Eli Lilly's RET Inhibitor Selpercatinib Proposed for Priority Review in China for RET Fusion-Positive NSCLC

On August 26, according to the latest announcement on the official website of the Center for Drug Evaluation (CDE), Eli Lilly's RET inhibitor selpercatinib capsules have been proposed for priority review for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) positive for RET gene fusions.

Screenshot from: CDE Official Website

Selpercatinib, developed by Loxo Oncology at Lilly, a subsidiary of Eli Lilly and Company, demonstrated promising efficacy in early clinical studies of RET-positive NSCLC. Among 39 treatment-naïve patients with RET fusion-positive NSCLC, 85% experienced significant tumor shrinkage following treatment with LOXO-292. In 105 patients with RET fusion-positive NSCLC who progressed after prior chemotherapy, 64% achieved significant tumor reduction with LOXO-292, and 81% of patients maintained a duration of response of at least 6 months. Furthermore, selpercatinib can cross the blood-brain barrier and has demonstrated significant clinical efficacy in patients with brain metastases.

In May 2020, the U.S. FDA approved selpercatinib for the treatment of adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC), as well as patients with advanced or metastatic RET-mutant medullary thyroid cancer or advanced or metastatic RET fusion-positive thyroid cancer, becoming the first precision therapy approved for cancer patients harboring RET genetic alterations. This approval was based on the global phase I/II LIBRETTO-001 trial, which demonstrated that selpercatinib exhibits significant clinical efficacy with mild toxicity in RET fusion-positive NSCLC.

The RET gene is located on chromosome 10q11.2 and encodes a receptor tyrosine kinase composed of 1,100 amino acids, known as the RET protein. Activation of its signaling promotes cell survival, migration, and growth via downstream STAT/PLCγ pathways. The pathogenesis of RET-associated tumors primarily involves RET gene alterations and aberrant expression of the wild-type RET gene. RET gene alterations occur in two forms: RET fusions and RET mutations.

Currently, multiple companies are actively developing RET inhibitors. Among them, international companies with ongoing R&D include, besides Eli Lilly, Bayer, Roche, Takeda, Boston Pharmaceuticals, Helsinn Healthcare, NantCell, NantKwest, Nerviano Medical Sciences, and Taiho Pharmaceutical; in China, they include CStone Pharmaceuticals, Chia Tai Tianqing, CSPC, Aosaikang, Betta Pharmaceuticals, and BeiGene.

According to incomplete statistics, the global sales volume of currently marketed RET-targeted inhibitors has reached approximately $5.71 billion. In 2020, sales of alectinib were $1.21 billion, cabozantinib $1.06 billion, and lenvatinib $1.04 billion; as single-target inhibitors, pralsetinib and selpercatinib were approved later, resulting in a relatively smaller sales contribution. By 2025, the overall market size for RET-targeted inhibitors is expected to approach $11.6 billion, with a compound annual growth rate (CAGR) of 14.6%.