Skip to main content

Advertisement

SpringerLink
Log in

Treatment of Refractory Colorectal Cancer: Regorafenib vs. TAS-102

  • Systemic Therapies in Colorectal Cancer (RD Kim, Section Editor)
  • Published:
Current Colorectal Cancer Reports

Abstract

Purpose of Review

This paper reviews the development, mechanism of action, clinical efficacy, and safety of regorafenib and TAS-102. Through this review, we aimed to help clinicians make an appropriate choice in patients who progressed after standard therapies.

Recent Findings

Regorafenib and TAS-102 have shown superior survival results compared with placebo in refractory metastatic colorectal cancer (mCRC). In the phase III CORRECT study, regorafenib showed significant improvement in overall survival (OS) and progression-free survival (PFS). TAS-102 was associated with OS and PFS benefit as well in the phase III RECOURSE study. However, the toxicity profiles were quite different between the two agents.

Summary

Regorafenib and TAS-102 are approved for the management of refractory mCRC. Optimal treatment sequence for using these two novel agents is not defined yet. Safety profiles and patient’s condition should be considered before using these two agents in clinical settings. Further investigation is needed to identify the predictive biomarkers of both agents. These results will allow patients to benefit more from regorafenib and TAS-102.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7–30.

    Article  PubMed  Google Scholar 

  2. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–86.

    Article  CAS  PubMed  Google Scholar 

  3. Oh C-M, Won Y-J, Jung K-W, Kong H-J, Cho H, Lee J-K, et al. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2013. Cancer Res Treat. 2016;48(2):436–50.

    Article  PubMed  PubMed Central  Google Scholar 

  4. National Comprehensive Cancer Network (2017) NCCN clinical practice guidelines in oncology (NCCN guidelines): colon cancer. Version 1. [Internet]. [cited 2017 Jan 27]. Available from: https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf

  5. Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, et al (2016) ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016;27(8):1386–1422.

  6. Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26(12):2013–9.

    Article  CAS  PubMed  Google Scholar 

  7. Bennouna J, Sastre J, Arnold D, Österlund P, Greil R, Van Cutsem E, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013;14(1):29–37.

    Article  CAS  PubMed  Google Scholar 

  8. Jonker DJ, O’Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au H-J, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357(20):2040–8.

    Article  CAS  PubMed  Google Scholar 

  9. Van Cutsem E, Köhne C-H, Hitre E, Zaluski J, Chang Chien C-R, Makhson A, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360(14):1408–17.

    Article  PubMed  Google Scholar 

  10. Venook AP, Niedzwiecki D, Lenz H-J, Innocenti F, Mahoney MR, O’Neil BH, et al. CALGB/SWOG 80405: phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum. J Clin Oncol. 2014;32(5s):abstr LBA3.

    Article  Google Scholar 

  11. Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausová J, Macarulla T, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012;30(28):3499–506.

    Article  PubMed  Google Scholar 

  12. Tabernero J, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015;16(5):499–508.

    Article  CAS  PubMed  Google Scholar 

  13. •• Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303–12. A pivotal randomized phase III study that showed the benefit of overall survival when adding regorafenib in patients with metastatic colorectal cancer in whom standard treatments have failed.

    Article  CAS  PubMed  Google Scholar 

  14. •• Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015;372(20):1909–19. A landmark randomized phase III study that showed an overall survival gain in patients with metastatic colorectal cancer with adding TAS-102, whose disease had progressed after standard therapies.

    Article  PubMed  Google Scholar 

  15. Twelves C, Gollins S, Grieve R, Samuel L. A randomised cross-over trial comparing patient preference for oral capecitabine and 5-fluorouracil/leucovorin regimens in patients with advanced colorectal cancer. Ann Oncol Off J Eur Soc Med Oncol. 2006;17(2):239–45.

    Article  CAS  Google Scholar 

  16. Liu G, Franssen E, Fitch MI, Warner E. Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol. 1997;15(1):110–5.

    Article  CAS  PubMed  Google Scholar 

  17. Wilhelm SM, Dumas J, Adnane L, Lynch M, Carter CA, Schütz G, et al. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer. 2011;129(1):245–55.

    Article  CAS  PubMed  Google Scholar 

  18. Schmieder R, Hoffmann J, Becker M, Bhargava A, Müller T, Kahmann N, et al. Regorafenib (BAY 73-4506): antitumor and antimetastatic activities in preclinical models of colorectal cancer. Int J Cancer. 2014;135(6):1487–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Mross K, Frost A, Steinbild S, Hedbom S, Büchert M, Fasol U, et al. A phase I dose-escalation study of regorafenib (BAY 73-4506), an inhibitor of oncogenic, angiogenic, and stromal kinases, in patients with advanced solid tumors. Clin Cancer Res. 2012;18(9):2658–67.

    Article  CAS  PubMed  Google Scholar 

  20. Strumberg D, Scheulen ME, Schultheis B, Richly H, Frost A, Büchert M, et al. Regorafenib (BAY 73-4506) in advanced colorectal cancer: a phase I study. Br J Cancer. 2012;106(11):1722–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sunakawa Y, Furuse J, Okusaka T, Ikeda M, Nagashima F, Ueno H, et al. Regorafenib in Japanese patients with solid tumors: phase I study of safety, efficacy, and pharmacokinetics. Investig New Drugs. 2014;32(1):104–12.

