Vismodegib


Article Author:
Patrick Zito


Article Editor:
Richard Scharf


Editors In Chief:
Amanda Oakley
Jules Lipoff
Shyam Verma


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Frank Smeeks
Kristina Soman-Faulkner
Trevor Nezwek
Radia Jamil
Patrick Le
Sobhan Daneshfar
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
2/19/2019 4:54:02 PM

Indications

Initially approved in 2012, vismodegib is the first FDA-approved, pharmacologic agent that targets the Hedgehog signaling pathway (sonic hedgehog, SHH), a pathway involved in many basal cell carcinomas. Basal cell carcinoma (BCC) is the most common nonmelanoma skin cancer (NMSC) accounting for over one-half of all NMSC diagnoses. BCC affects over 3.3 million a year in the United States. Approximately 40% of patients that are diagnosed with BCC will develop another BCC within 5 years of the initial diagnosis. Management is primarily done with surgical intervention, except in some cases, where topical therapy is utilized. Not all patients are suitable candidates for surgery or topical therapy due to locally advanced or metastatic basal cell carcinoma. This is when vismodegib has a place in therapy.[1][2][3][4][5]

Vismodegib is indicated for the following:

  • Metastatic basal cell carcinoma
  • Locally-advanced basal cell carcinoma that has recurred following surgery
  • Patients who are not candidates for surgery
  • Patients who are not candidates for radiation therapy

Vismodegib was first approved after results of the ERIVANCE study, which showed results of treating locally or advanced metastatic basal cell carcinoma in situations where simple excision would not result in a cure. The ERIVANCE study showed a response rate of 45% in those that had locally advanced disease. In patients with metastatic basal cell carcinoma, an independently assessed response rate was 30%. A systematic review showed that patients with locally advanced basal cell carcinoma had a complete response rate of in the range of 0% to 54.1% with a weighted average of 31.1%. Partial response rates for those with locally advanced disease were between 25.5% and 66.7%, with a weighted average of 33.6%. A partial response indicated greater than 30% reduction in total tumor size, and a complete response rate indicated that within subsequent biopsies no residual basal cell carcinoma tumor was found.

Recently, vismodegib was examined as a neoadjuvant therapy.  In an open-label, clinical trial of 15 patients using vismodegib as a neoadjuvant treatment before surgery in high-risk basal cell carcinoma resulted in a decrease in the final surgical defect size by 34.8% with no recurrence and no skipped areas were seen in the tumor blocks that were sectioned. This was a small size study where only 11 patients completed therapy with vismodegib. However, future studies may examine this topic further.

Mechanism of Action

The Hedgehog pathway regulates cell growth and differentiation in embryogenesis. This pathway is not active in adult tissue. PTCH1 is a tumor suppressor gene involved in the SHH pathway. SMO is a G-protein-coupled transmembrane receptor involved in signal transduction of the SHH pathway. Mutations in the smoothened (SMO) and PTCH1 genes are believed to lead to abnormal up-regulation and activation of the SHH signaling pathway. Protein patched homolog 1 (patched) is produced by the gene PTCH1 and functions as a transmembrane receptor that when activated suppresses the migration of suppresses the migration of the SMO receptor to the cell membrane. When the SHH ligand binds to patched, the SMO receptor is released into the cell membrane after which activation of cell proliferation occurs. In basal cell carcinoma, mutations in the Hedgehog pathway can result in an unrestricted proliferation of basal cells; it has been noted that this pathway is relevant in more than 90% of basal cell carcinoma cases. One of the mechanisms believed to be involved in tumorigenesis involves ligand-independent pathway activation by SMO.

Vismodegib is a selective Hedgehog pathway inhibitor that binds to and competitively inhibits SMO. Inhibition of SMO results in transcription factors GLI1 and GLI2 to remaining inactive; this prevents the expression of tumor-mediating genes within the hedgehog pathway.[6][7][8]

Mutations in PTCH1 have been associated with nevoid basal cell carcinoma syndrome (AKA Gorlin syndrome), trichoepitheliomas, squamous cell carcinoma of the esophagus, transitional cell carcinoma of the bladder, and holoprosencephaly. Medulloblastoma is nervous system tumor associated with Hedgehog pathway mutations in as much as 30% of cases.

