Precision Targeted Therapy with BLU

Targeting oncogenic driver kinases with specifically tailored inhibitors has transformed the management of a variety of hematologic malignancies and solid tumors. First-generation kinase inhibitors directed against oncogenic drivers such as BCR–ABL fusions (imatinib), EGFR mutations (erlotinib and gefitinib), and ALK rearrangements (crizotinib) have demonstrated vast improvements over cytotoxic chemotherapy in chronic myelogenous leukemia and kinase-driven non–small cell lung cancer (NSCLC), respectively (1–4). These early successes established a new treatment paradigm for the use of targeted kinase inhibitors to benefit genetically defined patient populations. Despite the effectiveness of these approaches, however, acquired resistance to therapy has emerged as a major clinical challenge, spurring efforts to develop more potent and selective next-generation kinase inhibitors that also encompass activity against observed and predicted resistance mutations (5–9).

Rearranged during transfection (RET) is a receptor tyrosine kinase and bona fide oncogene that drives various cancers (10–16). RET normally plays a critical role in kidney morphogenesis and embryonic development of the enteric nervous system. However, oncogenic RET alterations promote ligand-independent, constitutive RET kinase activation, which drives tumorigenesis. To date, two major mechanisms of RET kinase activation have been described: (i) RET point mutations and (ii) RET gene rearrangements. RET missense mutations can occur in extracellular cysteine residues (e.g., C620R and C634R/W), which trigger aberrant receptor dimerization, or in the intracellular kinase domain, which promotes ligand-independent kinase activation (e.g., V804L/M, M918T; ref. 17). Activating point mutations are most commonly found in medullary thyroid cancer (MTC); approximately 50% of sporadic MTCs harbor activating RET mutations, and nearly all cases of familial MTC contain a germline activating RET mutation (17, 18). Alternatively, RET activation can occur via gene rearrangement. RET rearrangements create a fusion protein juxtaposing the RET kinase domain and a dimerization domain of another protein, creating a constitutively activated dimer (19). RET fusions are seen in 10% to 20% of papillary thyroid cancer (PTC), 1% to 2% of NSCLCs, and multiple other cancer subtypes, including colorectal and breast cancers (10–18). Together, these data indicate that dysregulated RET signaling can act as an important driver across multiple tumor indications.

Although RET was one of the first kinase fusions cloned from an epithelial tumor (20), patients with RET-driven cancers have derived only modest benefit from RET-directed strategies to date. It should be noted, however, that RET therapies thus far have largely centered around multikinase inhibitors (MKI) that have been repurposed to treat patients with RET alterations. For example, the MKIs cabozantinib and vandetanib were originally designed to target other kinases, such as VEGFR2, tyrosine–protein kinase MET, and EGFR, and they inhibit these targets more potently than RET (21, 22). Cabozantinib and vandetanib are both approved for the treatment of patients with metastatic or locally advanced MTC and have documented activity in patients with RET fusion–driven NSCLC, yet each agent has produced limited disease control and lower response rates compared with selective kinase inhibitors targeting other oncogenic drivers in NSCLC (23–26). In addition, the significant side-effect profiles of each can either limit use in certain patients or limit the dose that patients can tolerate. Furthermore, these agents are biochemically inactive against the RET V804L/M mutants. This gatekeeper position is associated with acquired resistance to tyrosine kinase inhibitors in other targeted therapy/kinase pairs, and mutations at this residue act as primary driver mutations in a subset of hereditary MTCs. Additional MKIs with ancillary RET activity, such as sunitinib, lenvatinib, regorafenib, and RXDX-105, have also been tested in RET-driven tumors with equally disappointing results (27). Together, these findings have led some investigators to question whether RET is a dominant oncogenic driver or whether currently available MKIs insufficiently inhibit RET in vivo due to narrow therapeutic indices.

Here, we describe BLU-667, a next-generation small-molecule RET inhibitor specifically designed for highly potent and selective targeting of oncogenic RET alterations, including the most prevalent RET fusions (e.g., KIF5B–RET and CCDC6–RET) and RET-activating mutations (e.g., C634W, M918T, and V804L/M). BLU-667 demonstrated increased RET potency and selectivity relative to MKIs both in vitro and in in vivo models of RET-driven thyroid, lung, and colorectal cancers. In early clinical testing, BLU-667 attenuated RET signaling and induced durable responses in patients with RET-altered NSCLC and MTC without notable off-target toxicity, establishing initial proof of principle for highly selective RET targeting in RET-driven malignancies.