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Vismodegib and the Hedgehog Pathway: A New Treatment for Basal Cell Carcinoma

  • Author Footnotes
    ⁎ Current affiliation: New York–Presbyterian Hospital, Department of Pharmacy, New York, New York.
    Frank Cirrone
    Footnotes
    ⁎ Current affiliation: New York–Presbyterian Hospital, Department of Pharmacy, New York, New York.
    Affiliations
    Department of Pharmacy Practice, Massachusetts College of Pharmacy and Health Sciences, Boston, Massachusetts
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  • Christy S. Harris
    Correspondence
    Address correspondence to: Christy S. Harris, PharmD, BCPS, BCOP, Department of Pharmacy Practice, Massachusetts College of Pharmacy and Health Sciences, 179 Longwood Avenue, Boston, MA 02115-5896
    Affiliations
    Department of Pharmacy Practice, Massachusetts College of Pharmacy and Health Sciences, Boston, Massachusetts
    Search for articles by this author
  • Author Footnotes
    ⁎ Current affiliation: New York–Presbyterian Hospital, Department of Pharmacy, New York, New York.

      Abstract

      Background

      Vismodegib is an oral inhibitor of the Hedgehog pathway approved by the US Food and Drug Administration. It is the first systemic treatment for patients with locally advanced or metastatic basal cell carcinoma that is not amenable to surgery and radiation. This is the first drug to use the Hedgehog pathway to inhibit the proliferation of tumors and is also implicated in the development of other cancers such as medulloblastoma.

      Objective

      The goal of this review was to summarize the development, pharmacology, efficacy, and safety of vismodegib.

      Methods

      Relevant English-language literature was identified and then evaluated based on results from database searches of MEDLINE and EMBASE from 1975 to June 19, 2012. The terms searched included, but were not limited to, vismodegib, Erivedge, GDC-0449, basal cell carcinoma, and 2-chloro-N-[4-chloro-3-(pyridin-2-yl)phenyl]-4-(methylsulfonyl)benzamide. Additional literature was identified by assessing the reference lists of previously identified articles and through abstracts presented by the American Society of Clinical Oncology.

      Results

      A total of 70 full text citations were identified although two national conference proceedings were then excluded. An additional 10 published abstracts were also identified. A Phase II, nonrandomized, multicenter, international study demonstrated a 30.3% objective response rate in metastatic basal cell carcinoma and a 42.9% objective response rate in locally advanced basal cell carcinoma. The adverse effect profile for vismodegib is similar to other identified Hedgehog pathway inhibitors; muscle cramps (71.7%), alopecia (63.8%), and dysgeusia (55.1%) were the most common adverse effects seen in trials. A Phase II, randomized, placebo-controlled trial in Gorlin syndrome patients with basal cell carcinoma concluded that vismodegib was significantly better than placebo at reducing new basal cell carcinoma lesions (P < 0.001) and at decreasing the sum of the longest diameter of existing lesions (P = 0.003).

      Conclusions

      For patients with unresectable basal cell carcinoma or where resection would be cosmetically disadvantageous, vismodegib is an effective therapy with good response rates. At this time, the data are too limited to determine overall survival. The Hedgehog pathway is a newly identified area in which mutations or dysregulation can occur, leading to the development and progression of tumors. Studies continue to look at other cancers with involvement of the Hedgehog pathway.

