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Molecular Drivers in Lung Adenocarcinoma: Therapeutic Implications
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Imayavaramban Lakshmanan, Apar Kishor Ganti
Several MET pathway inhibitors like HGF inhibitors (ficlatuzumab), anti-MET monoclonal antibodies (onartuzumab), and MET tyrosine kinase inhibitors (crizotinib, tivantinib) are currently being studied in combination with EGFR-TKIs [50, 56] (Table 3). A study by Mok et al. involving 188 Asian patients with stage IIIB/IV lung adenocarcinoma, who received either ficlatuzumab and gefitinib or gefitinib alone, did not find any statistically significant improvement with the combination [56]. However, preliminary results in a subset of patients with both EGFR sensitizing mutations and low c-Met biomarker levels showed that the combination had a trend towards ORR and PFS improvement, and for prolonged OS in those with high stromal HGF (P = 0.03) [56]. In another phase II study, onartuzumab, a monovalent antibody against c-MET-, was associated with improved PFS and OS in the MET-positive population while the MET-negative patients had worse outcomes [57]. Sequist et al. compared erlotinib alone with the combination of erlotinib and tivantinib (ARQ 197), a non-patients in the study had MET gene copy number ≥ 4, equally distributed between the treatment arms. There were no statistically significant differences in PFS or OS, though the combination of erlotinib and tivantinib had a trend towards benefit in patients with increased MET gene copy number [58] (Table 3).
Hepatocellular Carcinoma
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Daniel H. Palmer, Philip J. Johnson
A better understanding of the mechanisms of resistance to VEGF-targeted therapies may help improve therapeutic strategies. For example there is evidence that hepatocyte growth factor (HGF) signaling through its receptor, c-met, may play a role in mediating such resistance and, indeed, may contribute to the emergence of a more aggressive phenotype during anti-VEGF therapy. This suggests a potential role for c-met inhibition as a second-line strategy, or in combination with anti-angiogenic therapy. The c-met inhibitor tivantinib has been investigated in a randomized phase II trial for patients with HCC and significantly prolonged time to progression, the primary endpoint of the study, compared with best supportive care (HR 0.64). An exploratory analysis of survival according to c-met expression assessed by immunohistochemistry on tumor biopsies suggested that c-met was an adverse prognostic factor and that patients with high c-met may derive greatest benefit.94 However, a prospective phase III trial enrolling patients with high c-met expression failed to demonstrate a survival benefit in this population.95 Conversely, a phase III placebo-controlled trial of cabozantinib, which also inhibits c-met (as well as other targets), did demonstrate a survival benefit in patients previously treated with anti-angiogenic drugs (largely sorafenib) without any biomarker selection.96
Genome-Based Personalized Medicine in Liver Cancer
Published in II-Jin Kim, Cancer Genetics and Genomics for Personalized Medicine, 2017
Sorafenib, an oral multikinase inhibitor, is an only proven systemic agent to increase overall survival in patients with advanced HCC.9 However, its antineoplastic effect is marginal, suggesting that only a small fraction of patients might respond to the treatment. Recently, extensive search for informative biomarkers has been taking place to identify patients who would get greater benefits from sorafenib treatment.10, 11, 12–13 However, no robust markers have emerged from screening yet. Thus, selecting an optimal candidate for sorafenib treatment is a challenge to many clinicians. Until 2013, most phase III clinical trials with multikinase inhibitors, including sunitinib, brivanib, linifanib, and erlotinib, have failed in patients with advanced HCC.14, 15, 16–17 The major reason of the failure is not clear; however, genetic heterogeneity of liver cancer and lack of understanding of critical drivers of tumor progression might be accountable for the failure.8 In a phase II trial, tivantinib (a selective oral inhibitor of MET) showed no effect on liver cancer, but a significant survival benefit was achieved when MET-positive patients were included.18 Large-scale mutational screening approaches have enabled the identification of new disease drivers in some solid tumors such as lung, breast, or melanoma.19 This approach will open the opportunity to identify underlying drivers in liver cancer, too. Molecular classification of liver cancer would have a greater role in future rationalized clinical trials and will enable identification of the patients who will benefit from certain treatments. Recent development in technology have shown that personalized medicine is not far from becoming a reality.
