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

Cirrone, Frank; Harris, Christy

doi:10.1016/j.clinthera.2012.08.011

Cited by 55 publications

(45 citation statements)

References 29 publications

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“…In a two-stage phase I study, daily dosing of oral vismodegib reached steady state within 7 -14 days, regardless of the dose [3,9]. Vismodegib has nonlinear kinetics due to its high protein binding affinity (99%), especially for α1-acid glycoprotein (AAG) [3,5].…”

Section: Pharmacokineticsmentioning

confidence: 99%

“…Vismodegib has nonlinear kinetics due to its high protein binding affinity (99%), especially for α1-acid glycoprotein (AAG) [3,5]. It also binds to human serum albumin at a lower binding affinity, leaving less than 1% unbound in the serum [3,10].…”

Section: Pharmacokineticsmentioning

confidence: 99%

“…The two largest oxidative metabolites recovered from the feces are produced from recombinant cytochrome P450 (CYP) 2C9 and CYP3A4/5 [3,5,11]. Elimination of vismodegib is primarily through the liver, with 82% of the drug recovered in the feces and 4.4% found in the urine [11].…”

Section: Pharmacokineticsmentioning

confidence: 99%

“…Elimination of vismodegib is primarily through the liver, with 82% of the drug recovered in the feces and 4.4% found in the urine [11]. The elimination half-life is about 12 days after a single dose, but decreases to 4 days with daily continuous dosing [3,5,12]. …”

Section: Pharmacokineticsmentioning

confidence: 99%

“…After this discovery, researchers found that abnormalities in the Hh signaling pathway were implicated in a majority of sporadic BCC cases [2]. Since then, several Hh pathway inhibitors have been in development, with vismodegib (Erivedge®, Genentech, South San Francisco, CA) being the first to gain FDA approval for the treatment of locally advanced (laBCC) or metastatic basal cell carcinoma (mBCC) on January 30, 2012 [3,4].…”

Section: Introductionmentioning

confidence: 99%

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Vismodegib Provides a Novel Treatment for Advanced Basal Cell Carcinoma

Kelm¹,

Magliaro²,

Anderson³

et al. 2014

JCT

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Objective: To review and evaluate vismodegib, the first US Food and Drug Administration (FDA) approved treatment for locally advanced (laBCC) or metastatic basal cell carcinoma (mBCC) that has recurred after surgery or for patients in which surgery or radiation is not an option. Data Sources: A literature search using PubMed was conducted through January 2013, using the terms vismodegib, GDC-0449, and Erivedge. Additional literature was found through the reference citations of identified articles. Study Selection and Data Extraction: Potential sources were limited to human studies published in English with a priority placed on those focused on laBCC or mBCC. Data Synthesis: Vismodegib is a selective inhibitor of the hedgehog (Hh) pathway approved for the treatment of laBCC or mBCC that has recurred after surgery, or for patients for whom surgery or radiation is contraindicated. Vismodegib inhibits cancer cell growth and survival by binding Smoothened, a transmembrane protein involved in the Hedgehog signal transduction. Vismodegib is administered orally at a dose of 150 mg daily. It is primarily eliminated through the feces unchanged but does have some oxidative metabolites produced from the recombinant cytochrome P450 (CYP) 2C9 and CYP3A4/5. Despite CYP450 involvement, it appears to have very few drug interactions. The most common adverse events reported with vismodegib include muscle spasms, dysgeusia, alopecia, weight loss, fatigue, nausea, anorexia, and diarrhea. FDA approval was based on a single arm phase II study that demonstrated an objective response rate of 30% in mBCC patients and 45% in laBCC patients. Vismodegib was approved by the FDA on January 30, 2012 for use in patients with advanced basal cell carcinoma, and continues to be studied in other patient populations for additional potential uses. Conclusions: Based on a review of current evidence, vismodegib provides an effective and well-tolerated treatment for otherwise untreatable basal cell carcinoma.

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Section: Pharmacokineticsmentioning

confidence: 99%

Section: Pharmacokineticsmentioning

confidence: 99%

Section: Pharmacokineticsmentioning

confidence: 99%

Section: Pharmacokineticsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Vismodegib Provides a Novel Treatment for Advanced Basal Cell Carcinoma

Kelm¹,

Magliaro²,

Anderson³

et al. 2014

JCT

View full text Add to dashboard Cite

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Vismodegib for Locally Advanced Basal Cell Carcinoma in a Heart Transplant Patient

et al. 2015

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To our knowledge, this is the first report that details vismodegib use in an immunosuppressed heart transplant patient receiving cyclosporine therapy. With a growing immunosuppressed organ transplant population at high risk for basal cell carcinoma, therapeutic options for locally advanced or metastatic disease are limited. Vismodegib appears to be a safe option for patients receiving cyclosporine therapy with routine monitoring. Future research is needed to evaluate the safety profile of vismodegib with other immunosuppressive agents.

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Increased Risk of Cutaneous Squamous Cell Carcinoma After Vismodegib Therapy for Basal Cell Carcinoma

et al. 2016

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IMPORTANCE Smoothened inhibitors (SIs) are a new type of targeted therapy for advanced basal cell carcinoma (BCC), and their long-term effects, such as increased risk of subsequent malignancy, are still being explored. OBJECTIVE To evaluate the risk of developing a non-BCC malignancy after SI exposure in patients with BCC. DESIGN, SETTING, AND PARTICIPANTS A case-control study at Stanford Medical Center, an academic hospital. Participants were higher-risk patients with BCC diagnosed from January 1, 1998, to December 31, 2014. The dates of the analysis were January 1 to November 1, 2015. EXPOSURES The exposed participants (cases) comprised patients who had confirmed prior vismodegib treatment, and the nonexposed participants (controls) comprised patients who had never received any SI. Because vismodegib was the first approved SI, only patients exposed to this SI were included. MAIN OUTCOMES AND MEASURES Hazard ratio for non-BCC malignancies after vismodegib exposure, adjusting for covariates. RESULTS The study cohort comprised 180 participants. Their mean (SD) age at BCC diagnosis was 56 (16) years, and 68.9% (n = 124) were male. Fifty-five cases were compared with 125 controls, accounting for age, sex, prior radiation therapy or cisplatin treatment, Charlson Comorbidity Index, clinical follow-up time, immunosuppression, and basal cell nevus syndrome status. Patients exposed to vismodegib had a hazard ratio of 6.37 (95% CI, 3.39-11.96; P < .001), indicating increased risk of developing a non-BCC malignancy. Most non-BCC malignancies were cutaneous squamous cell carcinomas, with a hazard ratio of 8.12 (95% CI, 3.89-16.97; P < .001), accounting for age and basal cell nevus syndrome status. There was no significant increase in other cancers. CONCLUSIONS AND RELEVANCE Increased risk for cutaneous squamous cell carcinomas after vismodegib therapy highlights the importance of continued skin surveillance after initiation of this therapy.

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

Cited by 55 publications

References 29 publications

Vismodegib Provides a Novel Treatment for Advanced Basal Cell Carcinoma

Vismodegib Provides a Novel Treatment for Advanced Basal Cell Carcinoma

Vismodegib for Locally Advanced Basal Cell Carcinoma in a Heart Transplant Patient

Increased Risk of Cutaneous Squamous Cell Carcinoma After Vismodegib Therapy for Basal Cell Carcinoma

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