    Article  CAS  Google Scholar 

  22. •• Li J, Qin S, Xu R, Yau TCC, Ma B, Pan H, et al. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015;16(6):619–29. A randomized phase III study that confirmed an overall survival benefit with regorafenib in Asian patients with metastatic colorectal cancer who failed to standard chemotherapies.

    Article  CAS  PubMed  Google Scholar 

  23. •• Kim TW, Shen L, Xu JM, Sriuranpong V, Pan H, Xu R, et al. TERRA: a randomized, double-blind, placebo-controlled phase 3 study of TAS-102 in Asian patients with metastatic colorectal cancer. Ann Oncol. 2016;27(suppl_6):465PD. A randomized phase III study of TAS-102 that demonstrated an improvement of overall survival in Asian patients with metastatic colorectal cancer who failed conventional chemotherapies.

    Google Scholar 

  24. U.S Food and Drug Administration. Approval letter for stivarga [Internet]. [cited 2016 Dec 15]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203085Orig1s000Approv.pdf

  25. Heidelberger C, Parsons DG, Remy DC. Syntheses of 5-trifluoromethyluracil and 5-trifluoromethyl-2′-deoxyuridine. J Med Chem. 1964;7(11):1–5.

    Article  CAS  PubMed  Google Scholar 

  26. Heidelberger C, Anderson SW. Fluorinated pyrimidines. XXI. The tumor-inhibitory activity of 5-Trifluoromethyl-2′-deoxyuridine. Cancer Res. 1964;24:1979–85.

    CAS  PubMed  Google Scholar 

  27. Santi DV, Sakai TT. Thymidylate synthetase. Model studies of inhibition by 5-trifluoromethyl-2′-deoxyuridylic acid. Biochemistry. 1971;10(19):3598–607.

    Article  CAS  PubMed  Google Scholar 

  28. Wilson PM, Danenberg PV, Johnston PG, Lenz H-J, Ladner RD. Standing the test of time: targeting thymidylate biosynthesis in cancer therapy. Nat Rev Clin Oncol. 2014;11(5):282–98.

    Article  CAS  PubMed  Google Scholar 

  29. Ansfield FJ, Ramirez G. Phase I and II studies of 2′-deoxy-5-(trifluoromethyl)-uridine (NSC-75520). Cancer Chemother Rep. 1971;55(2):205–8.

    CAS  PubMed  Google Scholar 

  30. Dexter DL, Wolberg WH, Ansfield FJ, Helson L, Heidelberger C. The clinical pharmacology of 5-trifluoromethyl-2′-deoxyuridine. Cancer Res. 1972;32(2):245–53.

    Google Scholar 

  31. Fukushima M, Suzuki N, Emura T, Yano S, Kazuno H, Tada Y, et al. Structure and activity of specific inhibitors of thymidine phosphorylase to potentiate the function of antitumor 2′-deoxyribonucleosides. Biochem Pharmacol. 2000;59(10):1227–36.

    Article  CAS  PubMed  Google Scholar 

  32. Emura T, Suzuki N, Fujioka A, Ohshimo H, Fukushima M. Potentiation of the antitumor activity of a, a, a-trifluorothymidine by the co-administration of an inhibitor of thymidine phosphorylase at a suitable molar ratio in vivo. Int J Oncol. 2005;27(2):449–55.

    CAS  PubMed  Google Scholar 

  33. Emura T, Suzuki N, Yamaguchi M, Ohshimo H, Fukushima M. A novel combination antimetabolite, TAS-102, exhibits antitumor activity in FU-resistant human cancer cells through a mechanism involving FTD incorporation in DNA. Int J Oncol. 2004;25(3):571–8.

    CAS  PubMed  Google Scholar 

  34. Emura T, Murakami Y, Nakagawa F, Fukushima M, Kitazato K. A novel antimetabolite, TAS-102 retains its effect on FU-related resistant cancer cells. Int J Mol Med. 2004;13(4):545–9.

    CAS  PubMed  Google Scholar 

  35. Hong DS, Abbruzzese JL, Bogaard K, Lassere Y, Fukushima M, Mita A, et al. Phase I study to determine the safety and pharmacokinetics of oral administration of TAS-102 in patients with solid tumors. Cancer. 2006;107(6):1383–90.

    Article  CAS  PubMed  Google Scholar 

  36. Overman MJ, Kopetz S, Varadhachary G, Fukushima M, Kuwata K, Mita A, et al. Phase I clinical study of three times a day oral administration of TAS-102 in patients with solid tumors. Cancer Investig. 2008;26(8):794–9.

    Article  CAS  Google Scholar 

  37. Overman MJ, Varadhachary G, Kopetz S, Thomas MB, Fukushima M, Kuwata K, et al. Phase 1 study of TAS-102 administered once daily on a 5-day-per-week schedule in patients with solid tumors. Investig New Drugs. 2008;26(5):445–54.

