FUTURE DIRECTIONS


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The future of tivantinib, like that of many other drugs, rests on appropriate patient selection. The identification of biomarkers for tivantinib sensitivity is an active area of research with promising early results. The first biomarker for tivantinib in HCC patients was tumor MET status. It was published that patients with MET-high tumors showed a significant survival benefit, with longer median TTP (2.7 months vs. 1.4 months), longer median PFS (2.2 months vs. 1.4 months) and longer median overall survival (7.2 months vs. 3.8 months) on tivantinib compared to placebo.34 No difference in efficacy was found between tivantinib and placebo in patients with MET-low tumors. In a combination study of tivantinib with sorafenib, the combination therapy demonstrated a trend toward significance regarding increased disease control rate, defined as the combination of complete responses, partial responses and stable disease for at least 8 weeks.44 While only four cases of MET-high HCC were observed, three of the four patients achieved disease control. Based on these promising results, both of the active Phase III trials are evaluating tivantinib in HCC patients with MET-high tumor status.

A preclinical study evaluated whether HGF tumor concentration could be used as a marker for HCC, but no significant differences were found between HGF-high and HGF-low groups in clinicopathological factors or patient outcomes.56 A more recent study that specifically evaluated MET, HGF and AFP as circulating biomarkers (by 75 percentile) found that they were prognostic markers for overall survival in patients with HCC.57 Circulating MET was also a pharmacodynamic biomarker for tivantinib: patients on treatment with a ≥10% decrease in circulating MET levels demonstrated increased overall survival compared to those with a <10% decrease (13.3 months vs. 6.3 months; HR: 0.46 [95% CI: 0.24–0.86], p=0.01). Additionally, tumor MET levels were correlated with response to tivantinib treatment, the only biomarker thus far to predict response to treatment. These results support the use of tivantinib exclusively in MET-high tumor patients, although more definitive data will be forthcoming with the results of the METIV-HCC trial, which will analyze over 900 tumor samples and validate the use of select biomarkers in HCC.

Additional studies are needed to assess the use of tivantinib in those with more severe cirrhosis. The vast majority of trials have evaluated tivantinib in patients who are Child-Pugh Class A, with only a few trials including patients who are Child-Pugh Class B. Although theoretically tivantinib could also be used for those who are Child-Pugh Class C, this has not yet been studied. Moreover, it may not be safe to attempt such a trial given the anticipated side effects. Nevertheless, future development of more specific targeted biologic markers may enable treating physicians to administer agents such as tivantinib in a safer and more effective way.

CONCLUSION

Tivantinib, a potent inhibitor of c-MET, appears to be a promising therapy for those with advanced-stage HCC that has progressed or is intolerant to sorafenib. Tivantinib has demonstrated increased overall survival, PFS and TTP compared to placebo in patients with MET-high tumors. Serious hematologic side effects (neutropenia, anemia and leukopenia) are anticipated to be less prominent at lower dosing regimens (120 mg BID), at which dose good treatment efficacy is still maintained. Two large Phase III trials, METIV-HCC and JET-HCC, are currently ongoing. To date, there is no FDA-approved salvage or second-line therapy for patients with HCC who have failed or progressed with sorafenib. Whether tivantinib will be able to fill that need still remains to be determined.

Disclosure

The authors report no conflicts of interest in this work.


Daniel Pievsky,1 Nikolaos Pyrsopoulos2

1Department of Internal Medicine, 2Division of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, University Hospital, Newark, NJ, USA 


References

1. Fact Sheets by Cancer [webpage on the Internet]. All Cancers (Excluding Non-Melanoma Skin Cancer) Estimated Incidence, Mortality and Prevalence Worldwide in 2012. Available from: http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed June 12, 2016.

2. Deng G-L, Zeng S, Shen H. Chemotherapy and target therapy for hepatocellular carcinoma: new advances and challenges. World J Hepatol. 2015;7(5):787–798.

3. El-Serag HB. Hepatocellular carcinoma. N Engl J Med. 2011;365(12):1118–1127.

4. National Cancer Institute [webpage on the Internet]. A Snapshot of Liver Cancers. Available from: http://www.cancer.gov/research/progress/snapshots/liver. Accessed August 23, 2016.

5. Finn RS. Development of molecularly targeted therapies in hepatocellular carcinoma: where do we go now? Clin Cancer Res. 2010;16(2):390–397.

6. Cho YK, Kim JK, Kim MY, Rhim H, Han JK. Systematic review of randomized trials for hepatocellular carcinoma treated with percutaneous ablation therapies. Hepatology. 2009;49(2):453–459.

