kinase and increased cell proliferation, migration, and survival. Phase II studies investigated the activity of multi-targeted tyrosine kinase inhibitors in patients with NSCLC with a confirmed RET rearrangement. These agents have limited potency against RET, and activity against the epidermal growth factor receptor and vascular endothelial growth factor pathways. These agents revealed modest activity, and were poorly tolerated due to the off-target toxicities. These struggles contributed to the development of more potent and specific RET tyrosine kinase inhibitors. Preliminary results from early phase trials of selpercatinib (LOXO-292) and pralsetinib (BLU-667) revealed promising efficacy and improved tolerability. The availability of these agents will make routine testing for RET rearrangements a priority.