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DRUG RECORD

 

VISMODEGIB

OVERVIEW
Vismodegib

 

Introduction

Vismodegib is a kinase inhibitor active used in the therapy of unresectable or metastatic basal cell carcinoma.  Vismodegib therapy is associated with a low rate or transient elevations in serum aminotransferase during therapy and has been linked to rare cases of clinically apparent acute liver injury.

 

Background

Vismodegib (vis” moe deg’ ib) is an orally available, kinase inhibitor with specific activity against a key step (activation of smoothened: SMO) in the hedgehog signaling pathway.  Hedgehog is a key regulator of embryonic development, cell growth and differentiation.  Mutations in this pathway have been identified in several malignant diseases including basal cell carcinoma.  Clinical trials of vismodegib in patients with metastatic or locally advanced basal cell carcinoma reported at least partial responses in up to half of patients.  Vismodegib, the first hedgehog pathway inhibitor, was approved for use in the United States in 2012.  Current indications include metastatic or locally advanced, recurrent or unresectable basal cell carcinoma.  Vismodegib is available in capsules of 150 mg under the brand name Erivedge.  The typical dose is 150 mg once daily until disease progression or unacceptable toxicity occurs.  Side effects are common and often dose limiting, although rarely life threatening.  Common side effects include muscle spasms, alopecia, anorexia, dysguesia, weight loss, nausea, diarrhea, fatigue and arthralgias.  Potential serious adverse events include severe weight loss, squamous cell skin cancer and embryo-fetal toxicity.

 

Hepatotoxicity

Most clinical trials of vismodegib included few patients and rates of liver tests abnormalities were usually not reported.  The product label for vismodegib includes no mention serum enzyme elevations or hepatotoxicity.  However, a subsequent review of all published studies of vismodegib mentions that liver enzyme elevations occurred in 1.4% of a total of 363 patients treated.  Since its approval and more general use, reports of clinically apparent liver injury linked to vismodegib have appeared.  In one report, an elderly man presented with fatigue, nausea and jaundice 41 days after starting vismodegib with a cholestatic pattern of serum enzyme elevations and rapid improvement on stopping (Case 1).  In addition, review of 7 years of spontaneous adverse event reporting to the FDA revealed 94 reports of hepatotoxicity during vismodegib therapy, including 20 that were considered serious and 4 that resulted in hepatic failure.  Thus, clinically apparent liver injury from vismodegib occurs, but is somewhat rare. 

 

Likelihood score: C (probable cause of clinically apparent liver injury). 

 

Mechanism of Injury

The cause of liver injury from vismodegib is unknown, but likely due to hypersensitivity. Vismodegib has a prolonged half-life (~19 days) and is metabolized at least in part in the liver via multiple cytochrome P450 enzymes, including CYP 3A4, 2C8, 2C9 and 2C19. While it theoretically should have several drug-drug interactions, there is little clinical data on its effects on other drugs or vice versa.

 

Outcome and Management

In using kinase inhibitors for treatment of cancer, monitoring of routine liver tests before starting and at intervals during therapy is warranted.  Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) or any elevations accompanied by jaundice or symptoms should lead to temporary cessation.  Restarting vismodegib after cessation for liver test abnormalities should be done with caution and only after the abnormalities have resolved or improved significantly.   The various protein kinase inhibitors vary greatly in chemical structure and there is little evidence for cross sensitivity to the liver injury.

 

Drug Class:  Antineoplastic Agents, Protein Kinase Inhibitors

 

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CASE REPORT
Vismodegib

 

Case 1.  Cholestatic hepatitis attributed to vismodegib therapy.
[Modified from: Ash MM, Jolly PS. Cholestatic hepatic injury associated with vismodegib, aspirin, and naproxen use: a case study and review of vismodegib safety. Int J Dermatol 2014 Jul 11. [Epub ahead of print] PubMed Citation]

 

