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Drug Safety

pp 1–23 | Cite as

Safety and Tolerability of c-MET Inhibitors in Cancer

  • Alberto Puccini
  • Nagore I. Marín-Ramos
  • Francesca Bergamo
  • Marta Schirripa
  • Sara Lonardi
  • Heinz-Josef Lenz
  • Fotios Loupakis
  • Francesca BattaglinEmail author
Review Article
  • 91 Downloads

Abstract

The role of aberrant hepatocyte growth factor receptor (c-MET, also known as tyrosine-protein kinase MET)/hepatocyte growth factor (HGF) signaling in cancer progression and invasion has been extensively studied. c-MET inhibitors have shown promising pre-clinical and early phase clinical trial anti-tumor activity in several tumor types, although results of most phase III trials with these agents have been negative. To date, two small molecule c-MET inhibitors, cabozantinib and crizotinib, have been approved by regulatory authorities for the treatment of selected cancer types, but several novel c-MET inhibitors (either monoclonal antibodies or small molecule c-MET tyrosine kinase inhibitors) and treatment combinations are currently under study in different settings. Here we provide an overview of the mechanism of action and rationale of c-MET inhibition in cancer, the efficacy of approved agents, and novel promising c-MET-inhibitors and novel targeted combination strategies under development in different cancer types, with a focus on the safety profile and tolerability of these compounds.

Notes

Author Contributions

FB, AP and NIM-R drafted the manuscript. FB supervised the manuscript. All authors directly provided their contribution, read and approved the final manuscript.

Compliance with Ethical Standards

Conflict of interest

Francesca Battaglin has received honoraria for lectures from Eli Lilly and Company, and travel/accommodation support from Bayer and Amgen Inc. Heinz-Josef Lenz has received clinical trial financial support from Merck Serono and Roche, honoraria for advisory board membership and lectures from Bayer, Boehringer Ingelheim, Genentech, Pfizer, Merck Serono and Roche, and travel/accommodation support from Bayer, Merck Serono and Roche. Fotios Loupakis has received travel/accommodation support from Amgen Inc., Merck Serono and Roche. Sara Lonardi has received research funding from Merck Serono and Amgen Inc., honoraria for consulting/advisory roles from Amgen Inc., Bayer Healthcare, Merck Serono and Eli Lilly and Company, and honoraria for speakers’ bureau from Eli Lilly and Company, Bristol-Myers Squibb and Roche. Alberto Puccini, Nagore I. Marín-Ramos, Francesca Bergamo and Marta Schirripa have no conflicts of interest that are directly relevant to the content of this manuscript.

Funding

This manuscript was partly supported by the National Cancer Institute (grant number P30CA014089), the Gloria Borges WunderGlo Foundation–The Wunder Project, the Dhont Family Foundation, the San Pedro Peninsula Cancer Guild, the Daniel Butler Research Fund, and the Call to Cure Research Fund. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.

