Skip to main content
SpringerLink
Log in

Regorafenib: A Review in Metastatic Colorectal Cancer

  • Adis Drug Evaluation
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

Regorafenib (Stivarga®) is an oral small-molecule multiple kinase inhibitor. It is indicated worldwide for patients with metastatic colorectal cancer (mCRC). In the EU and USA it is indicated for patients with mCRC who have been previously treated with, or are not considered candidates for available therapies, including fluoropyrimidine-based chemotherapy, an anti-VEGF therapy and, if RAS wild-type, an anti-EGFR therapy. In Japan, it is indicated for the treatment of unresectable, advanced/recurrent CRC. The addition of regorafenib to best supportive care prolonged median overall survival (OS; by up to 2.5 months) and progression-free survival (PFS; by up to 1.5 months) relative to the addition of placebo in double-blind phase 3 studies (CORRECT and CONCUR) in patients with mCRC who had progressed after failure of standard therapy. Health-related quality of life was not adversely affected with regorafenib relative to placebo. A large open-label phase 3 study (CONSIGN) and several large real-world studies supported the efficacy of regorafenib in this setting. Regorafenib had a generally manageable tolerability profile, which was consistent with the profile of a typical small-molecule multiple kinase inhibitor. Treatment-related adverse events (AEs), mostly of mild or moderate severity, were reported in the majority of patients receiving regorafenib, with dermatological toxicities and liver enzyme elevations among the most common AEs. Although identification of biomarkers/parameters predicting efficacy outcomes with regorafenib will help to individualize therapy, current evidence indicates that regorafenib is a valuable treatment option for patients with refractory mCRC who have a very poor prognosis.

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

Fig. 1

Similar content being viewed by others

References

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

    Article  PubMed  CAS  Google Scholar 

  2. Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016;27(8):1386–422.

    Article  PubMed  Google Scholar 

  3. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: colon cancer (version 2.2018). 2018. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed 8 Mar 2018.

  4. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: rectal cancer (version 1.2018). 2018. https://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf. Accessed 25 May 2018.

  5. Bayer AG. Stivarga (regorafenib): summary of product characteristics. 2017. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002573/WC500149164.pdf. Accessed 25 May 2018.

  6. Bayer HealthCare Pharmaceuticals Inc. Stivarga (regorafenib) tablets: US prescribing information. 2013. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/203085s007lbl.pdf. Accessed 25 May 2018.

  7. Bayer Pharmaceutical Co Ltd. Stivarga (regorafenib): Japanese prescribing information. Osaka: Bayer Pharmaceutical Co Ltd; 2018.

    Google Scholar 

  8. Carter NJ. Regorafenib: a review of its use in previously treated patients with progressive metastatic colorectal cancer. Drugs Aging. 2014;31(1):67–78.

    Article  PubMed  CAS  Google Scholar 

  9. Wilhelm SM, Dumas J, Adnane L, 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  PubMed  CAS  Google Scholar 

  10. European Medicines Agency. Stivarga (regorafenib): assessment report. 2013. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002573/WC500149166.pdf. Accessed 25 May 2018.

  11. Abou-Elkacem L, Arns S, Brix G, et al. Regorafenib inhibits growth, angiogenesis and metastasis in a highly aggressive, orthotopic colon cancer model. Mol Cancer Ther. 2013;12(7):1322–31.

    Article  PubMed  CAS  Google Scholar 

  12. Fan LC, Teng HW, Shiau CW, et al. Regorafenib (Stivarga) pharmacologically targets epithelialmesenchymal transition in colorectal cancer. Oncotarget. 2016;7(39):64136–47.

    PubMed  PubMed Central  Google Scholar 

  13. Mross K, Frost A, Steinbild S, 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  PubMed  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Jones RL, Bendell JC, Smith DC, et al. A phase I open-label trial evaluating the cardiovascular safety of regorafenib in patients with advanced cancer. Cancer Chemother Pharmacol. 2015;76(4):777–84.

