The U.S. Food and Drug Administration (FDA) recently granted Breakthrough Therapy designation to LOXO-292, a selective RET inhibitor, for:
The LOXO-292 Breakthrough Therapy designation was based on data from the ongoing global phase I/II LIBRETTO-001 clinical trial.
LOXO-292 and RET-Altered Cancers
LOXO-292 is an oral, selective investigational new drug in clinical development for the treatment of patients with cancers that harbor abnormalities in the rearranged during transfection (RET) kinase. RET fusions and mutations occur across multiple tumor types with varying frequency. LOXO-292 was designed to inhibit native RET signaling, as well as anticipated acquired resistance mechanisms that could otherwise limit the activity of this therapeutic approach.
Genomic alterations in the RET kinase, which include fusions and activating point mutations, lead to overactive RET signaling and uncontrolled cell growth. RET fusions have been identified in approximately 2% of patients with NSCLC, 10% to 20% of those with papillary and other thyroid cancers, and a subset of other cancers.
Activating RET point mutations account for approximately 60% of medullary thyroid cancer. Both RET fusion cancers and RET-mutant medullary thyroid cancer are primarily dependent on this single activated kinase for their proliferation and survival. This dependency, often referred to as “oncogene addiction,” renders such tumors highly susceptible to small-molecule inhibitors targeting RET.