References

  1. 1.
    Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2010;141(7):1117–34.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Schmidt C, Bladt F, Goedecke S, Brinkmann V, Zschiesche W, Sharpe M, et al. Scatter factor/hepatocyte growth factor is essential for liver development. Nature. 1995;373(6516):699–702.PubMedCrossRefGoogle Scholar
  3. 3.
    Chmielowiec J, Borowiak M, Morkel M, Stradal T, Munz B, Werner S, et al. c-Met is essential for wound healing in the skin. J Cell Biol. 2007;177(1):151–62.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Uehara Y, Minowa O, Mori C, Shiota K, Kuno J, Noda T, et al. Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor. Nature. 1995;373(6516):702–5.PubMedCrossRefGoogle Scholar
  5. 5.
    Boccaccio C, Comoglio PM. MET, a driver of invasive growth and cancer clonal evolution under therapeutic pressure. Curr Opin Cell Biol. 2014;31:98–105.PubMedCrossRefGoogle Scholar
  6. 6.
    Zhang Y, Xia M, Jin K, Wang S, Wei H, Fan C, et al. Function of the c-Met receptor tyrosine kinase in carcinogenesis and associated therapeutic opportunities. Mol Cancer. 2018;17(1):45.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Cappuzzo F, Marchetti A, Skokan M, Rossi E, Gajapathy S, Felicioni L, et al. Increased MET gene copy number negatively affects survival of surgically resected non-small-cell lung cancer patients. J Clin Oncol. 2009;27(10):1667–74.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Zhao X, Qu J, Hui Y, Zhang H, Sun Y, Liu X, et al. Clinicopathological and prognostic significance of c-Met overexpression in breast cancer. Oncotarget. 2017;8(34):56758–67.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Garajova I, Giovannetti E, Biasco G, Peters GJ. c-Met as a target for personalized therapy. Transl Oncogenom. 2015;7(Suppl 1):13–31.Google Scholar
  10. 10.
    Ko B, He T, Gadgeel S, Halmos B. MET/HGF pathway activation as a paradigm of resistance to targeted therapies. Ann Transl Med. 2017;5(1):4.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Crizotinib (Xalkori®) FDA label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/202570s021lbl.pdf. Accessed 4 Octob 2018.
  12. 12.
  13. 13.
    Cabozantinib (Cometriq®) FDA label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203756lbl.pdf. Accessed 4 Oct 2018.
  14. 14.
  15. 15.
    Cabozantinib (Cabometyx®) FDA label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208692s000lbl.pdf. Accessed 4 Oct 2018.
  16. 16.
  17. 17.
    Qiu P, Wang S, Liu M, Ma H, Zeng X, Zhang M, et al. Norcantharidin inhibits cell growth by suppressing the expression and phosphorylation of both EGFR and c-Met in human colon cancer cells. BMC Cancer. 2017;17(1):55.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Hughes VS, Siemann DW. Have clinical trials properly assessed c-Met inhibitors? Trends Cancer. 2018;4(2):94–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Organ SL, Tsao MS. An overview of the c-MET signaling pathway. Ther Adv Med Oncol. 2011;3(1 Suppl):S7–19.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Parikh PK, Ghate MD. Recent advances in the discovery of small molecule c-Met Kinase inhibitors. Eur J Med Chem. 2018;143:1103–38.PubMedCrossRefGoogle Scholar
  21. 21.
    Mo H-N, Liu P. Targeting MET in cancer therapy. Chronic Dis Transl Med. 2017;3(3):148–53.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Goździk-Spychalska J, Szyszka-Barth K, Spychalski Ł, Ramlau K, Wójtowicz J, Batura-Gabryel H, et al. c-MET inhibitors in the treatment of lung cancer. Curr Treat Options Oncol. 2014;15(4):670–82.PubMedCrossRefGoogle Scholar
  23. 23.
    Bouattour M, Raymond E, Qin S, Cheng AL, Stammberger U, Locatelli G, et al. Recent developments of c-Met as a therapeutic target in hepatocellular carcinoma. Hepatology (Baltimore, MD). 2018;67(3):1132–49.CrossRefGoogle Scholar
  24. 24.
    Ou S-HI, Kwak EL, Siwak-Tapp C, Dy J, Bergethon K, Clark JW, et al. Activity of crizotinib (PF02341066), a dual mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK) inhibitor, in a non-small cell lung cancer patient with de novo MET amplification. J Thoracic Oncol. 2011;6(5):942–6.Google Scholar
  25. 25.
    Crinò L, Kim D, Riely GJ, Janne PA, Blackhall FH, Camidge DR, et al. Initial phase II results with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC): PROFILE 1005. J Clin Oncol. 2011;29(15_suppl):7514.Google Scholar
  26. 26.