    Article  PubMed  CAS  Google Scholar 

  16. Grothey A, Van Cutsem E, Sobrero A, 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.

    Article  PubMed  CAS  Google Scholar 

  17. Li J, Qin S, Xu R, 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.

    Article  PubMed  CAS  Google Scholar 

  18. Yoshino T, Komatsu Y, Yamada Y, 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 

  19. Teufel M, Kalmus J, Rutstein M, et al. Analysis of biomarkers in circulating tumor DNA from the phase 3 CONCUR study of regorafenib in Asian patients with metastatic colorectal cancer (mCRC): correlation with clinical outcome [abstract no. 2013]. Eur J Cancer. 2015;51(Suppl 3):S332.

    Article  Google Scholar 

  20. Van Cutsem E, Ciardiello F, Seitz JF, et al. CONSIGN: an open-label phase 3b study of regorafenib in patients with metastatic colorectal cancer (mCRC) who failed standard therapy [abstract no. 2139]. Eur J Cancer. 2015;51(Suppl 3):S378–9.

    Article  Google Scholar 

  21. Van Cutsem E, Ciardiello F, Ychou M, et al. Regorafenib in previously treated metastatic colorectal cancer (mCRC): analysis of age subgroups in the open-label phase Illb CONSIGN trial [abstract no. 3524]. J Clin Oncol. 2016;34(15 Suppl).

  22. Van Cutsem E, Ciardiello F, Ychou M, et al. Analysis of patients ≥ 75 years in the open-label phase 3b CONSIGN trial of regorafenib in previously treated metastatic colorectal cancer (mCRC) [abstract no. PD-012]. Ann Oncol. 2016;27(Suppl 2):ii106.

    PubMed Central  Google Scholar 

  23. Verma U, Arriaga YE, Lenz HJ, et al. Regorafenib for previously treated metastatic colorectal cancer (mCRC): a subgroup analysis of 364 patients in the USA treated in the international, open-label phase IIIb CONSIGN study [abstract no. 735]. J Clin Oncol. 2016;34(4 Suppl).

  24. Grothey A, Falcone A, Humblet Y, et al. Characteristics of patients (pts) with metastatic colorectal cancer (mCRC) treated with regorafenib (REG) who had progression-free survival (PFS) > 4 months (m): subgroup analysis of the phase 3 CORRECT trial [abstract no. 516P]. Ann Oncol. 2016;27(Suppl 6).

  25. Garcia-Carbonero R, Van Cutsem E, Ciardiello F, et al. Subgroup analysis of patients with metastatic colorectal cancer (mCRC) treated with regorafenib (REG) in the phase 3b CONSIGN trial who had progression-free survival (PFS) > 4 months (m) [abstract no. 506P]. Ann Oncol. 2016;27(Suppl 6).

  26. Ricotta R, Verrioli A, Ghezzi S, et al. Radiological imaging markers predicting clinical outcome in patients with metastatic colorectal carcinoma treated with regorafenib: post hoc analysis of the CORRECT phase III trial (RadioCORRECT study). ESMO Open. 2016;1(6):e000111.

    Article  PubMed  Google Scholar 

  27. Tabernero J, Lenz HJ, Siena S, 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  PubMed  CAS  Google Scholar 

  28. Teufel M, Kalmus J, Rutstein MD, et al. Analysis of plasma protein biomarkers from the phase 3 CONCUR study of regorafenib in Asian patients with metastatic colorectal cancer (mCRC) [abstract no. 672]. J Clin Oncol. 2016;34(4 Suppl).

  29. Lambrechts D, Koechert K, Schulz A, et al. Analysis of single-nucleotide polymorphisms (SNPs) in the phase 3 CORRECT trial of regorafenib vs placebo in patients with metastatic colorectal cancer (mCRC) [abstract no. PD-003]. Ann Oncol. 2016;27(Suppl 2):ii102.

