Skip to main content

Advertisement

SpringerLink
Log in

Safety and anti-tumor activity of sorafenib (Nexavar®) in combination with other anti-cancer agents: a review of clinical trials

  • Review
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Sorafenib (Nexavar®) is an oral multi-kinase inhibitor that inhibits Raf serine/threonine kinases and receptor tyrosine kinases involved in tumor growth and angiogenesis. Sorafenib has demonstrated preclinical and clinical activity against several tumor types, as a monotherapy and in combination with other anti-cancer agents.

Methods

This review summarizes the safety, pharmacokinetics, and anti-tumor activity of sorafenib combined with other targeted agents or cytotoxics from a series of Phase I/II trials in approximately 600 patients with advanced solid tumors.

Results

Sorafenib in combination with other agents was generally well tolerated, and most adverse events were mild to moderate in severity. Frequent drug-related toxicities were dermatologic, gastrointestinal, or constitutional. Most trials supported sorafenib 400 mg bid as the recommended dose for combination. Sorafenib generally had little effect on the pharmacokinetics of coadministered agents and vice versa. Preliminary anti-tumor activity was observed; overall disease control rates (partial response plus stable disease) ranged from 33 to 92%. Particularly promising activity was observed in patients with melanoma, hepatocellular carcinoma, and non-small-cell lung cancer receiving sorafenib plus paclitaxel/carboplatin, doxorubicin, and gefitinib, respectively.

Conclusions

Sorafenib demonstrated a good safety profile and encouraging anti-tumor effects when coadministered with other agents in patients with advanced solid tumors.

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

  1. Downward J (2003) Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 3:11–22

    Article  PubMed  CAS  Google Scholar 

  2. Wilhelm SM, Carter C, Tang L et al (2004) BAY 43-9006 exhibits broad spectrum oral anti-tumor activity and targets the Raf/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64:7099–7109

    Article  PubMed  CAS  Google Scholar 

  3. Escudier B, Eisen T, Stadler WM et al (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125–134

    Article  PubMed  CAS  Google Scholar 

  4. Kane RC, Farrell AT, Saber H et al (2006) Sorafenib for the treatment of advanced renal cell carcinoma. Clin Cancer Res 12:7271–7278

    Article  PubMed  CAS  Google Scholar 

  5. Strumberg D, Clark JW, Awada A et al (2007) Safety, pharmacokinetics, and preliminary antitumor activity of sorafenib: a review of four phase I trials in patients with advanced refractory solid tumors. Oncologist 12:426–437

    Article  PubMed  CAS  Google Scholar 

  6. Ratain MJ, Eisen T, Stadler WM et al (2006) Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 24:2505–2512

    Article  PubMed  CAS  Google Scholar 

  7. Chatelut E, Delord JP, Canal P (2003) Toxicity patterns of cytotoxic drugs. Invest New Drugs 21:141–148

    Article  PubMed  CAS  Google Scholar 

  8. Mewani RR, Tang W, Rahman A et al (2004) Enhanced therapeutic effects of doxorubicin and paclitaxel in combination with liposome-entrapped ends-modified raf antisense oligonucleotide against human prostate, lung and breast tumor models. Int J Oncol 24:1181–1188

    PubMed  CAS  Google Scholar 

  9. Pei J, Zhang C, Gokhale PC et al (2004) Combination with liposome-entrapped, ends-modified raf antisense oligonucleotide (LErafAON) improves the anti-tumor efficacies of cisplatin, epirubicin, mitoxantrone, docetaxel and gemcitabine. Anticancer Drugs 15:243–253

    Article  PubMed  CAS  Google Scholar 

  10. Mickisch GH (1994) Chemoresistance of renal cell carcinoma: 1986–1994. World J Urol 12:214–223

    PubMed  CAS  Google Scholar 

  11. Vincent P, Zhang X, Chen C et al (2003) Preclinical chemotherapy with the Raf kinase inhibitor BAY 43-9006 in combination with gefitinib, vinorelbine, gemcitabine or doxorubicin. Proc Am Assoc Cancer Res 44:164