    Blackhall F, Ross Camidge D, Shaw AT, Soria JC, Solomon BJ, Mok T, et al. Final results of the large-scale multinational trial PROFILE 1005: efficacy and safety of crizotinib in previously treated patients with advanced/metastatic ALK-positive non-small-cell lung cancer. ESMO Open. 2017;2(3):e000219.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Camidge DR, Bang YJ, Kwak EL, Iafrate AJ, Varella-Garcia M, Fox SB, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 2012;13(10):1011–9.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Shaw AT, Kim DW, Nakagawa K, Seto T, Crino L, Ahn MJ, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368(25):2385–94.PubMedCrossRefGoogle Scholar
  29. 29.
    Solomon BJ, Mok T, Kim D-W, Wu Y-L, Nakagawa K, Mekhail T, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371(23):2167–77.CrossRefGoogle Scholar
  30. 30.
    Solomon BJ, Kim D-W, Wu Y-L, Nakagawa K, Mekhail T, Felip E, et al. Final overall survival analysis from a study comparing first-line crizotinib versus chemotherapy in ALK-mutation-positive non–small-cell lung cancer. J Clin Oncol. 2018;36(22):2251–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Shaw AT, Ou SH, Bang YJ, Camidge DR, Solomon BJ, Salgia R, et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med. 2014;371(21):1963–71.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Drilon AE, Camidge DR, Ou S-HI, Clark JW, Socinski MA, Weiss J, et al. Efficacy and safety of crizotinib in patients (pts) with advanced MET exon 14-altered non-small cell lung cancer (NSCLC). J Clin Oncol. 2016;34(15_suppl):108.Google Scholar
  33. 33.
    Gambacorti-Passerini C, Orlov S, Zhang L, Braiteh F, Huang H, Esaki T, et al. Long-term effects of crizotinib in ALK-positive tumors (excluding NSCLC): a phase 1b open-label study. Am J Hematol. 2018;93(5):607–14.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Mossé YP, Voss SD, Lim MS, Rolland D, Minard CG, Fox E, et al. Targeting ALK with crizotinib in pediatric anaplastic large cell lymphoma and inflammatory myofibroblastic tumor: a Children’s Oncology Group Study. J Clin Oncol. 2017;35(28):3215–21.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Schoffski P, Wozniak A, Kasper B, Aamdal S, Leahy MG, Rutkowski P, et al. Activity and safety of crizotinib in patients with alveolar soft part sarcoma with rearrangement of TFE3: European Organization for Research and Treatment of Cancer (EORTC) phase II trial 90101 ‘CREATE’. Ann Oncol. 2018;29(3):758–65.PubMedCrossRefGoogle Scholar
  36. 36.
    Schoffski P, Wozniak A, Stacchiotti S, Rutkowski P, Blay JY, Lindner LH, et al. Activity and safety of crizotinib in patients with advanced clear-cell sarcoma with MET alterations: European Organization for Research and Treatment of Cancer phase II trial 90101 ‘CREATE’. Ann Oncol. 2017;28(12):3000–8.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Schoffski P, Wozniak A, Escudier B, Rutkowski P, Anthoney A, Bauer S, et al. Crizotinib achieves long-lasting disease control in advanced papillary renal-cell carcinoma type 1 patients with MET mutations or amplification. EORTC 90101 CREATE trial. Eur J Cancer (Oxford, England: 1990). 2017;87:147–63.Google Scholar
  38. 38.
    Ou SI, Govindan R, Eaton KD, Otterson GA, Gutierrez ME, Mita AC, et al. Phase I results from a study of crizotinib in combination with erlotinib in patients with advanced nonsquamous non-small cell lung cancer. J Thorac Oncol. 2017;12(1):145–51.PubMedCrossRefGoogle Scholar
  39. 39.
    Janne PA, Shaw AT, Camidge DR, Giaccone G, Shreeve SM, Tang Y, et al. Combined pan-HER and ALK/ROS1/MET inhibition with dacomitinib and crizotinib in advanced non-small cell lung cancer: results of a phase I study. J Thorac Oncol. 2016;11(5):737–47.PubMedCrossRefGoogle Scholar
  40. 40.
    Kato S, Jardim DL, Johnson FM, Subbiah V, Piha-Paul S, Tsimberidou AM, et al. Phase I study of the combination of crizotinib (as a MET inhibitor) and dasatinib (as a c-SRC inhibitor) in patients with advanced cancer. Invest New Drugs. 2018;36(3):416–23.PubMedCrossRefGoogle Scholar
  41. 41.
    Broniscer A, Jia S, Mandrell B, Hamideh D, Huang J, Onar-Thomas A, et al. Phase 1 trial, pharmacokinetics, and pharmacodynamics of dasatinib combined with crizotinib in children with recurrent or progressive high-grade and diffuse intrinsic pontine glioma. Pediatr Blood Cancer. 2018;65(7):e27035.PubMedCrossRefGoogle Scholar
  42. 42.
    Spigel DR, Reynolds C, Waterhouse D, Garon EB, Chandler J, Babu S, et al. Phase 1/2 study of the safety and tolerability of nivolumab plus crizotinib for the first-line treatment of anaplastic lymphoma kinase translocation—positive advanced non-small cell lung cancer (CheckMate 370). J Thorac Oncol. 2018;13(5):682–8.PubMedCrossRefGoogle Scholar
  43. 43.
    Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011;10(12):2298–308.PubMedCrossRefGoogle Scholar
  44. 44.
    Bentzien F, Zuzow M, Heald N, Gibson A, Shi Y, Goon L, et al. In vitro and in vivo activity of cabozantinib (XL184), an inhibitor of RET, MET, and VEGFR2, in a model of medullary thyroid cancer. Thyroid. 2013;23(12):1569–77.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Kurzrock R, Sherman SI, Ball DW, Forastiere AA, Cohen RB, Mehra R, et al. Activity of XL184 (cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol. 2011;29(19):2660–6.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Choueiri TK, Pal SK, McDermott DF, Morrissey S, Ferguson KC, Holland J, et al. A phase I study of cabozantinib (XL184) in patients with renal cell cancer. Ann Oncol. 2014;25(8):1603–8.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Nguyen HM, Ruppender N, Zhang X, Brown LG, Gross TS, Morrissey C, et al. Cabozantinib inhibits growth of androgen-sensitive and castration-resistant prostate cancer and affects bone remodeling. PLoS One. 2013;8(10):e78881.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Sadiq AA, Salgia R. MET as a possible target for non-small-cell lung cancer. J Clin Oncol. 2013;31(8):1089–96.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Drilon A, Rekhtman N, Arcila M, Wang L, Ni A, Albano M, et al. Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm trial. Lancet Oncol. 2016;17(12):1653–60.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Elisei R, Schlumberger MJ, Muller SP, Schoffski P, Brose MS, Shah MH, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31(29):3639–46.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Cabanillas ME, Brose MS, Holland J, Ferguson KC, Sherman SI. A phase I study of cabozantinib (XL184) in patients with differentiated thyroid cancer. Thyroid. 2014;24(10):1508–14.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Cabanillas ME, de Souza JA, Geyer S, Wirth LJ, Menefee ME, Liu SV, et al. Cabozantinib as salvage therapy for patients with tyrosine kinase inhibitor-refractory differentiated thyroid cancer: results of a multicenter phase II International Thyroid Oncology Group trial. J Clin Oncol. 2017;35(29):3315–21.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1814–23.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Choueiri TK, Halabi S, Sanford BL, Hahn O, Michaelson MD, Walsh MK, et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN trial. J Clin Oncol. 2017;35(6):591–7.PubMedCrossRefGoogle Scholar
  55. 55.
    Choueiri TK, Escudier B, Powles T, Tannir NM, Mainwaring PN, Rini BI, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17(7):917–27.PubMedCrossRefGoogle Scholar
  56. 56.
    Motzer RJ, Escudier B, Powles T, Scheffold C, Choueiri TK. Long-term follow-up of overall survival for cabozantinib versus everolimus in advanced renal cell carcinoma. Br J Cancer. 2018;118(9):1176–8.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Choueiri TK, Halabi S, Sanford B, Hahn O, Michaelson MD, Walsh M, et al. CABOzantinib versus SUNitinib (CABOSUN) as initial targeted therapy for patients with metastatic renal cell carcinoma (mRCC) of poor and intermediate risk groups: results from ALLIANCE A031203 trial. Ann Oncol. 2016;27(suppl_6):LBA30_PR-LBA_PR.Google Scholar
  58. 58.
    Abou-Alfa GK, Meyer T, Cheng A-L, El-Khoueiry AB, Rimassa L, Ryoo B-Y, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379(1):54–63.PubMedCrossRefGoogle Scholar
  59. 59.
    Nadal R, Mortazavi A, Stein M, Pal SK, Davarpanah N, Parnes HL, et al. 846OFinal results of a phase I study of cabozantinib (cabo) plus nivolumab (nivo) and cabonivo plus ipilimumab (Ipi) in patients (pts) with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignancies. Ann Oncol. 2017;28(suppl_5):mdx371.001–mdx371.001.Google Scholar
  60. 60.
    Nadal R, Mortazavi A, Stein MN, Pal SK, Lee DK, Parnes HL, et al. Clinical efficacy of cabozantinib plus nivolumab (CaboNivo) and CaboNivo plus ipilimumab (CaboNivoIpi) in patients (pts) with chemotherapy-refractory metastatic urothelial carcinoma (mUC) either naïve (n) or refractory (r) to checkpoint inhibitor (CPI). J Clin Oncol. 2018;36(15_suppl):4528.Google Scholar
  61. 61.
    Choueiri TK, Apolo AB, Powles T, Escudier B, Aren OR, Shah A, et al. A phase 3, randomized, open-label study of nivolumab combined with cabozantinib vs sunitinib in patients with previously untreated advanced or metastatic renal cell carcinoma (RCC; CheckMate 9ER). J Clin Oncol. 2018;36(15_suppl):TPS4598-TPS.Google Scholar
  62. 62.