Experimental drug treatments for hepatocellular carcinoma: clinical trial failures 2015 to 2021
Published in Expert Opinion on Investigational Drugs, 2022
Zachary J. Brown, D. Brock Hewitt, Timothy M. Pawlik
The c-MET inhibitors, tepotinib, capmatinib, and tivantinib have also been studied in patients with advanced HCC. Capmatinib had an ORR of 30%, including 1 durable CR and 2 PRs in a subgroup of 10 patients with MET-high HCC [40]. In a phase 1b/2 study, tepotinib produced a median TTP of 4 months in patients with HCC previously treated with sorafenib and MET overexpression. In a phase 3 study of tivantinib in MET-high advanced HCC, tivantinib did not improve OS compared to placebo with a median OS of 8.4 months in the tivantinib group and 9.1 months in the placebo group (p = 0 · 81) [41]. In this trial, tivantinib was given at a dose of 120 mg twice daily, while in the phase II study patients were treated with 360 mg daily. The dose reduction was due to the high incidence of grade 3 or worse neutropenia associated with the higher dose [42]. Of note, a defined immunohistochemistry score has been used to define HCC tumor sensitivity to MET inhibition, as well as the presence of high intratumoral heterogeneity of MET expression in HCC [43,44]. Other kinase inhibitors have been utilized in the treatment of HCC, such as foretinib, selumetinib, nintedanib, tivozanib, and donafenib with mixed results [45–49]. (Table 2).
Capmatinib for the treatment of non-small cell lung cancer
Published in Expert Review of Anticancer Therapy, 2019
Johan Filip Vansteenkiste, Charlotte Van De Kerkhove, Els Wauters, Pierre Van Mol
Small-molecule MET inhibitors are now being explored. These tyrosine kinase inhibitors (TKIs) are divided into types I (subtype Ia and Ib), II, and III. Type I inhibitors block ATP binding, thereby preventing phosphorylation/activation of the receptor; type Ib inhibitors (e.g. capmatinib, tepotinib, savolitinib, AMG 337) are more specific for MET than type Ia inhibitors (e.g. crizotinib). Type II inhibitors (e.g. cabozantinib, glesatinib, merestinib) are also ATP competitive, binding to a hydrophobic pocket adjacent to the ATP binding site, whereas type III (e.g. tivantinib) inhibitors bind to allosteric sites rather than the ATP-binding site [21]. MET-targeted therapies currently in clinical development include type I and type II inhibitors [21], whether they aim to target MET exon 14 skipping mutations, MET amplification (e.g. SAR125844 and AMG 337) [22,23], or both MET exon 14 skipping mutations and MET amplification (e.g. crizotinib, savolitinib, tepotinib, and capmatinib) [24–29]. Of note, clinical trials investigating the small-molecule MET inhibitor tivantinib were terminated early due to futility [30,31], which could partly be due to poor selection of patients into the trials [32]. However, the toxicity observed with tivantinib treatment might have been a result of its microtubule disruption activity [33].
Optimization techniques for novel c-Met kinase inhibitors
Published in Expert Opinion on Drug Discovery, 2019
Zhi-Gang Sun, Yong-An Yang, Zhi-Gang Zhang, Hai-Liang Zhu
There are three groups of c-Met kinase inhibitors [38], including two adenosine triphosphate (ATP)-competitive c-Met inhibitor groups (type I and II) and one ATP noncompetitive c-Met inhibitor group. Type I c-Met inhibitors are believed to interact with the U-shaped ATP binding pocket of c-Met, specifically with residue Met1160 by hydrogen bonding in the hinge region. This makes type I c-Met inhibitors more selective than type II c-Met inhibitors. They also interact with the residue Tyr1230 with a typical π–π stacking. Crizotinib is a type I inhibitor of not only c-Met but also c-ros oncogene 1, receptor tyrosine kinase (ROS1), recepteur d’origine nantais, and anaplastic lymphoma kinase. Type II c-Met inhibitors recognize inactivated conformation of the c-Met activation loop, which is called DFG-out, and they usually can inhibit multiple kinases. Cabozantinib is a type II c-Met inhibitor and inhibits vascular endothelial growth factor receptor 2, c-Met, FMS-like tyrosine kinase-3, and Kit (stem-cell factor receptor). Tivantinib is an ATP noncompetitive c-Met inhibitor which interacts with the inactive c-Met conformation.