    Google Scholar 

  12. Vincent R, Bernando V, Chen C, Zhang X, Carter C (2003) Chemotherapy with BAY 43-9006 in combination with Irinotecan or administered as repeated cycles of therapy against the DLD-1 human tumor xenograft. Clin Cancer Res 44:4469 (Abstract)

    Google Scholar 

  13. Richly H, Kupsch P, Passage K et al (2004) Results of a phase I trial of BAY 43-9006 in combination with doxorubicin in patients with primary hepatic cancer. Int J Clin Pharmacol Ther 42:650–651

    PubMed  CAS  Google Scholar 

  14. Richly H, Henning BF, Kupsch P et al (2006) Results of a Phase I trial of sorafenib (BAY 43-9006) in combination with doxorubicin in patients with refractory solid tumors. Ann Oncol 17:866–873

    Article  PubMed  CAS  Google Scholar 

  15. Eisen T, Ahmad T, Marais R et al (2005) Phase I trial of sorafenib (BAY 43-9006) combined with dacarbazine (DTIC) in patients with metastatic melanoma. Eur J Cancer Suppl 3:349

    Google Scholar 

  16. Kupsch P, Henning BF, Passarge K et al (2005) Results of a phase I trial of sorafenib (BAY 43-9006) in combination with oxaliplatin in patients with refractory solid tumors, including colorectal cancer. Clin Colorectal Cancer 5:188–196

    Article  PubMed  Google Scholar 

  17. Figer A, Moscovici M, Bulconic S et al (2004) Phase I trial of BAY 43-9006 in combination with 5-fluorouracil (5-FU) and leucovorin (LCV) in patients with advanced refractory solid tumors. Ann Oncol 15:iii87 (Abstract 327)

    Google Scholar 

  18. Siu LL, Awada A, Takimoto CH et al (2006) Phase I trial of sorafenib and gemcitabine in advanced solid tumors with an expanded cohort in advanced pancreatic cancer. Clin Cancer Res 12:144–151

    Article  PubMed  CAS  Google Scholar 

  19. Flaherty KT, Lee RJ, Humphries R, O’Dwyer PJ, Schiller J (2003) Phase I trial of BAY 43-9006 in combination with carboplatin (C) and paclitaxel (P). Proc Am Soc Clin Oncol 22:710

    Google Scholar 

  20. Robert C, Lassau N, Angevin E et al (2005) Phase I trial of sorafenib (BAY 43-9006) in combination with interferon alpha 2a in patients with unresectable and/or metastatic renal cell carcinoma and malignant melanoma. Eur J Cancer Suppl 3:254

    Google Scholar 

  21. Adjei AA, Mandrekar S, Marks RS et al (2005) A phase I study of BAY 43-9006 and gefitinib in patients with refractory or recurrent non small cell lung cancer (NSCLC). J Clin Oncol 23:208s

    Google Scholar 

  22. Steinbild S, Baas F, Gmehling D et al (2005) Phase I study of BAY 43-9006 (sorafenib), a Raf kinase and VEGFR inhibitor, combined with irinotecan (CPT-11) in advanced solid tumors. J Clin Oncol 23:3115 (Abstract)

    Google Scholar 

  23. Azad NS, Posadas EM, Kwitkowski VE et al (2006) Increased efficacy and toxicity with combination anti-VEGF therapy using sorafenib and bevacizumab. J Clin Oncol 24:3004 (Meeting Abstracts)

    Google Scholar 

  24. Posadas EM, Kwitkowski V, Liel MS et al (2005) Clinical synergism from combinational VEGF signal transduction inhibition in patients with advanced solid tumors - early results from a Phase I study of sorafenib (BAY 43-9006) and bevacizumab. Eur J Cancer Suppl 3:419