      Key words

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      References

        • US Food and Drug Administration (2012)
        FDA approves new treatment for most common type of skin cancer.
        ([News Release]) (Accessed August 14, 2012)
        • National Cancer Institute
        General information about skin cancer.
        (Accessed August 14, 2012)
        • American Cancer Society
        Skin cancer: basal and squamous cell.
        (Accessed August 14, 2012)
        • Donovan J.
        Review of the hair follicle origin hypothesis for basal cell carcinoma.
        Dermatol Surg. 2009; 35: 1311-1323
        • Grachtchouk M.
        • Pero J.
        • Yang S.H.
        • et al.
        Basal cell carcinomas in mice arise from hair follicle stem cells and multiple epithelial progenitor populations.
        J Clin Invest. 2011; 121: 1768-1781
        • Madan V.
        • Lear J.T.
        • Szeimies R.M.
        Non-melanoma skin cancer.
        Lancet. 2010; 375: 673-685
        • Rogers H.W.
        • Weinstock M.A.
        • Harris A.R.
        • et al.
        Incidence estimate of nonmelanoma skin cancer in the United States, 2006.
        Arch Dermatol. 2010; 146: 283-287
        • Stern R.S.
        Prevalence of a history of skin cancer in 2007: results of an incidence-based model.
        Arch Dermatol. 2010; 146: 279-282
        • Christenson L.J.
        • Borrowman T.A.
        • Vachon C.M.
        • et al.
        Incidence of basal cell and squamous cell carcinomas in a population younger than 40 years.
        JAMA. 2005; 294: 681-690
        • Amini S.
        • Viera M.H.
        • Valins W.
        • Berman B.
        Nonsurgical innovations in the treatment of nonmelanoma skin cancer.
        J Clin Aesthet Dermatol. 2010; 3: 20-34
        • 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
        • Walling H.W.
        • Fosko S.W.
        • Geraminejad P.A.
        • et al.
        Aggressive basal cell carcinoma: presentation, pathogenesis, and management.
        Cancer Metastasis Rev. 2004; 23: 389-402
        • Lear J.T.
        Oral hedgehog-pathway inhibitors for basal-cell carcinoma.
        N Engl J Med. 2012; 366: 2225-2226
        • Tang J.Y.
        • Mackay-Wiggan J.M.
        • Aszterbaum M.
        • et al.
        Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome.
        N Engl J Med. 2012; 366: 2180-2188
        • Caro I.
        • Low J.A.
        The role of the hedgehog signaling pathway in the development of basal cell carcinoma and opportunities for treatment.
        Clin Cancer Res. 2010; 16: 3335-3359
        • Rudin C.M.
        • Hann C.L.
        • Laterra J.
        • et al.
        Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449.
        N Engl J Med. 2009; 361: 1173-1178
        • Low J.A.
        • de Sauvage F.J.
        Clinical experience with Hedgehog pathway inhibitors.
        J Clin Oncol. 2010; 28: 5321-5326
        • Ganti A.K.
        • Kessinger A.
        Systemic therapy for disseminated basal cell carcinoma: an uncommon manifestation of a common cancer.
        Cancer Treat Rev. 2011; 37: 440-443
        • LoRusso P.M.
        • Rudin C.M.
        • Reddy J.C.
        • et al.
        Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors.
        Clin Cancer Res. 2011; 17: 2502-2511
        • Gupta S.
        • Takebe N.
        • Lorusso P.
        Targeting the Hedgehog pathway in cancer.
        Ther Adv Med Oncol. 2010; 2: 237-250
        • Lin T.L.
        • Matsui W.
        Hedgehog pathway as a drug target: smoothened inhibitors in development.
        Onco Targets Ther. 2012; 5: 47-58
        • Dijkgraaf G.J.
        • Alicke B.
        • Weinmann L.
        • et al.
        Small molecule inhibition of GDC-0449 refractory smoothened mutants and downstream mechanisms of drug resistance.
        Cancer Res. 2011; 71: 435-444
        • Von Hoff D.D.
        • LoRusso P.M.
        • Rudin C.M.
        • et al.
        Inhibition of the hedgehog pathway in advanced basal-cell carcinoma.