Pharmacokinetics/Pharmacodynamics

Vismodegib has a bioavailability of approximately 32% and has time to peak levels at approximately 2.4 days. Greater than 98% of the drug circulates as the original compound. Once absorbed, it has a volume of distribution (Vd) between 16 and 26.6 liters and is highly protein bound (greater than 99%) to serum albumin and alpha acid glycoprotein (AAG). Vismodegib undergoes metabolism by oxidation, glucuronidation, and ring cleavage. It is a minor substrate for CYP2C9 and CYP3A4. The half-life of elimination after a single dose is approximately 12 days, but with continuous daily dosing, it becomes 4 days before it is eliminated primarily in the feces (82%) and urine (4%).

It should be noted that vismodegib concentrates in semen of men.

Administration

Vismodegib is available as a 150-mg oral use capsule. It is dosed at 150 mg orally once daily until disease progression or unacceptable toxicity. 

However, adverse effects associated with vismodegib may serve as a barrier to lifelong treatment. Recently in an article published in Lancet Oncology, intermittent dosing protocols were examined over a 73-week period comparing 2 groups with different dosing, Group A and Group B.  Group A was given 12 weeks of vismodegib followed by 8 weeks of placebo. This was repeated until the 73-week mark. Group B was given vismodegib initially for 24 weeks followed by 8 weeks of placebo and then alternating 8 weeks vismodegib with 8 weeks placebo until the 73-week mark.

Both groups A and B had a reduction in the mean number of basal cell carcinoma lesions from baseline (62.7% and 54% respectively). However, the number of treatment-emergent events was higher in group B. Treatment activity and adherence was also lower within group B when compared to group A. It is likely that different dosing protocols will be examined going forward to balance adverse effects with treatment effectiveness.

Adverse Effects

Adverse effects of vismodegib have been a limiting factor for the medication. All patients in the ERIVANCE trial experienced at least 1 adverse event. In the ERIVANCE trial, 57% had a mild (grade 1) or moderate (grade 2) adverse event. A total of 13 individuals (12%) had an adverse event that ultimately led to discontinuation of vismodegib.

The most common adverse effects include muscle spasm (72%), fatigue (40%), alopecia (64%), dysgeusia (55%), and weight loss (45%). Other adverse effects associated with vismodegib include nausea, diarrhea, constipation, decreased appetite, ageusia, and arthralgias. Some patients may experience electrolyte disturbances including hypokalemia or hyponatremia. Additionally, there may be elevated creatine phosphokinase levels and azotemia.

Recently, researchers at the University of California San Francisco evaluated vismodegib to see if there was a risk in the development of subsequent squamous cell carcinoma following use. It was determined in a retrospective cohort study that vismodegib was not associated with an increased risk of SCC compared to those with standard surgical treatment for basal cell carcinoma. However, further studies are likely to examine this topic.

Contraindications

Vismodegib is contraindicated in pregnant women or women who may become pregnant.

Boxed Warning of Embryofetal Toxicity 

Embryotoxic effects include:

  • Craniofacial abnormalities
  • Anorectal defects
  • Fused or absent digits

Blood Donations

Patients should be advised to not to donate blood or blood products during vismodegib treatment and for at least 24 months after the last dose.

Important Special Warnings

Counseling of both male and females on vismodegib is necessary.

Women

Following a negative pregnancy test, initiate highly effective contraception before the first dose of vismodegib and continue for 7 months after treatment.

Men

During treatment, and for 3 months following treatment, men should not donate sperm and should use condoms with spermicide (even after vasectomy) as vismodegib may be present in seminal fluid.  This precaution is to avoid exposure to patients that may be pregnant.

Monitoring

Pregnancy test within 1 week prior to treatment initiation.

Enhancing Healthcare Team Outcomes

The prescription of vismodegib is limited to the oncologist and dermatologist. However, the pharmacist also needs to know the basic principles about this agent. Initially approved in 2012, vismodegib is the first FDA-approved, pharmacologic agent that targets the Hedgehog signaling pathway (sonic hedgehog, SHH), a pathway involved in many basal cell carcinomas. Not all patients are suitable candidates for surgery or topical therapy due to locally advanced or metastatic basal cell carcinoma. This is when vismodegib has a place in therapy.

