RET inhibitor

, AXL and RET 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). 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. ==Investigational therapies==

Single-compounds Several other molecules are currently being investigated as selective RET inhibitors. Boston Therapeutics' BOS172738 seemingly falls in the same category as the approved first-generation inhibitors, with selectivity against VEGFR2, similar clinical activity, and susceptibility to the G810 resistance mutation. Combinations While selective inhibitors are not yet (as of 2021) being evaluated in combination with other compounds to treat therapy-naïve patients, they are still being investigated to treat RET fusions arising as resistance mechanisms to other treatments. Notably, around 5% of EGFR-mutated non-small-cell lung cancers develop RET fusions as a resistance mechanism to the third-generation EGFR inhibitor osimertinib. For these patients, the combination of osimertinib and selpercatinib is currently being evaluated in a cohort of the ORCHARD study. Discontinued compounds Among older compounds being investigated for RET inhibition, RXDX-105 was being developed by Ignyta as a VEGF-sparing multikinase inhibitor of BRAF, RET and EGFR. It was discontinued after acquisition of the company by Hoffmann-La Roche, citing a poor efficacy profile compared to the selective inhibitors being developed parallel to it. While it boasted a 75% response rate among fusions with non-KIF5B partners (6 out of 8 patients), there were no responses for patients with the KIF5B fusion partner (0 out of 20 patients), which represents more than 65% of RET fusions in NSCLC. Among cited reasons for this difference is the KIF5B promoter inducing higher expression of the KIF5B-RET fusion protein compared to other partners, which would result in incomplete inhibition at clinical doses of RXDX-105 and reduced therapeutic activity. ==Diagnostics==

In order to identify patients most likely to benefit from RET inhibitors, several companion diagnostic assays are approved. Regardless of the alteration, tissue-based NGS remains the gold standard with very high specificity and sensitivity. In the case of rearrangements, RT-PCR is a proven technique with high specificity and sensitivity, but it will miss fusions with rare partners. FISH can be used where other techniques are not available, but the relative subjectivity of the test along with the proximity of common partners to the RET gene can make it difficult to discern rearrangements. Plasma-based NGS assays are becoming more and more prevalent because of their ease of use and high specificity, although they are limited by how much circulating tumor DNA is present in the sample, which itself depends upon how much DNA the tumors shed into the blood. This means that while a positive result may be taken as certainty, a negative result might simply mean not enough material was collected, and should be confirmed with another technique to rule out a false-negative. == References ==