        N Engl J Med. 2009; 361: 1164-1172
        • Sekulic A.
        • Migden M.R.
        • Oro A.E.
        • et al.
        Efficacy and safety of vismodegib in advanced basal-cell carcinoma.
        N Engl J Med. 2012; 366: 2171-2179
        • Graham R.A.
        • Lum B.L.
        • Cheeti S.
        • et al.
        Pharmacokinetics of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with locally advanced or metastatic solid tumors: the role of alpha-1-acid glycoprotein binding.
        Clin Cancer Res. 2011; 17: 2512-2520
        • Lorusso P.M.
        • Jimeno A.
        • Dy G.
        • et al.
        Pharmacokinetic dose-scheduling study of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with locally advanced or metastatic solid tumors.
        Clin Cancer Res. 2011; 17: 5774-5782
        • Graham R.
        • Hop C.
        • Borin M.
        • et al.
        Single- and multiple-dose intravenous and oral pharmacokinetics of the Hedgehog pathway inhibitor vismodegib in healthy female subjects.
        Br J Clin Pharmacol. 2012 Mar 28; ([Epub ahead of print])
        • Sharma M.
        • Kang S.P.
        • Karrison T.
        • et al.
        Evaluation of food effect on pharmacokinetics (PK) of GDC-0449 (G) in advanced solid tumor patients.
        in: Abstract presented at: American Society of Clinical Oncology Annual ConferenceJune 1–5, 2012 (Chicago, Ill)
      1. Erivedge.
        ([package insert]) Genentech, Inc, San Francisco, Calif2012
        • Lorusso P.
        • Piha-Paul S.A.
        • Colevas A.D.
        • et al.
        Pharmacokinetic assessment of drug-drug interaction potential when rosiglitazone or combined oral contraceptive is coadministered with vismodegib in patients with locally advanced or metastatic solid tumors.
        in: Abstract presented at: AACR-NCI-EORTC Molecular Targets and Cancer TherapeuticsNovember 12–16, 2011 (San Francisco, Calif)
        • Graham R.A.
        • Lum B.L.
        • Morrison G.
        • et al.
        A single dose mass balance study of the Hedgehog pathway inhibitor vismodegib (GDC-0449) in humans using accelerator mass spectrometry.
        Drug Metab Dispos. 2011; 39: 1460-1467
        • Gajjar A.J.
        • Stewart C.F.
        • Ellison D.W.
        • et al.
        • Pediatric Brain Tumor Consortium (PBTC 25)
        A phase I pharmacokinetic trial of sonic hedgehog (SHH) antagonist GDC-0449 in pediatric patients with recurrent or refractory medulloblastoma.
        J Clin Oncol. 2010; 28
        • Sekulic A.
        • Migden M.R.
        • Oro A.E.
        • et al.
        Efficacy and safety of the hedgehog pathway inhibitor vismodegib in patients with advanced basal cell carcinoma (BCC): ERIVANCE BCC study update.
        in: Abstract presented at: American Society of Clinical Oncology Annual ConferenceJune 1–5, 2012 (Chicago, Ill)
        • US Department of Health and Human Services, National Cancer Institute. Common toxicity criteria for adverse events, version 4.0
        (Accessed August 14, 2012)
        • Mudigonda T.
        • Pearce D.J.
        • Yentzer B.A.
        • et al.
        The economic impact of non-melanoma skin cancer: a review.
        J Natl Compr Canc Netw. 2010; 8: 888-896
        • Manternach T.
        • Housman T.S.
        • Williford P.M.
        • et al.
        Surgical treatment of nonmelanoma skin cancer in the Medicare population.
        Dermatol Surg. 2003; 29 (discussion 1169): 1167-1169
        • Pollack A.
        FDA approves drug for an advanced skin cancer.
        New York Times. January 30, 2012; (Accessed August 14, 2012)
        • Tang T.
        • Tang J.Y.
        • Li D.
        • et al.
        Targeting superficial or nodular basal cell carcinoma with topically formulated small molecule inhibitor of smoothened.
        Clin Cancer Res. 2011; 17: 3378-3387
        • McMillan R.
        • Matsui W.
        Molecular pathways: the Hedgehog signaling pathway in cancer.
        Clin Cancer Res. 2012 June 19; ([Epub ahead of print])