    Google Scholar 

  25. Duran I, Hotte S, Chen E et al (2007) Dual inhibition of the MAPK pathway by combination targeted therapy: a phase I trial of sorafenib (SOR) and erlotinib (ERL) in advanced solid tumors. Eur J Cancer (supp) 4:167

    Article  Google Scholar 

  26. Flaherty KT, Brose M, Schuchter LM et al (2006) Sorafenib combined with carboplatin and paclitaxel for metastatic melanoma: PFS and response versus B-Raf status. Ann Oncol 17:iii33

    Google Scholar 

  27. Schiller JH, Flaherty KT, Redlinger M et al (2006) Sorafenib combined with carboplatin/paclitaxel for advanced non-small cell lung cancer: a phase I subset analysis. J Clin Oncol 24:7194 (Meeting Abstracts)

    Article  CAS  Google Scholar 

  28. Lorigan P, Corrie P, Chao D et al (2006) Phase II trial of sorafenib combined with dacarbazine in metastatic melanoma patients. J Clin Oncol 24:8012 (Meeting Abstracts)

    Google Scholar 

  29. Adjei AA, Argiris A, Murren JR (1999) Docetaxel and irinotecan, alone and in combination, in the treatment of non-small cell lung cancer. Semin Oncol 26:32–40

    PubMed  CAS  Google Scholar 

  30. Amaravadi RK, Schuchter LM, Kramer A et al (2006) Preliminary results of a randomized phase II study comparing two schedules of temzolomide in combination with sorafenib in patients with advanced melanoma. J Clin Oncol 24(Part 1):8009 (Meeting Abstracts)

    Google Scholar 

  31. Gollob J, Richmond T, Jones J et al (2006) Phase II trial of sorafenib plus interferon-alpha 2b (IFN-{alpha}2b) as first- or second-line therapy in patients (pts) with metastatic renal cell cancer (RCC). J Clin Oncol 24:4538 (Meeting Abstracts)

    Google Scholar 

  32. Ryan CW, Goldman BH, Lara PN Jr et al (2006) Sorafenib plus interferon-{alpha}2b (IFN) as first-line therapy for advanced renal cell carcinoma (RCC): SWOG 0412. J Clin Oncol 24:4525 (Meeting Abstracts)

    Google Scholar 

  33. Flaherty KT, Brose M, Schuchter L et al (2004) Phase I/II trial of BAY 43-9006, carboplatin (C) and paclitaxel (P) demonstrates preliminary antitumor activity in the expansion cohort of patients with metastatic melanoma. J Clin Oncol 22:7507 (Abstract)

    Google Scholar 

  34. Keilholz U, Punt CJ, Gore M et al (2005) Dacarbazine, cisplatin, and interferon-alfa-2b with or without interleukin-2 in metastatic melanoma: a randomized phase III trial (18951) of the European Organisation for Research and Treatment of Cancer Melanoma Group. J Clin Oncol 23:6747–6755

    Article  PubMed  CAS  Google Scholar 

  35. Welch S, Hirte H, Schilder RJ et al (2006) Phase II study of sorafenib (BAY 43-9006) in combination with gemcitabine in recurrent epithelial ovarian cancer: A PMH phase II consortium trial. J Clin Oncol 24:5084 (Meeting Abstracts)

    Google Scholar 

  36. 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 42:548–556

    Article  PubMed  CAS  Google Scholar 

  37. Staehler M, Rohrmann K, Haseke N, Stief CG, Siebels M (2005) Targeted agents for the treatment of advanced renal cell carcinoma. Curr Drug Targets 6:835–846

    Article  PubMed  CAS  Google Scholar 

  38. Odabaei G, Chatterjee D, Jazirehi AR et al (2004) Raf-1 kinase inhibitor protein: structure, function, regulation of cell signaling, and pivotal role in apoptosis. Adv Cancer Res 91:169–200

    Article  PubMed  CAS  Google Scholar 

  39. Wang HG, Miyashita T, Takayama S et al (1994) Apoptosis regulation by interaction of Bcl-2 protein and Raf-1 kinase. Oncogene 9:2751–2756