A 72 year old man with multiple basal cell carcinomas developed worsening nausea, dysgeusia, anorexia, weight loss and muscle cramps followed by appearance of jaundice 5 to 6 weeks after starting vismodegib.  He also had a sudden loss of voice, decreased fluid intake and melena without sore throat, fever or rash.  He had no history of liver disease or alcohol abuse, and all liver tests had been normal before vismodegib therapy was begun (Table).  Medications that he took chronically included tadalafil, amlodipine, and valsartan, and he had recently started naproxen and aspirin because of muscle cramps attributed to vismodegib.  On presentation, he was jaundiced and had mild hepatic tenderness.  Serum bilirubin was 10.7 mg/dL, ALT 525 U/L, AST 206 U/L, alkaline phosphatase 807 U/L, GGT 550 U/L and INR 1.1.  He had a mild increase in serum creatinine (2.2 mg/dL), possibly due to dehydration.  Vismodegib was stopped and he was admitted for evaluation and intravenous hydration.  Imaging of the liver showed no evidence of gall stones or biliary obstruction.  Symptoms and liver test abnormalities began to improve rapidly and two weeks later, jaundice had resolved and liver tests were minimally elevated.  Six months later, routine liver tests were all within the normal range.


Key Points

Medication:Vismodegib (300 mg daily)
Pattern: Cholestatic (R=1.2)
Severity:3+ (jaundice and hospitalization)
Latency:5-6 weeks
Recovery:~4 weeks
Other medications:Aspirin and naproxen acutely; tadalifil, amlodipine and varsartan chronically.

Laboratory Values

Time After Starting Time After Stopping

ALT 

(U/L)
Alk P (U/L) Bilirubin (mg/dL) Other
0 Pre 24 NA NA Started vismodegib
32 days Pre 57 NA NA Muscle cramps
41 days 0 525 807 10.7 Admission
6 weeks 2 days 253 510 5.9 Discharge
8 weeks 2 weeks 63 295 1.8
8 months 6 months 35 NA NA Asymptomatic
Normal Values <72 <126 <1.2

Comment

An elderly man with multiple basal cell carcinomas developed dysgeusia and muscle cramps within a month of starting vismodegib and was found to have mild serum ALT and AST elevations.  In the following two weeks, however, he developed worsening symptoms and jaundice and was found to have a cholestatic hepatitis.  He had also developed worsening side effects of treatment, dehydration, laryngitis and mild gastrointestinal bleeding.  Upon hospital admission and stopping vismodegib he improved rapidly, most liver tests being normal or near normal two weeks later.  Information on hepatitis serology, autoantibodies and eosinophil counts was not provided, but immunoallergic features were not present, and the clinical course and outcome were entirely compatible with a drug induced cholestatic hepatitis.  While most cases of acute liver injury attributed to kinase inhibitors have been described as hepatocellular, the actual aminotransferase and alkaline phosphatase values are often not provided.  Even this case might have been considered hepatocellular (ALT 525 U/L) had the other values not been available.

 

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REPRESENTATIVE TRADE NAMES
Vismodegib – Erivedge®

 

DRUG CLASS
Antineoplastic Agents

 

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

 

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DRUG CAS REGISTRY NO. MOLECULAR FORMULA STRUCTURE
Vismodegib 879085-55-9 C19-H14-Cl2-N2-O3-S Vismodegib chemical structure

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REFERENCES
Vismodegib

 

References updated: 25 June 2018

  1. Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.  (Review of hepatotoxicity published in 1999 before the availability of tyrosine kinase receptor inhibitors such as vismodegib).

  2. DeLeve LD. Erlotinib. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 556.  (Review of hepatotoxicity of cancer chemotherapeutic agents discusses several tyrosine kinase inhibitors including imatinib, gefitinib, erlotinib and crizotinib, but not vismodegib).

  3. Chabner BA, Barnes J, Neal J, Olson E, Mujagic H, Sequist L, Wilson W, et al. Targeted therapies: tyrosine kinase inhibitors, monoclonal antibodies, and cytokines. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1731-54.  (Textbook of pharmacology and therapeutics).

  4. Von Hoff DD, LoRusso PM, Rudin CM, Reddy JC, Yauch RL, Tibes R, Weiss GJ, et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med 2009; 361: 1164-72. PubMed Citation  (Among 33 patients with metastatic or locally advanced basal cell carcinoma treated with vismodegib in varying doses, 18 [55%] had an objective response and adverse events included fatigue, hyponatremia, weight loss, dyspnea and prolonged QTc interval; no mention of ALT elevations, but one patient had an Alk P elevation ≥3 times ULN).

  5. LoRusso PM, Rudin CM, Reddy JC, Tibes R, Weiss GJ, Borad MJ, Hann CL, 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: 2502-11. PubMed Citation  (Among 68 patients with locally advanced or metastatic solid tumors treated with vismodegib, tumor responses occurred in 20 patients [29%], all but one with basal cell carcinoma; difficult side effects included hyponatremia, abdominal pain and fatigue; no mention of liver injury).

