Vismodegib: A Hedgehog Pathway Inhibitor for Locally Advanced and Metastatic Basal Cell Carcinomas

October 2013 | Volume 12 | Issue 10 | Supplement Individual Articles | 154 | Copyright © October 2013


Joesph F. Sobanko MD,a Jonathan Okman BA MBA,b and Christopher Miller MDa

aDivision of Dermatologic Surgery and Cutaneous Oncology, University of Pennsylvania, Philadelphia, PA
bPerelman School of Medicine, University of Pennsylvania, Philadelphia, PA

BCC in a biopsy specimen), while 47% and 22% experienced a partial response with vismodegib.15,16

Questions That Still Remain

While early data appear promising, there is still much to be determined regarding vismodegib’s role in BCC treatment. First, the category of “inoperable” BCC is rather subjective and must be better developed. Many recurrent BCCs that are considered inoperable by one surgeon may be deemed surgically appropriate by another surgeon. This decision has significant financial implications too, because the cost of 10 months of vismodegib is $75,000 compared with less than $2,000 for the surgical treatment of most BCCs.18,19
Second, vismodegib may not offer better results than chemotherapeutic agents currently used for metastatic BCCs. Cisplatin-containing regimens have been associated with overall response rates of up to 77%, including complete response rates of up to 45%.20-23 Neutropenia and renal toxicity are feared adverse events (AEs) of cytotoxic cisplatin-based regimens; however, the side effects from vismodegib frequently result in medication termination.24 Twenty-seven percent of NBCCS patients at 8 months and 54% of patients at 18 months discontinued their medication because of side-effect intolerability.17 The most frequently reported AEs are muscle spasms, dysgeusia, weight loss, fatigue, nausea, diarrhea, and alopecia.15,16,24
Finally, the proper duration of vismodegib therapy must be determined. It appears that BCCs and other tumors that involve the Hh pathway develop resistance to vismodegib with subsequent disease progression.25,26,27 This may be the result of a missense mutation in the SMO receptor that decreases vismodegib’s affinity for the receptor. Additionally, the rebound of BCCs after vismodegib cessation have been reported in one patient.28 Future avenues of research that warrant further investigation include the use of vismodegib as a neoadjuvant medication prior to surgical resection.29 Other medications such as such as itraconazole and arsenic trioxide may also offer promising results for vismodegib-resistant BCCs that acquire SMO mutations.30

DISCLOSURES

The authors have no relevant conflicts of interest to disclose.