    PubMed  CAS  Google Scholar 

  40. Yu C, Bruzek LM, Meng XW et al (2005) The role of Mcl-1 downregulation in the proapoptotic activity of the multikinase inhibitor BAY 43-9006. Oncogene 24:6861–6869

    Article  PubMed  CAS  Google Scholar 

  41. Kim SH, Lee SH, Kwak NH, Kang CD, Chung BS (1996) Effect of the activated Raf protein kinase on the human multidrug resistance 1 (MDR1) gene promoter. Cancer Lett 98:199–205

    Article  PubMed  CAS  Google Scholar 

  42. Cornwell MM, Smith DE (1993) A signal transduction pathway for activation of the mdr1 promoter involves the proto-oncogene c-raf kinase. J Biol Chem 268:15347–15350

    PubMed  CAS  Google Scholar 

  43. Erhardt P, Schremser EJ, Cooper GM (1999) B-Raf inhibits programmed cell death downstream of cytochrome c release from mitochondria by activating the MEK/Erk pathway. Mol Cell Biol 19:5308–5315

    PubMed  CAS  Google Scholar 

  44. Karasarides M, Chiloeches A, Hayward R et al (2004) B-RAF is a therapeutic target in melanoma. Oncogene 23:6292–6298

    Article  PubMed  CAS  Google Scholar 

  45. Chapman PB, Einhorn LH, Meyers ML et al (1999) Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 17:2745–2751

    PubMed  CAS  Google Scholar 

  46. Hodi FS, Soiffer RJ, Clark J, Finkelstein DM, Haluska FG (2002) Phase II study of paclitaxel and carboplatin for malignant melanoma. Am J Clin Oncol 25:283–286

    Article  PubMed  Google Scholar 

  47. Zimpfer-Rechner C, Hofmann U, Figl R et al (2003) Randomized phase II study of weekly paclitaxel versus paclitaxel and carboplatin as second-line therapy in disseminated melanoma: a multicentre trial of the Dermatologic Co-operative Oncology Group (DeCOG). Melanoma Res 13:531–536

    Article  PubMed  CAS  Google Scholar 

  48. Ferrara N (2004) Vascular endothelial growth factor as a target for anticancer therapy. Oncologist 9(Suppl 1):2–10

    Article  PubMed  CAS  Google Scholar 

  49. Ferrara N (2005) VEGF as a therapeutic target in cancer. Oncology 69(Suppl 3):11–16

    Article  PubMed  CAS  Google Scholar 

  50. Gridelli C, Rossi A, Mongillo F et al (2007) A randomized phase II study of sorafenib/gemcitabine or sorafenib/erlotinib for advanced non-small-cell lung cancer in elderly patients or patients with a performance status of 2: treatment rationale and protocol dynamics. Clin Lung Cancer 8:396–398

    PubMed  Google Scholar 

  51. Sosman JA, Flaherty K, Atkins MB et al (2006) A phase I/II trial of sorafenib (S) with bevacizumab (B) in metastatic renal cell cancer (mRCC) patients (Pts). J Clin Oncol 24:3031 (Meeting Abstracts)

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. South Texas Accelerated Research Therapeutics (START), 4319 Medical Drive, Suite 205, San Antonio, TX, 78229, USA

    Chris H. Takimoto

  2. Medical Oncology Clinic, Jules Bordet Institute, 121 Boulevard de Waterloo, 1000, Brussels, Belgium

    Ahmad Awada

Authors
  1. Chris H. Takimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ahmad Awada
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chris H. Takimoto.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Takimoto, C.H., Awada, A. Safety and anti-tumor activity of sorafenib (Nexavar®) in combination with other anti-cancer agents: a review of clinical trials. Cancer Chemother Pharmacol 61, 535–548 (2008). https://doi.org/10.1007/s00280-007-0639-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-007-0639-9

Keywords

Search

Navigation