    Article  PubMed Central  Google Scholar 

  30. Kochert K, Beckmann G, Teufel M. Exploratory analysis of baseline microsatellite instability (MSI) status in patients with metastatic colorectal cancer (mCRC) treated with regorafenib (REG) or placebo in the phase 3 CORRECT trial [abstract no. 534P]. Ann Oncol. 2017;28(Suppl 5):180–1.

    Google Scholar 

  31. Vanwynsberghe H, Verbeke X, Coolen J, et al. Predictive value of early tumor shrinkage and density reduction of lung metastases in patients with metastatic colorectal cancer treated with regorafenib. Clin Colorectal Cancer. 2017;16(4):377–80.

    Article  PubMed  Google Scholar 

  32. Adenis A, de la Fouchardiere C, Paule B, et al. Survival, safety, and prognostic factors for outcome with regorafenib in patients with metastatic colorectal cancer refractory to standard therapies: results from a multicenter study (REBECCA) nested within a compassionate use program. BMC Cancer. 2016;16:412.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. O’Connor JM, Ohler L, Scheithauer W, et al. Real-world dosing of regorafenib in metastatic colorectal cancer (mCRC): interim analysis from the prospective, observational CORRELATE study [abstract no. PD-025]. Ann Oncol. 2017;28(Suppl 3):10.

    Google Scholar 

  34. Komatsu Y, Muro K, Yamaguchi K, et al. Safety and efficacy of regorafenib post-marketing surveillance (PMS) in Japanese patients with metastatic colorectal cancer (mCRC) [abstract no. 721]. J Clin Oncol. 2017;35(4 Suppl).

  35. Schulz H, Janssen J, Strauss UP, et al. Clinical efficacy and safety of regorafenib (REG) in the treatment of metastatic colorectal cancer (mCRC) in daily practice in Germany: final results of the prospective multicentre non-interventional RECORA study [abstract no. 748]. In: ASCO Gastrointestinal Cancers Symposium. 2018.

  36. Yoshino T, Arnold D, Taniguchi H, et al. Pan-Asian adapted ESMO consensus guidelines for the management of patients with metastatic colorectal cancer: a JSMO-ESMO initiative endorsed by CSCO, KACO, MOS, SSO and TOS. Ann Oncol. 2018;29(1):44–70.

    Article  PubMed  CAS  Google Scholar 

  37. Goldstein DA, Ahmad BB, Chen Q, et al. Cost-effectiveness analysis of regorafenib for metastatic colorectal cancer. J Clin Oncol. 2015;33(32):3727–32.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Barron A, Wilsdon T. Challenging perceptions about oncology product pricing in breast and colorectal cancer. Pharm Med. 2016;30(6):321–6.

    Article  CAS  Google Scholar 

  39. Whalen J, Chang J, Ozer-Stillman I, et al. The cost of survival gain in metastatic colorectal cancer (mCRC) in Spain [abstract no. P-213]. Ann Oncol. 2015;26(Suppl 4):iv62.

    Article  Google Scholar 

  40. Whalen J, Chang J, Ozer-Stillman I, et al. The cost of survival gain in metastatic colorectal cancer (mCRC) in France [abstract no. P-212]. Ann Oncol. 2015;26(Suppl 4):iv61–2.

    Article  Google Scholar 

  41. Suenaga M, Mashima T, Kawata N, et al. Serum VEGF-A and CCL5 levels as candidate biomarkers for efficacy and toxicity of regorafenib in patients with metastatic colorectal cancer. Oncotarget. 2016;7(23):34811–23.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Komori A, Taniguchi H, Hamauchi S, et al. Serum CA19-9 response is an early predictive marker of efficacy of regorafenib in refractory metastatic colorectal cancer. Oncology. 2017;93(5):329–35.

    Article  PubMed  CAS  Google Scholar 

  43. Del Prete M, Giampieri R, Loupakis F, et al. Prognostic clinical factors in pretreated colorectal cancer patients receiving regorafenib: implications for clinical management. Oncotarget. 2015;6(32):33982–92.

