Lilly Initiates Phase III Clinical Trial of Selpercatinib for RET-Mutant Medullary Thyroid Cancer in China

By Jia Yi

On September 1, the Insight database showed that Eli Lilly’s new drug Selpercatinib (also known as LOXO-292) initiated a Phase III clinical trial for the treatment of RET-mutant medullary thyroid cancer. This clinical trial marks the second Phase III indication study launched in China for this drug. The first clinical trial, targeting advanced or metastatic RET fusion-positive non-small cell lung cancer, is currently ongoing.

Source: Insight Database (http://db.dxy.cn/v5/)

Selpercatinib is a potent, oral, highly selective inhibitor of the Rearranged During Transfection (RET) kinase, developed by Eli Lilly and Company. As the first RET kinase inhibitor, it functions by suppressing the activity of aberrant RET kinases. The drug has received three Breakthrough Therapy designations and Priority Review status from the U.S. Food and Drug Administration (FDA). It was approved by the U.S. FDA on May 8, 2020, under the brand name Retevmo, for the treatment of metastatic, RET fusion-positive non-small cell lung cancer (NSCLC); advanced or metastatic, RET fusion-positive thyroid cancer requiring systemic therapy; and RET-mutant medullary thyroid cancer (MTC) requiring systemic therapy.

This is a randomized, open-label, parallel-group, international, multicenter Phase III clinical trial. The objective is to compare time to first failure of survival (TFFS) and other efficacy endpoints (assessed per RECIST 1.1 criteria) in patients with progressive, advanced, kinase inhibitor-naïve, RET-mutant medullary thyroid carcinoma (MTC) treated with selpercatinib versus those treated with cabozantinib or vandetanib, and to evaluate the safety and tolerability of these treatments. The primary endpoint is TFFS. Secondary endpoints include efficacy measures such as progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), and overall survival (OS), as well as safety measures including the incidence and severity of adverse events. The target enrollment in China is 60 participants.

RET is a relatively rare oncogene located on the long arm of human chromosome 10, encoding a receptor tyrosine kinase. Its genetic alterations include fusions/rearrangements and point mutations, which lead to hyperactive RET signaling and uncontrolled cell growth, serving as rare drivers in various types of tumors. RET fusions are present in approximately 2% of non-small cell lung cancers (NSCLC), 10–20% of papillary thyroid cancers (PTC) and other thyroid cancer subtypes, as well as in subsets of other cancers (such as colorectal cancer). Point mutations are found in approximately 60% of medullary thyroid cancers (MTC) and in 90% of patients with advanced MTC. Furthermore, RET gene mutations occur with low frequency in a variety of other malignancies, including colorectal cancer, breast cancer, and pancreatic cancer.

RET fusion/mutation-driven cancers primarily rely on RET kinase activation to sustain their proliferation and survival. This dependency, commonly referred to as “oncogene addiction,” renders these tumors highly sensitive to small-molecule inhibitors targeting RET. However, the development of highly selective RET-targeted therapies has proven challenging. Historically, patients with RET mutations were mainly treated with chemotherapy or multi-kinase inhibitors (such as cabozantinib and vandetanib), which yielded suboptimal efficacy and significant adverse effects. Selpercatinib is the first highly selective targeted therapy for RET mutations or fusions, offering new therapeutic hope for patients harboring such genetic alterations.

The drug’s FDA approval was based on data from the Phase I/II LIBRETTO-001 clinical trial. This trial involved patients with three types of tumors and evaluated the efficacy of selpercatinib in RET fusion–positive non-small cell lung cancer (NSCLC) and thyroid cancer. The results showed that among 105 adult patients with RET fusion–positive NSCLC who had previously received platinum-based chemotherapy, the overall response rate (ORR) was 64%, and 81% of responders maintained a response for at least 6 months. Among 19 patients with RET fusion–positive thyroid cancer who were refractory to radioactive iodine and had received another systemic therapy, the ORR was 79%, and 87% of responders maintained a response for at least 6 months. Among 55 patients with advanced or metastatic RET-mutant medullary thyroid cancer who had previously been treated with cabozantinib and/or vandetanib, the ORR was 69%, and 76% of responders maintained a response for at least 6 months. On August 27, Eli Lilly and Company announced that the results of this registrational clinical trial were published in the New England Journal of Medicine (NEJM).

According to the Insight database, there are currently three clinical trials of Selpercatinib being conducted in China, covering two indications: advanced or metastatic RET fusion-positive non-small cell lung cancer (NSCLC) and advanced medullary thyroid cancer with RET mutations (i.e., the clinical trial initiated this time).

Source: Insight Database (http://db.dxy.cn/v5/)

We look forward to the smooth progress of the Phase III clinical trials of Selpercatinib and its early approval in China, to benefit patients with RET fusion/mutation cancers in the country.