    Tolaney SM, Nechushtan H, Ron IG, Schoffski P, Awada A, Yasenchak CA, et al. Cabozantinib for metastatic breast carcinoma: results of a phase II placebo-controlled randomized discontinuation study. Breast Cancer Res Treat. 2016;160(2):305–12.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Hirota T, Muraki S, Ieiri I. Clinical pharmacokinetics of anaplastic lymphoma kinase inhibitors in non-small-cell lung cancer. Clin Pharmacokinet. 2018.  https://doi.org/10.1007/s40262-018-0689-7.CrossRefPubMedGoogle Scholar
  64. 64.
    Tan W, Wilner KD, Bang Y, Kwak EL, Maki RG, Camidge DR, et al. Pharmacokinetics (PK) of PF-02341066, a dual ALK/MET inhibitor after multiple oral doses to advanced cancer patients. J Clin Oncol. 2010;28(15_suppl):2596.Google Scholar
  65. 65.
    Xu H, O’Gorman M, Boutros T, Brega N, Kantaridis C, Tan W, et al. Evaluation of crizotinib absolute bioavailability, the bioequivalence of three oral formulations, and the effect of food on crizotinib pharmacokinetics in healthy subjects. J Clin Pharmacol. 2015;55(1):104–13.PubMedCrossRefGoogle Scholar
  66. 66.
    Johnson TR, Tan W, Goulet L, Smith EB, Yamazaki S, Walker GS, et al. Metabolism, excretion and pharmacokinetics of [14C]crizotinib following oral administration to healthy subjects. Xenobiotica. 2015;45(1):45–59.PubMedCrossRefGoogle Scholar
  67. 67.
    El-Khoueiry AB, Sarantopoulos J, O’Bryant CL, Ciombor KK, Xu H, O’Gorman M, et al. Evaluation of hepatic impairment on pharmacokinetics and safety of crizotinib in patients with advanced cancer. Cancer Chemother Pharmacol. 2018;81(4):659–70.PubMedCrossRefGoogle Scholar
  68. 68.
    Tan W, Yamazaki S, Johnson TR, Wang R, O’Gorman MT, Kirkovsky L, et al. Effects of renal function on crizotinib pharmacokinetics: dose recommendations for patients with ALK-positive non-small cell lung cancer. Clin Drug Investig. 2017;37(4):363–73.PubMedCrossRefGoogle Scholar
  69. 69.
    Shi J, Montay G, Chapel S, Hardy P, Barrett JS, Sack M, et al. Pharmacokinetics and safety of the ketolide telithromycin in patients with renal impairment. J Clin Pharmacol. 2004;44(3):234–44.PubMedCrossRefGoogle Scholar
  70. 70.
    Zhou WJ, Zhang X, Cheng C, Wang F, Wang XK, Liang YJ, et al. Crizotinib (PF-02341066) reverses multidrug resistance in cancer cells by inhibiting the function of P-glycoprotein. Br J Pharmacol. 2012;166(5):1669–83.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Eliesen GAM, van den Broek P, van den Heuvel JJ, Bilos A, Pertijs J, van Drongelen J, et al. Editor’s highlight: placental disposition and effects of crizotinib: an ex vivo study in the isolated dual-side perfused human cotyledon. Toxicol Sci. 2017;157(2):500–9.PubMedCrossRefGoogle Scholar
  72. 72.
    Tang SC, Nguyen LN, Sparidans RW, Wagenaar E, Beijnen JH, Schinkel AH. Increased oral availability and brain accumulation of the ALK inhibitor crizotinib by coadministration of the P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar. Int J Cancer. 2014;134(6):1484–94.PubMedCrossRefGoogle Scholar
  73. 73.
    Sato T, Ito H, Hirata A, Abe T, Mano N, Yamaguchi H. Interactions of crizotinib and gefitinib with organic anion-transporting polypeptides (OATP)1B1, OATP1B3 and OATP2B1: gefitinib shows contradictory interaction with OATP1B3. Xenobiotica. 2018;48(1):73–8.PubMedCrossRefGoogle Scholar
  74. 74.
    Wang E, Nickens DJ, Bello A, Khosravan R, Amantea M, Wilner KD, et al. Clinical implications of the pharmacokinetics of crizotinib in populations of patients with non-small cell lung cancer. Clin Cancer Res. 2016;22(23):5722–8.PubMedCrossRefGoogle Scholar
  75. 75.
    Lacy S, Yang B, Nielsen J, Miles D, Nguyen L, Hutmacher M. A population pharmacokinetic model of cabozantinib in healthy volunteers and patients with various cancer types. Cancer Chemother Pharmacol. 2018;81(6):1071–82.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Lacy SA, Miles DR, Nguyen LT. Clinical pharmacokinetics and pharmacodynamics of cabozantinib. Clin Pharmacokinet. 2017;56(5):477–91.PubMedCrossRefGoogle Scholar
  77. 77.
    Nguyen L, Benrimoh N, Xie Y, Offman E, Lacy S. Pharmacokinetics of cabozantinib tablet and capsule formulations in healthy adults. Anticancer Drugs. 2016;27(7):669–78.PubMedCrossRefGoogle Scholar
  78. 78.
    Bersanelli M, Buti S. Cabozantinib in metastatic renal cell carcinoma: latest findings and clinical potential. Ther Adv Med Oncol. 2017;9(10):627–36.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Foti RS, Rock DA, Wienkers LC, Wahlstrom JL. Selection of alternative CYP3A4 probe substrates for clinical drug interaction studies using in vitro data and in vivo simulation. Drug Metab Dispos. 2010;38(6):981–7.PubMedCrossRefGoogle Scholar
