RET Alterations in Advanced NSCLC

Stephen Liu, MD: RET does have a normal role in physiology. RET stands for rearranged during transfection, and it encodes a transmembrane receptor tyrosine kinase, which is important for the development of neurons. Particularly the enteric nervous system development of a lot of nerve signaling pathways. Its primary role in normal physiology is in the development of the gut, the enteric system, and the kidney.Mark A. Socinski, MD: RET alterations have been known since the 1980s. I’ve personally been involved with lung cancer programs that have tested for RET alterations for a decade or so. The frustration was that we didn’t have good selective RET inhibitors prior to the recent approval of pralsetinib and selpercatinib, which are highly active RET drugs. RET fusions, like ALK fusions, ROS1 fusions, and NTRK fusions, become oncogenic drivers. They turn on the growth pathway, survival pathways, and give the cancerous cells an advantage over the normal cell population, leading to uncontrolled proliferation, which is one of the hallmarks of cancer.

Ben Levy, MD: We now have data that shows RET has multiple fusion partners. In fact, there’s more than 40 unique fusion partners for RET, when we talk about RET fusions in lung cancer, and particularly other solid tumor cancers, like thyroid. Most importantly, the most common RET fusion partner is the KIF5B fusion partner. This is the one that we saw most commonly in both the selpercatinib data and the pralsetinib data, but there are other fusions that have been seen. CCDC6 and NCOA4 are also fusion partners that can be identified. Clearly, it’s important to make sure that you have a fusion. When you’re looking at a next-generation sequencing report, it’s not a RET mutation that predicts sensitivity to these new FDA-approved therapies, it’s the fusion. So yes, you can look at the fusion partner and see what it is, but I think we’re still trying to learn whether the type of fusion partner predicts efficacy to selpercatinib and pralsetinib. I think we know that the RET fusion partner, KIF5B, does predict efficacy to both pralsetinib and selpercatinib. But fusions aren’t mutations. When you’re getting a next-generation sequencing report, make sure it’s the fusion. And then yes, of course you can look at the partner. But did they tell a different story? That’s important to understand.

Transcript edited for clarity.