Selpercatinib is the world's first approved highly selective RET inhibitor, first approved in the United States in May 2020 and officially launched in mainland China in September 2022.

Indications for Selpercatinib

The FDA prescribing information currently lists four indications for Selpercatinib. The approvals in China cover a portion of the first three indications, while the fourth has not yet been approved domestically:

1. RET fusion-positive non-small cell lung cancer (NSCLC): The FDA version is indicated for adult patients with locally advanced or metastatic disease; it is approved in China, restricted to adults.

2. RET-mutant medullary thyroid cancer (MTC): The FDA version is indicated for adult and pediatric patients 2 years of age and older who require systemic therapy; it is approved in China, restricted to adults and pediatric patients 12 years of age and older.

3. RET fusion-positive thyroid cancer: Advanced or metastatic thyroid cancer in adult and pediatric patients 2 years of age and older who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is an appropriate treatment option). It is approved in China, restricted to adults and pediatric patients 12 years of age and older, and similarly limited to radioactive iodine-refractory cases.

4. Other RET fusion-positive solid tumors: The FDA version is indicated for adult and pediatric patients 2 years of age and older that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options; this indication has not yet been approved in China.

Mechanism of Action of Selpercatinib

In normal cells, the RET gene is responsible for transmitting growth signals and should turn off once the signal is delivered. When the RET gene undergoes fusion or specific point mutations, this "switch" gets stuck in the open position, continually transmitting signals downwards and causing cells to proliferate endlessly—this is the origin of RET-driven tumors.

The role of Selpercatinib is to directly bind to and inhibit both wild-type RET and multiple mutated RET proteins, cutting off this out-of-control signaling pathway. Additionally, it can cross the blood-brain barrier.

Precautions Before Using Selpercatinib

Before initiating treatment, the presence of a RET gene fusion (in lung cancer, thyroid cancer, and other solid tumors) or specific RET gene mutations (in medullary thyroid cancer) must be confirmed through testing.

The FDA prescribing information explicitly requires the use of an FDA-approved test, and currently, there is no approved companion diagnostic test for detecting RET fusions and mutations in plasma.

Selpercatinib is a first-generation highly selective RET inhibitor. Prior to its availability, patients with RET fusion-positive lung cancer mostly used multi-kinase inhibitors (such as cabozantinib and vandetanib); these drugs hit multiple targets simultaneously, resulting in poor selectivity and severe adverse reactions.