  80. 80.
    Lacy S, Hsu B, Miles D, Aftab D, Wang R, Nguyen L. Metabolism and disposition of cabozantinib in healthy male volunteers and pharmacologic characterization of its major metabolites. Drug Metab Dispos. 2015;43(8):1190–207.PubMedCrossRefGoogle Scholar
  81. 81.
    Sharma N, Adjei AA. In the clinic: ongoing clinical trials evaluating c-MET-inhibiting drugs. Ther Adv Med Oncol. 2011;3(1 Suppl):S37–50.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Wakelee HA, Gettinger S, Engelman J, Jänne PA, West H, Subramaniam DS, et al. A phase Ib/II study of cabozantinib (XL184) with or without erlotinib in patients with non-small cell lung cancer. Cancer Chemother Pharmacol. 2017;79(5):923–32.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Crizotinib (Xalkori®) DDI: http://www.pdr.net/drug-summary/Xalkori-crizotinib-472. Accessed 20 Sept 2018.
  84. 84.
    Cabozantinib (Cabometyx®) DDI: http://www.pdr.net/drug-summary/Cabometyx-cabozantinib-3908. Accessed 20 Sept 2018.
  85. 85.
    Nickens D, Tan W, Wilner K, Camidge DR, Shapiro G, Dezube B, et al. Abstract 1673: A pharmacokinetics/pharmacodynamics evaluation of the concentration-QTc relationship of PF-02341066 (PF-1066), an ALK and c-MET/HGFR dual inhibitor administered orally to patients with advanced cancer. Cancer Res. 2010;70(8 Supplement):1673.Google Scholar
  86. 86.
    Oser MG, Jänne PA. A severe photosensitivity dermatitis caused by crizotinib. J Thoracic Oncol. 2014;9(7):e51–3.CrossRefGoogle Scholar
  87. 87.
    Yang S, Wu L, Li X, Huang J, Zhong J, Chen X. Crizotinib-associated toxic epidermal necrolysis in an ALK-positive advanced NSCLC patient. Mol Clin Oncol. 2018;8(3):457–9.PubMedPubMedCentralGoogle Scholar
  88. 88.
  89. 89.
  90. 90.
  91. 91.
  92. 92.
    Catenacci DVT, Tebbutt NC, Davidenko I, Murad AM, Al-Batran SE, Ilson DH, et al. Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(11):1467–82.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Doi T, Kang Y-K, Muro K, Jiang Y, Jain RK, Lizambri R. A phase 3, multicenter, randomized, double-blind, placebo-controlled study of rilotumumab in combination with cisplatin and capecitabine (CX) as first-line therapy for Asian patients (pts) with advanced MET-positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: The RILOMET-2 trial. J Clin Oncol. 2015;33(3_suppl):TPS226-TPS.Google Scholar
  94. 94.
    Van Cutsem E, Eng C, Nowara E, Swieboda-Sadlej A, Tebbutt NC, Mitchell E, et al. Randomized phase Ib/II trial of rilotumumab or ganitumab with panitumumab versus panitumumab alone in patients with wild-type KRAS metastatic colorectal cancer. Clin Cancer Res. 2014;20(16):4240–50.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Affronti ML, Jackman JG, McSherry F, Herndon JE, Massey EC, Lipp E, et al. Phase II study to evaluate the efficacy and safety of rilotumumab and bevacizumab in subjects with recurrent malignant glioma. Oncologist. 2018;23(8):889–98.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Tarhini AA, Rafique I, Floros T, Tran P, Gooding WE, Villaruz LC, et al. Phase 1/2 study of rilotumumab (AMG 102), a hepatocyte growth factor inhibitor, and erlotinib in patients with advanced non-small cell lung cancer. Cancer. 2017;123(15):2936–44.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Mok T, Park K, Geater S, Agarwal S, Han M, Komarnitsky P, et al. A randomized phase 2 study with exploratory biomarker analysis of ficlatuzumab, a humanized hepatocyte growth factor (HGF) inhibitory monoclonal antibody, in combination with gefitinib versus gefitinib alone in Asian patients with lung adenocarcinoma. Ann Oncol. 2012;23(Suppl 9):1198P.CrossRefGoogle Scholar
  98. 98.
    Mok TS, Geater SL, Su WC, Tan EH, Yang JC, Chang GC, et al. A randomized phase 2 study comparing the combination of ficlatuzumab and gefitinib with gefitinib alone in Asian patients with advanced stage pulmonary adenocarcinoma. J Thorac Oncol. 2016;11(10):1736–44.PubMedCrossRefGoogle Scholar
  99. 99.
    Spigel DR, Edelman MJ, O’Byrne K, Paz-Ares L, Mocci S, Phan S, et al. Results from the phase III randomized trial of onartuzumab plus erlotinib versus erlotinib in previously treated stage IIIB or IV non-small-cell lung cancer: METLung. J Clin Oncol. 2017;35(4):412–20.PubMedCrossRefGoogle Scholar
  100. 100.
    Bendell JC, Hochster HS, Hart LL, Firdaus I, Mace JR, McFarlane JJ, et al. A randomized, double-blind, phase II study of first-line FOLFOX plus bevacizumab with onartuzumab versus placebo in patients with metastatic colorectal cancer (mCRC). J Clin Oncol. 2015;33(3_suppl):663.Google Scholar