  6. Sekulic A, Migden MR, Oro AE, Dirix L, Lewis KD, Hainsworth JD, Solomon JA, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med 2012; 366: 2171-9. PubMed Citation  (Among 96 patients with advanced or metastatic basal cell cancer treated with vismodegib, the response rate was 40% and side effects were common including muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea and diarrhea, and were severe in 26% of patients).

  7. Tang JY, Mackay-Wiggan JM, Aszterbaum M, Yauch RL, Lindgren J, Chang K, Coppola C, et al. Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med 2012; 366: 2180-8. PubMed Citation  (Among 41 patients with basal cell nevus syndrome, vismodegib therapy was associated with a lower rate of new tumors and decrease in size of existing tumors compared to placebo, but was associated with a high rate of side effects and 54% stopped therapy because of side effects; no mention of ALT elevations or hepatotoxicity).

  8. Vismodegib (Erivedge) for basal cell carcinoma. Med Lett Drugs Ther 2012; 54 (1394): 53-4. PubMed Citation  (Concise summary of mechanism of action, efficacy, safety and cost of vismodegib for basal cell carcinoma shortly after its approval in the US mentions that side effects are common, but not life-threatening).

  9. Spraggs CF, Xu CF, Hunt CM. Genetic characterization to improve interpretation and clinical management of hepatotoxicity caused by tyrosine kinase inhibitors. Pharmacogenomics 2013; 14: 541-54. PubMed Citation  (Review of genetic associations of serum ALT and bilirubin elevations during therapy with tyrosine kinase inhibitors, focusing on lapatinib and pazopanib).

  10. Shah RR, Morganroth J, Shah DR. Hepatotoxicity of tyrosine kinase inhibitors: clinical and regulatory perspectives. Drug Saf 2013; 36: 491-503. PubMed Citation  (Review of the hepatotoxicity of 18 tyrosine kinase inhibitors approved for use in cancer in the US as of 2013; vismodegib is not discussed).

  11. Chang AL, Solomon JA, Hainsworth JD, Goldberg L, McKenna E, Day BM, Chen DM, Weiss GJ. Expanded access study of patients with advanced basal cell carcinoma treated with the Hedgehog pathway inhibitor, vismodegib. J Am Acad Dermatol 2014; 70: 60-9. PubMed Citation  (Among 119 patients with advanced basal cell carcinoma treated with vismodegib for an average of 5.5 months in an open label expanded access study, objective responses occurred in 30-46% of patients and adverse events were common, but usually mild-to-moderate in severity and no treatment related deaths occurred; no mention of ALT elevations or hepatotoxicity). 

  12. Lyons TG, O'Kane GM, Kelly CM. Efficacy and safety of vismodegib: a new therapeutic agent in the treatment of basal cell carcinoma. Expert Opin Drug Saf 2014; 13: 1125-32. PubMed Citation  (Review of the mechanism of action, pharmacology, efficacy and safety of vismodegib; no mention of ALT elevations or hepatotoxicity). 

  13. Ventarola DJ, Silverstein DI. Vismodegib-associated hepatotoxicity: a potential side effect detected in postmarketing surveillance. J Am Acad Dermatol 2014 Aug; 71(2): 397-8. PubMed Citation(Review of spontaneous adverse event reports for reactions to vismodegib to the FDA for the first year of its general availability in the United States, revealed 65 cases, 23% of which were liver toxicity most of which were serum enzyme elevations only but some of which mentioned "hepatitis").

  14. Ash MM, Jolly PS. Cholestatic hepatic injury associated with vismodegib, aspirin, and naproxen use: a case study and review of vismodegib safety. Int J Dermatol 2015; 54: 370-4.  PubMed Citation  (72 year old man with basal cell carcinomas developed jaundice one month after starting vismodegib [bilirubin 10.7 mg/dL, ALT 525 U/L, Alk P 807 U/L], with resolution of jaundice within 2 weeks of stopping and enzyme shortly after; review of literature of clinical trials of vismodegib identified serum enzyme elevations in 1.4% of patients treated). 

  15. Vismodegib (ERIVEDGE°) In basal cell carcinoma: too many unknowns. Prescrire Int 2015; 24: 11-4. PubMed Citation.  (Reivew of the mechanism of action, clinical efficacy and safety of vismodegib for basal cell carcinoma concludes that caution should be used in its use because of its many side effects and lack of controlled data on its efficacy).   

