X-396 (Ensartinib) is a novel, potent anaplastic lymphoma kinase (ALK) small molecule tyrosine kinase inhibitor (TKI) with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1 and SLK. Ensartinib has demonstrated activity in ALK treatment naïve and previously treated patients and has a generally well tolerated safety profile. Ensartinib is currently in a global phase 3 trial in ALK positive non-small cell lung cancer (NSCLC) patients. The phase 1/2 clinical findings support the preclinical results that the use of ensartinib may result in favorable therapeutic outcomes in patients with ALK NSCLC, including patients with CNS metastases. In this study, ensartinib was generally well tolerated with the most common adverse event being a rash.

Tepotinib is an investigational small molecule inhibitor of the c-Met receptor tyrosine kinase. Alterations of the c-Met signaling pathway are found in various cancer types and correlate with aggressive tumor behavior and poor clinical prognosis. Tepotinib is a potent and selective c-Met inhibitor, >200-fold selective for c-Met than IRAK4, TrkA, Axl, IRAK1, and Mer. Tepotinib is currently in Phase I/II trials in liver cancer and lung cancer.

Capmatinib (INC280, INCB028060), is an orally bioavailable inhibitor of the proto-oncogene c-Met (hepatocyte growth factor receptor [HGFR]) with potential antineoplastic activity. Novartis acquired Incyte's capmatinib, which is in Phase II clinical trial as monotherapy in patients with advanced hepatocellular carcinoma. Capmatinib selectively binds to c-Met, thereby inhibiting c-Met phosphorylation and disrupting c-Met signal transduction pathways. This may induce cell death in tumor cells overexpressing c-Met protein or expressing constitutively activated c-Met protein. c-Met, a receptor tyrosine kinase overexpressed or mutated in many tumor cell types, plays key roles in tumor cell proliferation, survival, invasion, metastasis, and tumor angiogenesis.

Ripretinib (DCC-2618) is an investigational, orally available switch control kinase inhibitor being developed for the treatment of gastrointestinal stromal tumors (GIST), advanced systemic mastocytosis (ASM), gliomas, and other solid tumors driven by tyrosine-protein kinase KIT (KIT) or platelet-derived growth factor alpha (PDGFRα) kinase. Ripretinib acts by forcing the activation loop (or activation "switch") of kinases into an inactive conformation and is a type II kinase inhibitor demonstrated to broadly inhibit activation loop mutations in KIT and PDGFRA, previously thought only achievable with type I inhibitor. Ripretinib is developed by the company Deciphera and is being investigated in phase 3 clinical trials for the treatment of GIST, ASM and other tumors.

Cabozantinib (development code name XL184; marketed under the trade name Cometriq) is an orally bioavailable, small molecule receptor tyrosine kinase (RTK) inhibitor with potential antineoplastic activity. Cabozantinib strongly binds to and inhibits several RTKs, which are often overexpressed in a variety of cancer cell types, including hepatocyte growth factor receptor (MET), RET (rearranged during transfection), vascular endothelial growth factor receptor types 1 (VEGFR-1), 2 (VEGFR-2), and 3 (VEGFR-3), mast/stem cell growth factor (KIT), FMS-like tyrosine kinase 3 (FLT-3), TIE-2 (TEK tyrosine kinase, endothelial), tropomyosin-related kinase B (TRKB) and AXL. This may result in an inhibition of both tumor growth and angiogenesis, and eventually lead to tumor regression. Cabozantinib was granted orphan drug status by the U.S. Food and Drug Administration (FDA) in January 2011. It is currently undergoing clinical trials for the treatment of prostate, bladder, ovarian, brain, melanoma, breast, non-small cell lung, pancreatic, hepatocellular and kidney cancers.

Crizotinib (trade name Xalkori, Pfizer, Inc.) is an anti cancer drug approved for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. Crizotinib is an inhibitor of receptor tyrosine kinases including ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), ROS1 (c-ros), and Recepteur d’Origine Nantais (RON). Common adverse reactions in clinical trials with crizotinib, occurring at an incidence of 25% or higher, included visual disorders, nausea, diarrhea, vomiting, constipation, edema, elevated transaminases, and fatigue. Crizotinib is currently under investigational study for use in treatment of Uveal Melanoma.