  101. 101.
    Shah MA, Bang Y-J, Lordick F, Alsina M, Chen M, Hack SP, et al. Effect of fluorouracil, leucovorin, and oxaliplatin with or without onartuzumab in HER2-negative, MET-positive gastroesophageal adenocarcinoma: the METGastric randomized clinical trial. JAMA Oncol. 2017;3(5):620–7.PubMedCrossRefGoogle Scholar
  102. 102.
    Rosen LS, Goldman JW, Algazi AP, Turner PK, Moser B, Hu T, et al. A first-in-human phase I study of a bivalent MET antibody, emibetuzumab (LY2875358), as monotherapy and in combination with erlotinib in advanced cancer. Clin Cancer Res. 2017;23(8):1910–9.PubMedCrossRefGoogle Scholar
  103. 103.
    Hultberg A, Morello V, Huyghe L, De Jonge N, Blanchetot C, Hanssens V, et al. Depleting MET-expressing tumor cells by ADCC provides a therapeutic advantage over inhibiting HGF/MET signaling. Can Res. 2015;75(16):3373–83.CrossRefGoogle Scholar
  104. 104.
    Aftimos PG, Barthelemy P, Rolfo CD, Hanssens V, Jonge ND, Silence K, et al. A phase I, first-in-human study of argx-111, a monoclonal antibody targeting c-met in patients with solid tumors. J Clin Oncol. 2015;33(15_suppl):2580.Google Scholar
  105. 105.
    Kang Y-K, LoRusso P, Salgia R, Yen C-J, Lin C-C, Ramanathan RK, et al. Phase I study of ABT-700, an anti-c-Met antibody, in patients (pts) with advanced gastric or esophageal cancer (GEC). J Clin Oncol. 2015;33(3_suppl):167.Google Scholar
  106. 106.
    Strickler JH, Weekes CD, Nemunaitis J, Ramanathan RK, Heist RS, Morgensztern D, et al. First-in-human phase I, dose-escalation and -expansion study of telisotuzumab vedotin, an antibody-drug conjugate targeting c-Met, in Patients with advanced solid tumors. J Clin Oncol. 2018:Jco2018787697.Google Scholar
  107. 107.
    Goldman J, Angevin E, Strickler J, Camidge D, Heist R, Morgensztern D, et al. MA 02.10 Phase I study of ABBV-399 (telisotuzumab vedotin) as monotherapy and in combination with erlotinib in NSCLC. J Thorac Oncol. 2017;12(11):S1805-S6.Google Scholar
  108. 108.
    Schuler MH, Berardi R, Lim W-T, Geel RV, De Jonge MJ, Bauer TM, et al. Phase (Ph) I study of the safety and efficacy of the cMET inhibitor capmatinib (INC280) in patients (pts) with advanced cMET + non-small cell lung cancer (NSCLC). J Clin Oncol. 2016;34(15-suppl):9067.CrossRefGoogle Scholar
  109. 109.
    Wu Y-L, Kim D-W, Felip E, Zhang L, Liu X, Zhou CC, et al. Phase (Ph) II safety and efficacy results of a single-arm ph ib/II study of capmatinib (INC280) + gefitinib in patients (pts) with EGFR-mutated (mut), cMET-positive (cMET +) non-small cell lung cancer (NSCLC). J Clin Oncol. 2016;34(15-suppl):9020.CrossRefGoogle Scholar
  110. 110.
    Felip E, Horn L, Patel JD, Sakai H, Scheele J, Bruns R, et al. Tepotinib in patients with advanced non-small cell lung cancer (NSCLC) harboring MET exon 14-skipping mutations: phase II trial. J Clin Oncol. 2018;36(15_suppl):9016.Google Scholar
  111. 111.
    Qin S, Kim T-Y, Lim HY, Ryoo B-Y, Scheele J, Zhou D, et al. Phase Ib trial of tepotinib in Asian patients with advanced hepatocellular carcinoma (HCC): final data including long-term outcomes. J Clin Oncol. 2017;35(15_suppl):4087.Google Scholar
  112. 112.
    Yasui H, Go N, Yang H, Amore BM, Jung AS, Doi T. A Phase 1 study evaluating AMG 337 in Asian patients with advanced solid tumors. Jpn J Clin Oncol. 2017;47(8):772–6.Google Scholar
  113. 113.
    Chen HM, Tsai CH, Hung WC. Foretinib inhibits angiogenesis, lymphangiogenesis and tumor growth of pancreatic cancer in vivo by decreasing VEGFR-2/3 and TIE-2 signaling. Oncotarget. 2015;6(17):14940–52.PubMedPubMedCentralGoogle Scholar
  114. 114.
    Yau TCC, Lencioni R, Sukeepaisarnjaroen W, Chao Y, Yen CJ, Lausoontornsiri W, et al. A phase I/II multicenter study of single-agent foretinib as first-line therapy in patients with advanced hepatocellular carcinoma. Clin Cancer Res. 2017;23(10):2405–13.PubMedCrossRefGoogle Scholar
  115. 115.
    Eder JP, Shapiro GI, Appleman LJ, Zhu AX, Miles D, Keer H, et al. A phase I study of foretinib, a multi-targeted inhibitor of c-Met and vascular endothelial growth factor receptor 2. Clin Cancer Res. 2010;16(13):3507–16.PubMedCrossRefGoogle Scholar
  116. 116.
    Shapiro GI, McCallum S, Adams LM, Sherman L, Weller S, Swann S, et al. A phase 1 dose-escalation study of the safety and pharmacokinetics of once-daily oral foretinib, a multi-kinase inhibitor, in patients with solid tumors. Invest New Drugs. 2013;31(3):742–50.PubMedCrossRefGoogle Scholar
  117. 117.
    Leighl NB, Tsao M-S, Liu G, Tu D, Ho C, Shepherd FA, et al. A phase I study of foretinib plus erlotinib in patients with previously treated advanced non-small cell lung cancer: Canadian cancer trials group IND.196. Oncotarget. 2017;8(41):69651–62.Google Scholar
