Skip to main content

Advertisement

SpringerLink
Log in

Risk of hand-foot skin reaction with the novel multikinase inhibitor regorafenib: a meta-analysis

  • REVIEW
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

Background Regorafenib is a novel receptor tyrosine kinase inhibitor approved for use in metastatic colorectal cancer (mCRC) and locally advanced gastrointestinal stromal tumors (GISTs). The drug targets multiple receptors, including VEGF-R1/-R2/-R3, TIE-2, FGFR-1, PDGFR-α/β, KIT, RET, RAF, p38 MAPK. Adverse events include asthenia, hypertension, diarrhea, and hand-foot skin reaction (HFSR), with the latter representing one of the most clinically significant untoward events. The incidence and risk of HFSR with regorafenib have not been systematically investigated. Methods We conducted a meta-analysis to ascertain the incidence and risk of developing HFSR in cancer patients treated with regorafenib. Electronic databases (PubMed, Scopus, Web of Science) and the ASCO website were searched for publications from January 1998–January 2013. Eligible studies were limited to Phase II/III clinical trials employing regorafenib (160 mg/day). The incidence, relative risk (RR), and 95 % CIs were calculated using random- or fixed-effects models based on the heterogeneity of included studies. Results A total of 1,078 patients treated with regorafenib for mCRC, GIST, renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC) were included. The overall incidence of all-grade and high-grade HFSR were 60.5 % (95 % CI: 48.3–71.6 %) and 20.4 % (95 % CI: 15.4–26.6 %), respectively. The RRs of all-grade and high-grade HFSR with regorafenib in comparison to controls were increased for all-grade (RR = 5.4, 95 % CI: 3.76–7.76, p < 0.001) and high-grade (RR = 41.99, 95 % CI: 5.88–299.93, p < 0.001) HFSR. The incidence of HFSR varied significantly with tumor type (p = 0.007), and was 71.4 % (95 % CI: 57.4–82.3 %) for RCC, 60.2 % (95 % CI: 52.3–67.6 %) for GIST, 50.0 % (95 % CI: 34.2–65.8 %) for HCC, and 46.6 % (95 % CI: 42.3–51.0 %) for mCRC. Conclusion The incidence and risk of development of HFSR with regorafenib is high, and may vary significantly with tumor type. Knowledge of this is important for patient counseling and clinical trial development, to ensure adherence and maximize clinical outcomes.

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
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Regorafenib [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; 2013 (accessed from: http://labeling.bayerhealthcare.com/html/products/pi/Stivarga_PI.pdf, on March 17, 2013)

  2. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Regorafenib. Available from http://www.clinicaltrials.gov/ct2/results?term=regorafenib&Search=Search [accessed on Mar 20, 2013]

  3. Frost A, Buechert M, Unger C et al (2008) Phase I study of BAY 73-4506, an inhibitor of oncogenic and angiogenic kinases, in patients with advanced solid tumors: final results of a dose-escalation study. J Clin Oncol 26:126 (suppl; abstr 2558)

    Google Scholar 

  4. Kies MS, Blumenschein GRJ, Christensen O, Lin T, Tolcher AW (2010) Phase I study of regorafenib (BAY 73-4506), an inhibitor of oncogenic and angiogenic kinases, administered continuously in patients (pts) with advanced refractory non-small cell lung cancer (NSCLC). J Clin Oncol 28:15 (suppl; abstr 7585)

    Article  Google Scholar 

  5. Bolondi L, Tak WY, Gasbarrini A, Santoro A (2011) Phase II safety study of the oral multikinase inhibitor regorafenib (BAY 73-4506) as second-line therapy in patients with hepatocellular carcinoma. Eur J Cancer 47(Supplement 1):S464