    PubMed  PubMed Central  Google Scholar 

  44. Arai H, Miyakawa K, Denda T, et al. Early morphological change for predicting outcome in metastatic colorectal cancer after regorafenib. Oncotarget. 2017;8(66):110530–9.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Suenaga M, Schirripa M, Cao S, et al. Gene polymorphisms in the CCL5/CCR5 pathway as a genetic biomarker for outcome and hand-foot skin reaction in metastatic colorectal cancer patients treated with regorafenib. Clin Colorectal Cancer. 2018;17(2):e395–414.

    Article  PubMed  Google Scholar 

  46. Dy GK, Adjei AA. Understanding, recognizing, and managing toxicities of targeted anticancer therapies. CA Cancer J Clin. 2013;63(4):249–79.

    Article  PubMed  Google Scholar 

  47. Cai J, Ma H, Huang F, et al. Correlation of bevacizumab-induced hypertension and outcomes of metastatic colorectal cancer patients treated with bevacizumab: a systematic review and meta-analysis. World J Surg Oncol. 2013;11:306.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Grothey A, Huang L, Wagner A, et al. Hand-foot skin reaction (HFSR) and outcomes in the phase 3 CORRECT trial of regorafenib for metastatic colorectal cancer (mCRC) [abstract no. 3551]. J Clin Oncol. 2017;35(15 Suppl).

  49. Wakatsuki T, Shinozaki E, Suenaga M, et al. Associations between regorafenib-induced adverse events (AEs) and efficacy in metastatic colorectal cancer (mCRC) [abstract no. 556]. J Clin Oncol. 2017;35(4 Suppl).

  50. Bekaii-Saab TS, Ou FS, Anderson DM, et al. Regorafenib dose optimization study (ReDOS): randomized phase II trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mCRC). An ACCRU Network study [abstract no. 611]. J Clin Oncol. 2018;36(Suppl 4).

  51. Masuishi T, Taniguchi H, Hamauchi S, et al. Regorafenib versus trifluridine/tipiracil for refractory metastatic colorectal cancer: a retrospective comparison. Clin Colorectal Cancer. 2017;16(2):e15–22.

    Article  PubMed  Google Scholar 

  52. Moriwaki T, Fukuoka S, Taniguchi H, et al. Propensity score analysis of regorafenib versus trifluridine/tipiracil in patients with metastatic colorectal cancer refractory to standard chemotherapy (REGOTAS): a Japanese Society for Cancer of the Colon and Rectum multicenter observational study. Oncologist. 2018;23(1):7–15.

    Article  PubMed  CAS  Google Scholar 

  53. Weinberg BA, Marshall JL, Salem ME. Trifluridine/tipiracil and regorafenib: new weapons in the war against metastatic colorectal cancer. Clin Adv Hematol Oncol. 2016;14(8):630–8.

    PubMed  Google Scholar 

Download references

Acknowledgements

During the peer review process, the manufacturer of regorafenib was also offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit

Author information

Authors and Affiliations

  1. Springer, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand

    Sohita Dhillon

Authors
  1. Sohita Dhillon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sohita Dhillon.

Ethics declarations

Funding

The preparation of this review was not supported by any external funding.

Conflicts of interest

Sohita Dhillon is a salaried employee of Adis/Springer, is responsible for the article content and declares no relevant conflicts of interest.

Additional information

The manuscript was reviewed by: P. Gibbs, Department of Medical Oncology, The Western Hospital, Melbourne, VIC, Australia; P. M. Kasi, College of Medical Oncology, Mayo Clinic, Jacksonville, FL, USA; J. Rogers, The University of Texas-MD Anderson Cancer Center, Houston, TX, USA; Yu Sunakawa, Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dhillon, S. Regorafenib: A Review in Metastatic Colorectal Cancer. Drugs 78, 1133–1144 (2018). https://doi.org/10.1007/s40265-018-0938-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40265-018-0938-y

Search

Navigation