Advertisement

Cabozantinib: Multi-kinase Inhibitor of MET, AXL, RET, and VEGFR2

  • Carsten Grüllich
Chapter
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 211)

Abstract

Cabozantinib is a receptor tyrosine kinase inhibitor (TKI) with activity against a broad range of targets, including MET, RET, AXL, VEGFR2, FLT3, and c-KIT. Activity of cabozantinib towards a broad range of tumor models could be detected in several preclinical studies. Of note, cabozantinib decreases metastasis potential and tumor invasiveness when compared with placebo or agents that target VEGFR and have no activity against MET. Cabozantinib is clinically approved for the treatment of medullary thyroid cancer (MTC) and for renal cell cancer (RCC) in the second line. In MTC gain of function mutations, mutations of RET are central for tumorigenesis. Hereditary forms of MTC (MEN II) are caused by germline mutations of RET, in sporadic MTC up to 50% of cases RET mutations occur. Both MET and AXL have been described as mechanisms facilitating resistance against VEGFR-targeted tyrosine kinase therapy in clear cell RCC. Accordingly, cabozantinib has shown activity in RCC patients progressing after first-line VEGFR-TKI therapy in the pivotal METEOR trial. This phase III trial reported a benefit of 4.9 months in survival and an increase in response rate compared to standard everolimus over all patient subgroups. Of particular interest are the effects on patients with bone metastasis, which have a worse prognosis. In these patients, the beneficial effects of cabozantinib over everolimus were even more pronounced. Side effects of interest include diarrhea, hypertension, fatigue, and hand–foot syndrome.

Keywords

Multikinase-Inhibitor Renal cell cancer Medullary thyroid cancer MET AXL 

References

  1. Bean J et al (2007) MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci USA 104(52):20932–20937CrossRefPubMedGoogle Scholar
  2. Bussolino F et al (1992) Hepatocyte growth-factor is a potent angiogenic factor which stimulates endothelial-cell motility and growth. J Cell Biol 119(3):629–641CrossRefPubMedGoogle Scholar
  3. Choueiri TK et al (2015) Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373(19):1814–1823CrossRefPubMedPubMedCentralGoogle Scholar
  4. Choueiri TK et al (2016) Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol 17(7):917–927CrossRefPubMedGoogle Scholar
  5. Choueiri TK et al (2017) 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 35(6):591–597CrossRefPubMedGoogle Scholar
  6. Dietz S et al (2017) Patient-specific molecular alterations are associated with metastatic clear cell renal cell cancer progressing under tyrosine kinase inhibitor therapy. Oncotarget 8(43):74049–74057CrossRefPubMedPubMedCentralGoogle Scholar
  7. Direnzo MF et al (1995) Overexpression and simplification of the met/HGF receptor gene during the progression of colorectal-cancer. Clin Cancer Res 1(2):147–154Google Scholar
  8. Houldsworth J et al (1990) Gene amplification in gastric and esophageal adenocarcinomas. Can Res 50(19):6417–6422Google Scholar
  9. Kurzrock R et al (2011) Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol 29(19):2660–2666CrossRefPubMedPubMedCentralGoogle Scholar
  10. Macher-Goeppinger S et al (2017) MET expression and copy number status in clear-cell renal cell carcinoma: prognostic value and potential predictive marker. Oncotarget 8(1):1046–1057CrossRefPubMedGoogle Scholar
  11. Matsumoto K, Nakamura T (2001) Hepatocyte growth factor: renotropic role and potential therapeutics for renal diseases. Kidney Int 59(6):2023–2038CrossRefPubMedGoogle Scholar
  12. Michalopoulos GK, DeFrances MC (1997) Liver regeneration. Science 276(5309):60–66CrossRefPubMedGoogle Scholar
  13. Mizuno S, Matsumoto K, Nakamura T (2001) Hepatocyte growth factor suppresses interstitial fibrosis in a mouse model of obstructive nephropathy. Kidney Int 59(4):1304–1314CrossRefPubMedGoogle Scholar
  14. Nadal R, Mortazavi A, Stein M, Pal SK, Davarpanah N, Parnes HL, Ning YM, Cordes LM, Lin J, Bagheri M, Linderberg L, Berniger M, Steinberg SM, Moore T, Lancaster T, Aviles M, Costello R, Bottaro DP, Dahut WL, Apolo AB (2017) 846O Final 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 28(suppl_5), 1 September 2017, mdx371.001Google Scholar
  15. Nakagawa T et al (2012) Combined therapy with mutant-selective EGFR inhibitor and Met kinase inhibitor for overcoming erlotinib resistance in EGFR-mutant lung cancer. Mol Cancer Ther 11(10):2149–2157CrossRefPubMedGoogle Scholar
  16. Rankin EB, Giaccia AJ (2016) The receptor tyrosine kinase AXL in cancer progression. Cancers (Basel) 8(11)Google Scholar
  17. Schmidt L et al (1997) Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet 16(1):68–73CrossRefPubMedGoogle Scholar
  18. Schoffski P et al (2012) An international, double-blind, randomized, placebo-controlled phase III trial (EXAM) of cabozantinib (XL184) in medullary thyroid carcinoma (MTC) patients (pts) with documented RECIST progression at baseline. J Clin Oncol 30(15)Google Scholar
  19. Sennino B et al (2012) Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discov 2(3):270–287CrossRefPubMedPubMedCentralGoogle Scholar
  20. Sirotnak FM et al (2004) Microarray analysis of progression to reduced prostate cancer androgen dependence: studies in unique models contrasts early and late molecular events. Mol Carcinog 41(3):150–163CrossRefPubMedGoogle Scholar
  21. Soman NR et al (1991) The TPR-MET oncogenic rearrangement is present and expressed in human gastric-carcinoma and precursor lesions. Proc Natl Acad Sci USA 88(11):4892–4896CrossRefPubMedGoogle Scholar
  22. Takayama H et al (1996) Scatter factor/hepatocyte growth factor as a regulator of skeletal muscle and neural crest development. Proc Natl Acad Sci USA 93(12):5866–5871CrossRefPubMedGoogle Scholar
  23. Trusolino L, Comoglio PM (2002) Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nat Rev Cancer 2(4):289–300CrossRefPubMedGoogle Scholar
  24. Verras M et al (2007) The androgen receptor negatively regulates the expression of c-Met: implications for a novel mechanism of prostate cancer progression. Can Res 67(3):967–975CrossRefGoogle Scholar
  25. Yakes FM et al (2011) Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther 10(12):2298–2308CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Medical OncologyNational Center for Tumor Diseases, Heidelberg University Medical CenterHeidelbergGermany

Personalised recommendations