    Article  Google Scholar 

  6. Mross K, Frost A, Steinbild S et al (2012) 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 18(9):2658–2667

    Article  PubMed  CAS  Google Scholar 

  7. Strumberg D, Schultheis B (Jun 2012) Regorafenib for cancer. Expert Opin Investig Drugs 21(6):879–889

    Google Scholar 

  8. George S, Wang Q, Heinrich MC et al (2012) Efficacy and safety of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of imatinib and sunitinib: a multicenter phase II trial. J Clin Oncol 30(19):2401–2407

    Article  PubMed  CAS  Google Scholar 

  9. Eisen T, Joensuu H, Nathan PD et al (Oct 2012) Regorafenib for patients with previously untreated metastatic or unresectable renal-cell carcinoma: a single-group phase 2 trial. Lancet Oncol 13(10):1055–1062

    Google Scholar 

  10. Demetri GD, Reichardt P, Kang YK et al (2013) Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381(9863):295–302

    Article  PubMed  CAS  Google Scholar 

  11. Grothey A, Van Cutsem E, Sobrero A et al (2013) Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381(9863):303–312

    Article  PubMed  CAS  Google Scholar 

  12. Lacouture ME, Reilly LM, Gerami P, Guitart J (Nov 2008) Hand foot skin reaction in cancer patients treated with the multikinase inhibitors sorafenib and sunitinib. Ann Oncol 19(11):1955–1961

    Google Scholar 

  13. Nardone B, Hensley JR, Kulik L et al (Nov 2012) The effect of hand-foot skin reaction associated with the multikinase inhibitors sorafenib and sunitinib on health-related quality of life. J Drugs Dermatol 11(11):e61–65

    Google Scholar 

  14. Borenstein M, Hedges L, Higgins J, Rothstein H (2005) Comprehensive meta-analysis version 2. Biostat, Englewood NJ

    Google Scholar 

  15. Chu D, Lacouture ME, Fillos T, Wu S (2008) Risk of hand-foot skin reaction with sorafenib: a systematic review and meta-analysis. Acta Oncol 47(2):176–186

    Article  PubMed  CAS  Google Scholar 

  16. Chu D, Lacouture ME, Weiner E, Wu S (Jan 2009) Risk of hand-foot skin reaction with the multitargeted kinase inhibitor sunitinib in patients with renal cell and non-renal cell carcinoma: a meta-analysis. Clin Genitourin Cancer 7(1):11–19

    Google Scholar 

  17. Balagula Y, Wu S, Su X, Feldman DR, Lacouture ME (Aug 2012) The risk of hand foot skin reaction to pazopanib, a novel multikinase inhibitor: a systematic review of literature and meta-analysis. Invest New Drugs 30(4):1773–1781

    Google Scholar 

  18. Fischer A, Wu S, Ho AL, Lacouture ME (2013) The risk of hand-foot skin reaction to axitinib, a novel VEGF inhibitor: a systematic review of literature and meta-analysis. Invest New Drugs. Jan 24 2013

  19. Grothey A, Cutsem EV, Sobrero AF et al (2012) Time course of regorafenib-associated adverse events in the phase III CORRECT study. J Clin Oncol 30(suppl 34; abstr 467)

  20. Strumberg D, Awada A, Hirte H et al (2006) Pooled safety analysis of BAY 43-9006 (sorafenib) monotherapy in patients with advanced solid tumours: Is rash associated with treatment outcome? Eur J Cancer 42(4):548–556

    Article  PubMed  CAS  Google Scholar 

  21. Jain L, Gardner ER, Figg WD, Chernick MS, Kong HH (Jan 2010) Lack of association between excretion of sorafenib in sweat and hand-foot skin reaction. Pharmacotherapy 30(1):52–56

    Google Scholar 

  22. Ponten F, Ren Z, Nister M, Westermark B, Ponten J (1994) Epithelial-stromal interactions in basal cell cancer: the PDGF system. J Invest Dermatol 102(3):304–309