  16. Sofen H, Gross KG, Goldberg LH, Sharata H, Hamilton TK, Egbert B, Lyons B, et al. A phase II, multicenter, open-label, 3-cohort trial evaluating the efficacy and safety of vismodegib in operable basal cell carcinoma. J Am Acad Dermatol 2015 73: 99-105. PubMed Citation.   (Among 74 patients with inoperable basal cell carcinoma treated with 1 of 3 regimens of vismodegib, complete histologic clearance was achieved in 25 [34%], and common side effects were muscle spasms [76%], alopecia [58%], and dysgeusia [50%]; among 8 serious adverse events, 1 was due to "hepatitis", which was considered vismodegib-related and which resolved within 2 months of stopping).  

  17. Sekulic A, Migden MR, Lewis K, Hainsworth JD, Solomon JA, Yoo S, Arron ST, et al; ERIVANCE BCC investigators. Pivotal ERIVANCE basal cell carcinoma (BCC) study: 12-month update of efficacy and safety of vismodegib in advanced BCC. J Am Acad Dermatol 2015; 72: 1021-6. PubMed Citation. (Among 96 patients with basal cell carcinoma treated with vismodegib for a median of 12 months [Sekulic 2012] , further follow up showed that complete resposnes were maintained and no new adverse events were identified; no mention of ALT elevations or hepatotoxicity).

  18. Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. PubMed Citation  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 49 were attributed to antineoplastic agents [5.5%], 9 of which were attributed to kinase inhibitors [imatinib = 5, lapatinib = 2, regorafenib = 1], but none to vismodegib).

  19. Chang AL, Arron ST, Migden MR, Solomon JA, Yoo S, Day BM, McKenna EF, et al. Safety and efficacy of vismodegib in patients with basal cell carcinoma nevus syndrome: pooled analysis of two trials. Orphanet J Rare Dis 2016; 11: 120. PubMed Citation. (Retrospective and pooled analysis of 41 patients with basal cell carcinoma nevus syndrome who were enrolled in 2 trials of vismodegib found adverse events arose in 95% to 100% of patients; no mention of ALT elevations or hepatotoxicity).   

  20. Edwards BJ, Raisch DW, Saraykar SS, Sun M, Hammel JA, Tran HT, Wehr N, et al. Hepatotoxicity with vismodegib: an MD Anderson Cancer Center and Research on Adverse Drug Events and Reports Project. Drugs R D 2017; 17: 211-218. PubMed Citation.    (Review of heaptic adverse event reports received by the FDA between 2009 and 2016 found 94 reports of hepatotoxicity, 35 of which were "severe", 20 "serious" and 4 resulting in hepatic failure).

  21. Dréno B, Kunstfeld R, Hauschild A, Fosko S, Zloty D, Labeille B, Grob JJ, et al. Two intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas (MIKIE): a randomised, regimen-controlled, double-blind, phase 2 trial. Lancet Oncol 2017; 18: 404-412. PubMed Citation. (Among 229 patients with inoperable basal cell carcinoma treated with 1 of 2 regimens of vismodegib, lesion number was reduced by 54% to 63% and 95% of patients had at least one adverse event, most commonly muscle spasms, dysgeusia and alopecia; 22 patients had a serious adverse event, one due to serum ALT elevations).

  22. Sekulic A, Migden MR, Basset-Seguin N, Garbe C, Gesierich A, Lao CD, Miller C, et al; ERIVANCE BCC Investigators. Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: final update of the pivotal ERIVANCE BCC study. BMC Cancer 2017; 17: 332. PubMed Citation(Among 104 patients with advanced or metastatic basal cell carcinoma treated in an open label trial of vismodegib with follow up averaging 39 months after last enrollment, 69 [66%] patients were still alive but only 8 were still receiving vismodegib; among 36 serious adverse events, only 9 were considered related to vismodegib, none of which were liver-related).

  23. Bunchorntavakul C, Reddy KR. Drug hepatotoxicity: newer qgents. Clin Liver Dis 2017; 21: 115-34. PubMed Citation  (Review of the hepatotoxicity of recently approved medications including 17 tyrosine kinase inhibitors such as imatinib, lapatinib, erlotinib, nilotinib, crizotinib and regorafenib but not vismodegib).

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OTHER REFERENCE LINKS
Vismodegib
  1. PubMed logoRecent References on Vismodegib

  2. Clinical Trials logoTrials on Vismodegib

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