7. Nordenstedt H, White DL, El-Serag HB. The changing pattern of epidemiology in hepatocellular carcinoma. Dig Liver Dis. 2010;42(suppl 3):S206–S214.

8. Artinyan A, Mailey B, Sanchez-Luege N, et al. Race, ethnicity, and socioeconomic status influence the survival of patients with hepatocellular carcinoma in the United States. Cancer. 2010;116(5):1367–1377.

9. Cheng A-L, Kang Y-K, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10(1):25–34.

10. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–390.

11. Zhao X, Tian C, Puszyk WM, et al. OPA1 downregulation is involved in sorafenib-induced apoptosis in hepatocellular carcinoma. Lab Invest. 2013;93(1):8–19.

12. Bruix J, Merle P, Granito A, et al. LBA-03Efficacy and safety of regorafenib versus placebo in patients with hepatocellular carcinoma (HCC) progressing on sorafenib: results of the international, randomized phase 3 RESORCE trial. Ann Oncol. 2016;27(suppl 2):ii140–ii141.

13. Porta C, Paglino C. Medical treatment of unresectable hepatocellular carcinoma: going beyond sorafenib. World J Hepatol. 2010;2(3):103–113.

14. Munshi N, Jeay S, Li Y, et al. ARQ 197, a novel and selective inhibitor of the human c-Met receptor tyrosine kinase with antitumor activity. Mol Cancer Ther. 2010;9(6):1544–1553.

15. Cooper CS, Park M, Blair DG, et al. Molecular cloning of a new transforming gene from a chemically transformed human cell line. Nature. 1984;311(5981):29–33.

16. Bottaro DP, Rubin JS, Faletto DL, et al. Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science. 1991;251(4995):802–804.

17. Birchmeier C, Gherardi E. Developmental roles of HGF/SF and its receptor, the c-Met tyrosine kinase. Trends Cell Biol. 1998;8(10):404–410.

18. Sonnenberg E, Meyer D, Weidner KM, Birchmeier C. Scatter factor/hepatocyte growth factor and its receptor, the c-met tyrosine kinase, can mediate a signal exchange between mesenchyme and epithelia during mouse development. J Cell Biol. 1993;123(1):223–235.

19. Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF. Met, metastasis, motility and more. Nat Rev Mol Cell Biol. 2003;4(12):915–925.

20. Blumenschein GR, Mills GB, Gonzalez-Angulo AM. Targeting the hepatocyte growth factor-cMET axis in cancer therapy. J Clin Oncol. 2012;30(26):3287–3296.

21. Ma PC, Maulik G, Christensen J, Salgia R. c-Met: structure, functions and potential for therapeutic inhibition. Cancer Metastasis Rev. 2003;22(4):309–325.

22. Gao JJ, Inagaki Y, Xue X, Qu XJ, Tang W. c-Met: a potential therapeutic target for hepatocellular carcinoma. Drug Discov Ther. 2011;5(1):2–11.

23. Porta C, Giglione P, Ferrari A, et al. Tivantinib (ARQ197) in hepatocellular carcinoma. Expert Rev Anticancer Ther. 2015;15(6):615–622.

24. Venepalli NK, Goff L. Targeting the HGF-cMET axis in hepatocellular carcinoma. Int J Hepatol. 2013;2013:341636.

25. Au J, Frenette C. Development of tivantinib as treatment for hepatocellular carcinoma. J Clin Transl Hepatol. 2013;1(1):75–78.

26. Peyssonnaux C, Eychène A. The Raf/MEK/ERK pathway: new concepts of activation. Biol Cell. 2001;93(1–2):53–62.

27. Eathiraj S, Palma R, Volckova E, et al. Discovery of a novel mode of protein kinase inhibition characterized by the mechanism of inhibition of human mesenchymal-epithelial transition factor (c-Met) protein autophosphorylation by ARQ 197. J Biol Chem. 2011;286(23):20666–20676.

28. Aoyama A, Katayama R, Oh-hara T, Sato S, Okuno Y, Fujita N. Tivantinib (ARQ 197) exhibits antitumor activity by directly interacting with tubulin and overcomes abc transporter–mediated drug resistance. Am Assoc Cancer Res. 2014;13(12):2978–2990.

29. Basilico C, Pennacchietti S, Vigna E, et al. Tivantinib (ARQ197) displays cytotoxic activity that is independent of its ability to bind MET. Am Assoc Cancer Res. 2013;19(9):2381–2392.

30. Katayama R, Aoyama A, Yamori T, et al. Cytotoxic activity of tivantinib (ARQ 197) is not due solely to c-MET inhibition. Cancer Res. 2013;73(10):3087–3096.