RET inhibitors are targeted therapies that act on tumors with activating alterations in the RET proto-oncogene, such as point mutations or fusions. They fall under the category of the tyrosine kinase inhibitors, which work by inhibiting proteins involved in the abnormal growth of cancer cells. Existing molecules fall in two main categories: the older multikinase inhibitors and the more recent selective inhibitors. Although RET alterations are found at low frequency in a broad range of tumors, the three main indications for RET inhibitors today are non-small cell lung cancer (which harbor RET fusions at a frequency of 1-2%), medullary thyroid cancer (MTC, with activating RET mutations in 25% of cases) and papillary thyroid cancer (PTC, with up to 80% prevalence of fusions depending on the region). As of 2020, up to 48 fusion partners have been catalogued in NSCLC rearrangements, with KIF5B and CCDC6 being the most prevalent. At least 10 different fusion variants have been described for KIF5B-RET, each with different breakpoints within the partner gene, but unclear clinical impact as of 2018.
Multikinase inhibitors
Multikinase inhibitors are molecules that possess a broad range of targets along with RET. These included cabozantinib, lenvatinib, sunitinib and alectinib. Since they were not designed to bind RET specifically, these inhibitors have other targets such as VEGFR, c-MET, and c-KIT. Among them, the VEGFR-related toxicities commonly precluded patients from achieving therapeutic doses with these medications, resulting in incomplete inhibition of RET and suboptimal clinical outcomes. In NSCLC, overall response rates (ORR) were low (16% for lenvatinib, 28% for cabozantinib ), and progression-free survival (PFS) hovered around 6 months with a very high percentage of patients requiring dose reductions or discontinuing treatment (73% of patients on cabozantinib). Resistance to these medications included on-target mutations on the V804 gatekeeper residue, as well as off-target mechanisms such as EGFR pathway activation and MDM2 amplifications. Differences in efficacy also arose depending on the fusion partner, with non-KIF5B fusions typically responding better to these multikinase inhibitors than KIF5B-RET-driven tumors.
Compared to the much higher response rates and longer progression-free survivals achieved by selective inhibitors in other kinase fusions such as ALK or ROS1, these molecules offered much more limited clinical benefit, which highlighted a critical need for highly selective RET inhibitors.
Selective RET inhibitors
Around 2017, the first selective RET inhibitors selpercatinib (LOXO-292) and pralsetinib (BLU-667) started their first phase I/II clinical trials in solid tumors. They were designed to have high potency for RET, along with low affinity for other related targets such as VEGFR-family kinases to limit off-target toxicities. They were also designed to overcome the V804 gatekeeper mutations that some patients acquired under multikinase inhibitors. In patients who had previously received platinum chemotherapies for their lung cancers, ORRs hovered around 60% with median PFS between 17 months and not-evaluable (NE). Similar promising results came out for thyroid cancers as well, with response rates at 70-80% and median PFS between 18 and 22 months. The encouraging results of the phase I/II trials led to the FDA approvals of selpercatinib (Retevmo™) for RET-driven NSCLC, MTC and PTC in May 2020, and the approval of pralsetinib (Gavreto™) for RET-fusion NSCLC in September 2020, as well as MTC and PTC in December 2020.
Resistance mechanisms to this first generation of selective RET inhibitors include different on-target mutations on the G810 solvent-front residue, as well as off-target alterations such as MET amplifications and KRAS mutations among others. TP53 mutational status appears to have an impact on prognosis and resistance mechanisms, with TP53-mutated tumors showing shorter PFS and mostly off-target resistance mechanisms.