REFERENCES

  1. National Cancer Institute. Available at: http://www.cancer.gov/cancertopics/types/skin. Accessed August 26, 2013.
  2. Rogers HW, Weinstock MA, HarrisAR, et al. Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch Dermatol. 2010;146(3):283-287.
  3. Chren MM, Linos E, Torres JS, Stuart SE, Parvataneni R, Boscardin WJ. Tumor recurrence 5 years after treatment of cutaneous basal cell carcinoma and squamous cell carcinoma. J Invest Dermatol. 2013;133(5):1188-1196.
  4. von Domarus H, Stevens PJ. Metastatic basal cell carcinoma. Report of five cases and review of 170 cases in the literature. J Am Acad Dermatol. 1984;10(6):1043-1060.
  5. Göppner D, Leverkus M. Basal cell carcinoma: from the molecular understanding of the pathogenesis to targeted therapy of progressive disease. J Skin Cancer. 2011;650258.
  6. Walling HW, Fosko SW, Geraminejad PA, Whitaker DC, Arpey CJ. Aggressive basal cell carcinoma: presentation, pathogenesis, and management. Cancer Metastasis Rev. 2004;23(3-4):389-402.
  7. Evangelista M, Tian H, de Sauvage FJ. The hedgehog signaling pathway in cancer. Clin Cancer Res. 2006;12(20 Pt 1):5924-5928.
  8. Nüsslein-Volhard C, Wieschaus E. Mutations affecting segment number and polarity in Drosophila. Nature. 1980;287(5785):795-801.
  9. Aszterbaum M, Rothman A, Johnson RL, et al. Identification of mutations in the human PATCHED gene in sporadic basal cell carcinomas and in patients with the basal cell nevus syndrome. J Invest Dermatol. 1998;110(6):885-888.
  10. Wolter M, Reifenberger J, Sommer C, Ruzicka T, Reifenberger G. Mutations in the human homologue of the Drosophila segment polarity gene patched (PTCH) in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Cancer Res. 1997;57(13):2581-2585.
  11. Xie J, Murone M, Luoh SM, et al. Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature. 1998;391(6662):90-92.
  12. Hahn H, Wicking C, Zaphiropoulous PG, et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell. 1996;85(6):841-851.
  13. Johnson RL, Rothman AL, Xie J, et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science. 1996;272(5268):1668-1671.
  14. Reifenberger J, Wolter M, Knobbe CB, et al. Somatic mutations in the PTCH, SMOH, SUFUH and TP53 genes in sporadic basal cell carcinomas. Br J Dermatol. 2005;152(1):43-51.
  15. Von Hoff DD, LoRusso PM, Rudin CM, et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med. 2009;361(12):1164-1172.
  16. Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366(23):2171-2179.
  17. Tang JY, Mackay-Wiggan JM, Aszterbaum M, et al. Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med. 2012;366(23):2180-2188.
  18. The Pharma Letter. Faster-than-expected FDA approval of Roche’s vismodegib. Available at: http://thepharmaletter.com/file/110669/faster-than-expected-fda-approval-ofroches-vismodegib.html. Accessed August 26, 2013.
  19. Narayanan K, Hadid OH, Barnes EA. Mohs micrographic surgery versus surgical excision for periocular basal cell carcinoma. Cochrane Database Syst Rev. 2012;2:CD007041.
  20. Pfeiffer P, Hansen O, Rose C. Systemic cytotoxic therapy of basal cell carcinoma. A review of the literature. Eur J Cancer. 1990;26(1):73-77.
  21. Jefford M, Kiffer JD, Somers G, Daniel FJ, Davis ID. Metastatic basal cell carcinoma: rapid symptomatic response to cisplatin and paclitaxel. ANZ J Surg. 2004;74(8):704-705.
  22. Moeholt K, Aagaard H, Pfeiffer P, Hansen O. Platinum-based cytotoxic therapy in basal cell carcinoma--a review of the literature. Acta Oncol. 1996;35(6):677-682.
  23. Carneiro BA, Watkin WG, Mehta UK, Brockstein BE. Metastatic basal cell carcinoma: complete response to chemotherapy and associated pure red cell aplasia. Cancer Invest. 2006;24(4):396-400.
  24. Poggi L, Kolesar JM. Vismodegib for the treatment of basal cell skin cancer. Am J Health Syst Pharm. 2013;70(12):1033-1038.
  25. Genentech Inc. Erivedgeâ„¢ Prescribing Information. 2012. Available at: http://www.gene.com/download/pdf/erivedge_prescribing.pdf. Accessed August 26, 2013.
  26. Rudin CM, Hann CL, Laterra J, et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N Engl J Med. 2009;361(12):1173-1178.
  27. Yauch RL, Dijkgraaf GJ, Alicke B, et al. Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science. 2009;326(5952):572-574.
  28. Geeraert P, Williams JS, Brownell I. Targeting the hedgehog pathway to treat basal cell carcinoma. J Drugs Dermatol. 2013;12(5):519-523.
  29. Wolfe CM, Green WH, Cognetta AB Jr, Hatfield HK. Basal cell carcinoma rebound after cessation of vismodegib in a nevoid basal cell carcinoma syndrome patient. Dermatol Surg. 2012;38(11):1863-1866.
  30. Chang AL, Atwood SX, Tartar DM, Oro AE. Surgical excision after neoadjuvant therapy with vismodegib for a locally advanced basal cell carcinoma and resistant basal carcinomas in Gorlin syndrome. JAMA Dermatol. 2013;149(5):639-641.
  31. Kim J, Aftab BT, Tang JY, et al. Itraconazole and arsenic trioxide inhibit Hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists. Cancer Cell. 2013;23(1):23-34.

AUTHOR CORRESPONDENCE

Joesph F. Sobanko MDjoseph.sobanko@uphs.upenn.edu
Close Menu