Foretinib is an orally available multikinase inhibitor that targets c-MET and VEGFR2 with high affinity, which may result in the inhibition of tumor angiogenesis, tumor cell proliferation and metastasis. Foretinib is an experimental drug candidate for the treatment of cancer. It was in Phase II trials for the treatment breast cancer, non-small cell lung cancer, gastric cancer, head and neck cancer and papillary renal-cell carcinoma. The most frequent adverse events of any grade associated with foretinib were fatigue, hypertension, gastrointestinal toxicities, and nonfatal pulmonary emboli.

Merestinib (LY2801653) is a small molecule that has been shown in vitro to be a reversible type II ATP-competitive slowoff inhibitor of MET tyrosine kinase with a dissociation constant (Ki) of 2 nM, a pharmacodynamic residence time (Koff) of 0.00132 min−1 and a half-life (t1/2) of 525 min. Preclinical testing also has shown merestinib to inhibit several other receptor tyrosine oncokinases including MST1R, FLT3, AXL, MERTK, TEK, ROS1, NTRK1/2/3, and DDR1/2 and the serine/threonine kinases MKNK1/2. Merestinib is being investigated in a phase II clinical trials in patients with biliary tract cancer, non-small cell lung cancer and solid tumours.

Glesatinib (MGCD265) is an orally bioavailable, small-molecule, multitargeted tyrosine kinase inhibitor with potential antineoplastic activity. Glesatinib binds to and inhibits the phosphorylation of several receptor tyrosine kinases (RTKs), including the c-Met receptor (hepatocyte growth factor receptor); the Tek/Tie-2 receptor; vascular endothelial growth factor receptor (VEGFR) types 1, 2, and 3; and the macrophage-stimulating 1 receptor (MST1R or RON). Inhibition of these RTKs and their downstream signaling pathways may result in the inhibition of tumor angiogenesis and tumor cell proliferation in tumors overexpressing these RTKs. Studies in a gastric cancer xenograft model revealed that, in addition to the typically reported cellular activities, glesatinib in combination with erlotinib disrupted the glycolysis pathway, suggesting a novel mechanism of action for this drug. Glesatinib has been studied in a variety of advanced solid tumors including NSCLC, as a monotherapy and in combination with either docetaxel or erlotinib. In an ongoing phase 1 study in patients with MET positive or AXL-rearranged advanced solid tumors, glesatinib demonstrated preliminary single-agent activity, with all three patients with MET dysregulated NSCLC (two with METex14 alterations and one with increased GCN) showing significant tumor regression at the first assessment. A phase 2 study is currently recruiting patients with MET-dysregulated (mutated or amplified) advanced or metastatic NSCLC.

Sitravatinib (MGCD516) is a receptor tyrosine kinases (RTK) inhibitor that blocks a wide array of RTKs known to be amplified/overexpressed in sarcomas, which are key regulators of signaling pathways that lead to cell growth, survival and tumor progression. It is involved in driving sarcoma cell growth with IC50 of 3980 nM and is superior to other multi-kinase inhibitors in inhibiting cell proliferation, RTK phosphorylation, and phosphorylation of downstream effectors. The efficacy of sitravatinib was tested using a wide panel of sarcoma cell lines, including malignant peripheral nerve sheath tumor (MPNST), Ewing sarcoma (A673), osteosarcoma (Saos2), and liposarcoma (DDLS, LS141). Both in vitro and in vivo efficacy sitravatinib was significantly better that the other two multi-kinase inhibitors, imatinib and crizotinib. Sitravatinib treatment not only inhibits tumor cell proliferation at low nanomolar concentrations in vitro but also results significant tumor growth suppression in vivo in mouse xenograft models. Sitravatinib is being evaluated in a Phase 1b dose expansion cohort in selected patients with specific genetic alterations that are drivers of tumor growth, with an initial focus on Non-Small-Cell Lung carcinoma (NSCLC) and in other solid tumors where sitravatinib may confer a benefit. Its efficacy and safety is also being tested in Phase II clinical trials in patients with advanced liposarcoma as a monotherapy and NSCLC in combination with nivolumab.