    Article  PubMed  CAS  Google Scholar 

  23. Lammie A, Drobnjak M, Gerald W, Saad A, Cote R, Cordon-Cardo C (1994) Expression of c-kit and kit ligand proteins in normal human tissues. J Histochem Cytochem 42(11):1417–1425

    Article  PubMed  CAS  Google Scholar 

  24. Erber R, Thurnher A, Katsen AD et al (Feb 2004) Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J 18(2):338–340

    Google Scholar 

  25. Cascone T, Heymach JV (2012) Targeting the angiopoietin/Tie2 pathway: cutting tumor vessels with a double-edged sword? J Clin Oncol 30(4):441–444

    Article  PubMed  CAS  Google Scholar 

  26. Yang CH, Chuang CK, Hsieh JJ, Chang JW (2010) Targeted therapy and hand-foot skin reaction in advanced renal cell carcinoma. Expert Opin Drug Saf 9(3):459–470

    Article  PubMed  CAS  Google Scholar 

  27. Yoo C, Kim JE, Lee JL et al (2010) The efficacy and safety of sunitinib in korean patients with advanced renal cell carcinoma: high incidence of toxicity leads to frequent dose reduction. Jpn J Clin Oncol 40(10):980–985

    Article  PubMed  Google Scholar 

  28. Lim WT, Ng QS, Ivy P et al (2011) A Phase II study of pazopanib in Asian patients with recurrent/metastatic nasopharyngeal carcinoma. Clin Cancer Res 17(16):5481–5489

    Article  PubMed  CAS  Google Scholar 

  29. Tomita Y, Uemura H, Fujimoto H et al (2011) Key predictive factors of axitinib (AG-013736)-induced proteinuria and efficacy: a phase II study in Japanese patients with cytokine-refractory metastatic renal cell Carcinoma. Eur J Cancer 47(17):2592–2602

    Article  PubMed  CAS  Google Scholar 

  30. Ren Z, Zhu K, Kang H et al (2012) A randomized controlled phase II study of the prophylactic effect of urea-based cream on the hand-foot skin reaction associated with sorafenib in advanced hepatocellular carcinoma. J Clin Oncol 30(suppl; abstr 4008)

  31. Sibaud V, Dalenc F, Chevreau C et al (2011) HFS-14, a specific quality of life scale developed for patients suffering from hand-foot syndrome. Oncologist 16(10):1469–1478

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Dr Alessandro Granito, Dr Luigi Bolondi and Dr Suzanne George for assistance with their clinical trial data.

Source of support

Memorial Sloan-Kettering Cancer Center.

Disclosure statement

VRB and SW have nothing to disclose. MEL has a consultant or advisory role with Amgen, Bayer, BI, BMS, Genentech, Genzyme, GSK, Hara, ImClone, Lilly, Onyx, OSI, Pfizer, Roche, and Wyeth. He is also receiving research funding from Hana Biosciences and Onyx Pharmaceuticals.

Author information

Authors and Affiliations

  1. Dermatology Service, Memorial Sloan-Kettering Cancer Center, Rockefeller Outpatient Pavilion, Suite 228, 160 E 53rd St., New York, NY, 10022, USA

    Viswanath Reddy Belum & Mario E. Lacouture

  2. Division of Medical Oncology, Department of Medicine, State University of New York at Stony Brook, Stony Brook, NY, USA

    Shenhong Wu

Authors
  1. Viswanath Reddy Belum
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shenhong Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mario E. Lacouture
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mario E. Lacouture.

Additional information

Part of this work has been selected as an abstract for publication at the annual meeting of the American Society of Clinical Oncology May–June, 2013

Rights and permissions

Reprints and permissions

About this article

Cite this article

Belum, V.R., Wu, S. & Lacouture, M.E. Risk of hand-foot skin reaction with the novel multikinase inhibitor regorafenib: a meta-analysis. Invest New Drugs 31, 1078–1086 (2013). https://doi.org/10.1007/s10637-013-9977-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-013-9977-0

Keywords

Search

Navigation