  118. 118.
    Yan SB, Peek VL, Ajamie R, Buchanan SG, Graff JR, Heidler SA, et al. LY2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against MET, MST1R, and other oncoproteins, and displays anti-tumor activities in mouse xenograft models. Invest New Drugs. 2013;31(4):833–44.PubMedCrossRefGoogle Scholar
  119. 119.
    Konicek BW, Capen AR, Credille KM, Ebert PJ, Falcon BL, Heady GL, et al. Merestinib (LY2801653) inhibits neurotrophic receptor kinase (NTRK) and suppresses growth of NTRK fusion bearing tumors. Oncotarget. 2018;9(17):13796–806.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Fujita H, Gomori A, Fujioka Y, Kataoka Y, Tanaka K, Hashimoto A, et al. High potency VEGFRs/MET/FMS triple blockade by TAS-115 concomitantly suppresses tumor progression and bone destruction in tumor-induced bone disease model with lung carcinoma cells. PLoS One. 2016;11(10):e0164830.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Yamada S, Imura Y, Nakai T, Nakai S, Yasuda N, Kaneko K, et al. Therapeutic potential of TAS-115 via c-MET and PDGFRα signal inhibition for synovial sarcoma. BMC Cancer. 2017;17:334.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Matsubara N, Naito Y, Sasaki M, Yamamoto N, Takahashi S, Uemura H. 796P - Phase I expansion cohort of TAS-115, a novel oral MET/VEGFR/FMS inhibitor, for castration-resistant prostate cancer patients (CRPC pts) with bone metastases. Ann Oncol. 2017;28(suppl_5):v269–94.CrossRefGoogle Scholar
  123. 123.
    Rodon J, Postel-Vinay S, Hollebecque A, Nuciforo P, Azaro A, Cattan V, et al. First-in-human phase I study of oral S49076, a unique MET/AXL/FGFR inhibitor, in advanced solid tumours. Eur J Cancer (Oxford, England: 1990). 2017;81:142–50.Google Scholar
  124. 124.
    Chang G, Curigliano G, Lim W, Viteri S, Ciardiello F, Hida T, et al. MA 12.02 Phase I/II study of S49076, a MET/AXL/FGFR inhibitor, combined with gefitinib in NSCLC patients progressing on EGFR TKI. Journal of Thoracic Oncology. 2017;12(11):S1847-S8.Google Scholar
  125. 125.
    Mughal A, Aslam HM, Sheikh A, Khan AMH, Saleem S. c-Met inhibitors. Infect Agents Cancer. 2013;8:13.Google Scholar
  126. 126.
    Michieli P, Di Nicolantonio F. Targeted therapies: tivantinib–a cytotoxic drug in MET inhibitor’s clothes? Nat Rev Clin Oncol. 2013;10(7):372–4.PubMedCrossRefGoogle Scholar
  127. 127.
    Santoro A, Rimassa L, Borbath I, Daniele B, Salvagni S, Van Laethem JL, et al. Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study. Lancet Oncol. 2013;14(1):55–63.PubMedCrossRefGoogle Scholar
  128. 128.
    Rimassa L, Assenat E, Peck-Radosavljevic M, Pracht M, Zagonel V, Mathurin P, et al. Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC): a final analysis of a phase 3, randomised, placebo-controlled study. Lancet Oncol. 2018;19(5):682–93.PubMedCrossRefGoogle Scholar
  129. 129.
    Scagliotti G, von Pawel J, Novello S, Ramlau R, Favaretto A, Barlesi F, et al. Phase III multinational, randomized, double-blind, placebo-controlled study of tivantinib (ARQ 197) plus erlotinib versus erlotinib alone in previously treated patients with locally advanced or metastatic nonsquamous non-small-cell lung cancer. J Clin Oncol. 2015;33(24):2667–74.PubMedCrossRefGoogle Scholar
  130. 130.
    Scagliotti GV, Shuster D, Orlov S, von Pawel J, Shepherd FA, Ross JS, et al. Tivantinib in combination with erlotinib versus erlotinib alone for EGFR-mutant NSCLC: an exploratory analysis of the phase 3 MARQUEE study. J Thorac Oncol. 2018;13(6):849–54.PubMedCrossRefGoogle Scholar
  131. 131.
    Finisguerra V, Prenen H, Mazzone M. Preclinical and clinical evaluation of MET functions in cancer cells and in the tumor stroma. Oncogene. 2016;35(42):5457–67.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Alberto Puccini
    • 1
    • 2
  • Nagore I. Marín-Ramos
    • 3
  • Francesca Bergamo
    • 4
  • Marta Schirripa
    • 4
  • Sara Lonardi
    • 4
  • Heinz-Josef Lenz
    • 1
  • Fotios Loupakis
    • 4
  • Francesca Battaglin
    • 1
    • 4
    Email author
  1. 1.Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of MedicineUniversity of Southern CaliforniaLos AngelesUSA
  2. 2.Medical Oncology Unit 1IRCCS Ospedale Policlinico San MartinoGenoaItaly
  3. 3.Department of Neurosurgery, Keck School of MedicineUniversity of Southern CaliforniaLos AngelesUSA
  4. 4.Medical Oncology Unit 1, Clinical and Experimental Oncology DepartmentVeneto Institute of Oncology IOV-IRCCSPaduaItaly

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