    Article  CAS  Google Scholar 

  38. Doi T, Ohtsu A, Yoshino T, Boku N, Onozawa Y, Fukutomi A, et al. Phase I study of TAS-102 treatment in Japanese patients with advanced solid tumours. Br J Cancer. 2012;107(3):429–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bendell JC, Rosen LS, Mayer RJ, Goldman JW, Infante JR, Benedetti F, et al. Phase 1 study of oral TAS-102 in patients with refractory metastatic colorectal cancer. Cancer Chemother Pharmacol. 2015;76(5):925–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Green MC, Pusztai L, Theriault RL, Adinin RB, Hofweber M, Fukushima M, et al. Phase I study to determine the safety of oral administration of TAS-102 on a twice daily (BID) schedule for five days a week (wk) followed by two days rest for two wks, every (Q) four wks in patients (pts) with metastatic breast cancer (MBC). J Clin Oncol. 2006;24:abstr 10576.

    Google Scholar 

  41. • Yoshino T, Mizunuma N, Yamazaki K, Nishina T, Komatsu Y, Baba H, et al. TAS-102 monotherapy for pretreated metastatic colorectal cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2012;13(10):993–1001. Based on this randomized phase II study, RECOURSE study was conducted to evaluate the efficacy and safety of TAS-102 in patients with metastatic colorectal cancer.

    Article  CAS  PubMed  Google Scholar 

  42. U.S Food and Drug Administration. Approval letter for lonsurf [Internet]. [cited 2016 Dec 15]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207981Orig1s000Approv.pdf

  43. Bekaii-Saab TS, Ou F-S, Ciombor KK, Farhat MI, Kirshner JJ, Knost JA, et al. Regorafenib dose optimization study (ReDOS): a phase II randomized study of lower starting dose regorafenib compared to standard dose regorafenib in patients with refractory metastatic colorectal cancer (mCRC). J Clin Oncol. 2016;34:abstr TPS3630.

    Article  Google Scholar 

  44. Masuishi T, Taniguchi H, Hamauchi S, Komori A, Kito Y, Narita Y, et al. Regorafenib versus trifluridine/tipiracil for refractory metastatic colorectal cancer: a retrospective comparison. Clin Colorectal Cancer. 2017;16(2):e15-e22.

  45. Yoshino T, Komatsu Y, Yamada Y, Yamazaki K, Tsuji A, Ura T, et al. Randomized phase III trial of regorafenib in metastatic colorectal cancer: analysis of the CORRECT Japanese and non-Japanese subpopulations. Investig New Drugs. 2015;33(3):740–50.

    Article  CAS  Google Scholar 

  46. Tabernero J, Lenz H-J, Siena S, Sobrero A, Falcone A, Ychou M, et al. Analysis of circulating DNA and protein biomarkers to predict the clinical activity of regorafenib and assess prognosis in patients with metastatic colorectal cancer: a retrospective, exploratory analysis of the CORRECT trial. Lancet Oncol. 2015;16(8):937–48.

    Article  CAS  PubMed  Google Scholar 

  47. Yoshino T, Shinozaki E, Yamazaki K, Komatsu Y, Nishina T, Baba H, et al. Effect of thymidine kinase 1 expression on prognosis and treatment outcomes in refractory metastatic colorectal cancer: results from two randomized studies of TAS-102 versus a placebo. J Clin Oncol. 2017;37:abstr 529.

    Article  Google Scholar 

  48. Lee HJ, Oh SJ, Lee EJ, Chung JH, Kim Y, Ryu JS, et al. Positron emission tomography imaging of human colon cancer xenografts in mice with [18F]fluorothymidine after TAS-102 treatment. Cancer Chemother Pharmacol. 2015;75(5):1005–13.

    Article  CAS  PubMed  Google Scholar 

  49. Lim Y, Han SW, Yoon JH, Lee JM, Lee JM, Paeng JC, et al. Clinical implication of anti-angiogenic effect of regorafenib in metastatic colorectal cancer. Santini D, editor. PLoS One. 2015;10(12):e0145004.

Download references

Author information

Authors and Affiliations

  1. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea

    Jae Ho Jeong, Yong Sang Hong & Tae Won Kim

Authors
  1. Jae Ho Jeong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yong Sang Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tae Won Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tae Won Kim.

Ethics declarations

Conflict of Interest

Jae Ho Jeong declares that he has no conflict of interest.

Yong Sang Hong declares that he has no conflict of interest.

Tae Won Kim has received research funding through grants from Bayer and Taiho.

Human and Animal Rights

All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).

Funding

This study was supported in part by grants from the Asan Institute for Life Science (2015–414) and Korea Health 21 R&D Project, Ministry of Health and Welfare and Family Affairs (HI06C0868), Republic of Korea.

Additional information

This article is part of the Topical Collection on Systemic Therapies in Colorectal Cancer

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jeong, J.H., Hong, Y.S. & Kim, T.W. Treatment of Refractory Colorectal Cancer: Regorafenib vs. TAS-102. Curr Colorectal Cancer Rep 13, 325–333 (2017). https://doi.org/10.1007/s11888-017-0381-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11888-017-0381-6

Keywords

Search

Navigation