Selective RET kinase inhibition for patients with RET-altered cancers

Abstract

BackgroundAlterations involving the RET kinase are implicated in the pathogenesis of lung, thyroid and other cancers. However, the clinical activity of multikinase inhibitors (MKIs) with anti-RET activity in RET-altered patients appears limited, calling into question the therapeutic potential of targeting RET. LOXO-292 is a selective RET inhibitor designed to inhibit diverse RET fusions, activating mutations and acquired resistance mutations.Patients and methodsPotent anti-RET activity, high selectivity, and central nervous system coverage were confirmed preclinically using a variety of in vitro and in vivo RET-dependent tumor models. Due to clinical urgency, two patients with RET-altered, MKI-resistant cancers were treated with LOXO-292, utilizing rapid dose-titration guided by real-time pharmacokinetic assessments to achieve meaningful clinical exposures safely and rapidly.ResultsLOXO-292 demonstrated potent and selective anti-RET activity preclinically against human cancer cell lines harboring endogenous RET gene alterations; cells engineered to express a KIF5B-RET fusion protein −/+ the RET V804M gatekeeper resistance mutation or the common RET activating mutation M918T; and RET-altered human cancer cell line and patient-derived xenografts, including a patient-derived RET fusion-positive xenograft injected orthotopically into the brain. A patient with RET M918T-mutant medullary thyroid cancer metastatic to the liver and an acquired RET V804M gatekeeper resistance mutation, previously treated with six MKI regimens, experienced rapid reductions in tumor calcitonin, CEA and cell-free DNA, resolution of painful hepatomegaly and tumor-related diarrhea and a confirmed tumor response. A second patient with KIF5B-RET fusion-positive lung cancer, acquired resistance to alectinib and symptomatic brain metastases experienced a dramatic response in the brain, and her symptoms resolved.ConclusionsThese results provide proof-of-concept of the clinical actionability of RET alterations, and identify selective RET inhibition by LOXO-292 as a promising treatment in heavily pretreated, multikinase inhibitor-experienced patients with diverse RET-altered tumors.

Targetable gene fusions identified in radioactive iodine refractory advanced thyroid carcinoma

“…Similar approaches could be feasible in DTCs with rearrangements involving ALK, 0.6-2.2% of all PTC and 1% in our series (29,30). Furthermore, LOXO-292 and BLU-667, selective and potent RET inhibitors (31,32), are currently being studied in Phase1/2 trials. LOXO-292 demonstrates robust anti-tumor activity in RET fusion positive thyroid cancer, according to interim clinical data reported at the 2018 American Thyroid Association annual meeting.…”

A Phase I/Ib Trial of the VEGFR-Sparing Multikinase RET Inhibitor RXDX-105

“…Finally, newer RET inhibitors, specifically those that are more selective for RET, such as LOXO-292 (22) and BLU-667 (12), are currently in clinical testing. Preliminary data have shown that these drugs have increased activity and improved tolerability compared with multikinase inhibitors, including RXDX-105 (23).…”

The role of molecular genetics in the clinical management of sporadic medullary thyroid carcinoma: A systematic review

“…34 It is notable that the studies Furthermore, its use in a patient with advanced sMTC with a confirmed somatic RET M918T mutation resulted in tumour regression, a drop in serum calcitonin and symptom improvement. 35 The second drug, BLU-667, is also a selective RET inhibitor still in phase 2 trials; however, once again preliminary data have shown a good response in a patient with sMTC and multiple RET mutations. 36 Clearly, it is too early to draw conclusions on the efficacy of these novel drugs or the relative effects in patients with different RET mutations; however, these preliminary results are promising.…”