Adverse effects of vismodegib have been a limiting factor for the medication. The most common adverse effects include muscle spasm (72%), fatigue (40%), alopecia (64%), dysgeusia (55%), and weight loss (45%). There is renewed concern that the drug may induce development of squamous cell cancer. Hence, all patients prescribed vismodegib must be closely followed.[9][10]


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Vismodegib - Questions

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Vismodegib is FDA approved to treat patients with locally advanced basal cell carcinoma (BCC) who are not candidates for surgery/radiation and those with metastatic disease. The mechanism of action involves inhibition of the Smoothened protein in the Sonic Hedgehog pathway, thus impeding downstream signaling molecule Gli to enter the nucleus and induce proliferative effects. Which of the following is a commonly reported side effect of vismodegib?



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What is the mechanism of action of vismodegib?



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Which of the following are important considerations with vismodegib therapy?



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Which of the following is not an adverse effect of vismodegib?



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Which of the following is true regarding the pharmacokinetics of vismodegib?



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Vismodegib - References

References

Girardi D,Barrichello A,Fernandes G,Pereira A, Targeting the Hedgehog Pathway in Cancer: Current Evidence and Future Perspectives. Cells. 2019 Feb 12;     [PubMed]
Li J,Cai H,Li H,Liu Y,Wang Y,Shi Y,Sun Y,Song H,Wang D, Combined inhibition of sonic Hedgehog signaling and histone deacetylase is an effective treatment for liver cancer. Oncology reports. 2019 Jan 23;     [PubMed]
Gualdi G,Moro R,Regina V,Caravello S,Monari P,Calzavara-Pinton PG, PRISModegib: the use of the PRISM test to assess the Health-Related Quality of Life of patients with Locally Advanced Basal Cell Carcinoma undergoing Hedgehog Pathway Inhibitor Therapy. The British journal of dermatology. 2019 Feb 9;     [PubMed]
Hanna A,Metge BJ,Bailey SK,Chen D,Chandrashekar DS,Varambally S,Samant RS,Shevde LA, Inhibition of Hedgehog signaling reprograms the dysfunctional immune microenvironment in breast cancer. Oncoimmunology. 2019;     [PubMed]
Kuonen F,Huskey NE,Shankar G,Jaju P,Whitson RJ,Rieger KE,Atwood SX,Sarin KY,Oro AE, Loss of primary cilia drives switching from Hedgehog to Ras/MAPK pathway in resistant basal cell carcinoma. The Journal of investigative dermatology. 2019 Jan 29;     [PubMed]
Carpenter RL,Ray H, Safety and Tolerability of Sonic Hedgehog Pathway Inhibitors in Cancer. Drug safety. 2019 Jan 16;     [PubMed]
Yan BY,Hibler BP,Menge T,Dunn L,Ho AL,Rossi AM, Sonic Hedgehog Pathway Inhibitors: from Clinical Trials to Clinical Practice. The British journal of dermatology. 2019 Jan 28;     [PubMed]
Belgioia L,Desideri I,Errico A,Franzese C,Daidone A,Marino L,Fiore M,Borghetti P,Greto D,Fiorentino A, Safety and efficacy of combined radiotherapy, immunotherapy and targeted agents in elderly patients: A literature review. Critical reviews in oncology/hematology. 2019 Jan;     [PubMed]
Koelblinger P,Lang R, New developments in the treatment of basal cell carcinoma: update on current and emerging treatment options with a focus on vismodegib. OncoTargets and therapy. 2018;     [PubMed]
Woltsche N,Pichler N,Wolf I,Di Meo N,Zalaudek I, Managing adverse effects by dose reduction during routine treatment of locally advanced basal cell carcinoma with the hedgehog inhibitor vismodegib: a single centre experience. Journal of the European Academy of Dermatology and Venereology : JEADV. 2018 Nov 25;     [PubMed]

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