Two research studies report positive results with the use of the highly selective potent and brain-penetrant RET inhibitor selpercatinib, including first-line treatment of advanced RET fusion–positive non–small-cell lung cancer (NSCLC) and advanced RET-mutant medullary thyroid cancer.
Responding to the NSCLC study, an editorialist writes of the “science behind the study”: “Selpercatinib is a highly selective, small-molecule, ATP-competitive, RET tyrosine kinase inhibitor. Preliminary cell-based studies have shown that it inhibits different classes of variant RET, including chimeric RET fusion proteins and RET activated by the missense variants found in thyroid and adrenal cancers.5 Selpercatinib binds to RET, blocking both RET activation and activation of downstream signaling pathways that promote cell proliferation. Because selpercatinib has binding constraints that differ from those of multikinase inhibitors, it inhibits variant RET in which the ATP-binding pocket (the site where ATP interacts to trigger kinase activation) is directly affected. Thus, selpercatinib inhibits RET variants that are unaffected by previous multikinase inhibitors. In a previous phase 1–2 clinical study, selpercatinib improved progression-free and overall survival among patients with NSCLC and a RET fusion. Selpercatinib penetrates the blood−brain barrier and has showed efficacy in patients with NSCLC and brain metastasis.”
“This trial illustrates a new example of the way in which the identification of RET has changed the outcomes for patients with RET-mutant medullary thyroid cancer, a situation that, to our knowledge, is still one of the rare examples of the impact of a gene discovery on the diagnosis, monitoring, and care of patients,” editorialists write based on the thyroid cancer trial. “We are hopeful that more specific targeting of other driver oncogenes may improve outcomes in other cancer types.”