Vismodegib (Erivedge)

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Vismodegib (Erivedge) is a molecular inhibitor of the Hedgehog signaling pathway. It was developed by Genentech and approved by the FDA in January 2012 for the treatment of metastatic and locally advanced basal cell carcinoma (BCC).


Historical Background:

The hedgehog signaling cascade, which includes key receptor proteins such as Smoothened (SMO), have been implicated in cancers of the brain, lung, mammary gland, prostate and skin.1–5⁠ The discovery of cyclopamine, an endogenous steroidal plant alkaloid that binds to SMO and inhibits downstream gene expression, initiated the quest for the identification of other agents that could inhibit the Hedgehog pathway.6⁠ Vismodegib was one of the first such molecules to be developed and was originally used for the treatment of medulloblastoma.4⁠ It acts by binding to SMO and preventing the activation of downstream target genes.7⁠ When it was demonstrated in genetically engineered mice that the overactivation of the Hedgehog pathway was implicated in the development of other forms of cancer such as basal-cell carcinoma, investigators applied the Hedgehog inhibitors to halt these disease processes.8⁠

Proposed Mechanism of Action:

Vismodegib inhibits the Hedgehog signaling pathway. The Hedgehog pathway plays a crucial role during embryogenic development but has limited activity in most adult tissues, with the exception of hair, skin and stem cells.7, 9⁠ In more than 90% of BCC, the Hedgehog signaling pathway is abnormally upregulated.5, 10⁠ Mutations in key receptor proteins such as Patched (PTCH) and Smoothened (SMO) result in abnormal transcription of target genes that regulate basal cell growth and proliferation. Vismodegib acts as an SMO antagonist to prevent GLI1 and GLI2 transcription factor activation, blocking the signaling cascade. 2⁠

Indications/Dosing:

Vismodegib is FDA approved for the treatment of metastatic and locally advanced BCC that cannot be treated with surgery or radiation.

The dose for Vismodegib is 150mg orally once a day until disease progression or unacceptable toxicity is experienced.

Studies:

A Phase I clinical trial by Von Hoff et al. (2009)1⁠ studied the effect of vismodegib in three doses in 33 patients with metastatic or locally advanced basal-cell carcinoma: 150mg per day (17 patients), 270mg per day (15 patients) and 540mg per day (1 patient). Of the 33 patients, 18 had an objective response (2 complete, 16 partial), 11 had stable disease, and 4 had progressive disease. The median duration of response was 8.8 months. Molecular analysis of biopsy samples in 26 patients demonstrated over-expression of GLI1 mRNA expression in 25 patients. In a pharmacokinetic analysis, the median time to steady state was 14 days (range 7 to 22 days), and increasing the dose did not result in higher steady-state plasma levels. In 10 of 13 patients, there was a decrease in GLI1 expression by more than a factor of two in biopsy samples of treated patients compared with pretreatment biopsy-sample analysis. These findings confirmed the importance of the hedgehog pathway in basal-cell carcinoma and suggested the inhibitors of this pathway can be useful in treatment of these inoperable tumors.

A Phase II multicenter, international, two-cohort, nonrandomized study by Sekulic et al. (2012) studied the effect of vismodegib on patients with metastatic and locally advanced BCC.7⁠ Participants were deemed inappropriate surgical candidates based on multiple recurrences or substantial anticipated morbidity. All patients received once daily 150mg of oral vismodegib. In 33 patients with metastatic BCC, the response rate was 30% (95% confidence interval (CI), 16 to 48; P=0.001). In 63 patients with locally advanced BCC, the response rate was 43% (95% CI, 35 to 56; P<0.001) with complete responses in 13 patients (21%). The median duration for response was 7.6 months (range 1.0-12.9 months; 95% CI, 5.7-9.7).

A randomized, double-blind placebo-controlled trial by Tang et al. (2012) studied the effect of vismodegib on patients with the basal-cell nevus syndrome.11⁠ In 41 patients over a mean follow-up of 8 months, there was reduced per-patient rate of new surgically eligible BCC in the group treated with vismodegib than with placebo (2 vs. 29 cases per group per year, P<0.001). The size of existing BCC also showed significant reduction in the vismodegib group (-65% vs. -11%, P=0.003). The study also demonstrated a reduction of the hedgehog target gene expression by BCC by 90% (P<0.001) and diminished tumor-cell proliferation by analysis of the levels of messenger RNA encoding the hedgehog target gene glioma-associated oncogene homolog 1 (GLI1) in skin-shave biopsy samples of BCC taken at baseline and at 1 month after the start of vismodegib treatment.

Adverse Events:

In the Phase I clinical trial1⁠, there were 35 adverse events reported in total, of which 23 were grade 3 adverse events over a median follow-up time of 9.8 months. These included fatigue, hyponatremia, muscle spasm and atrial fibrillation. No dose-limiting toxic effects or grade 5 events were observed during the study period.

In the Phase II clinical trial7⁠⁠, adverse events occurred in more than 30% of patients with metastatic and locally advanced BCC, including muscle spasms, alopecia, dysgeusia (taste disturbance), weight loss and fatigue.

In Tang et al’s study11⁠, 54% of patients with basal-cell nevus syndrome (14 of 26) discontinued drug treatment due to adverse events. Patients receiving vismodegib were significantly more likely to experience adverse events compared to placebo, including hair loss, weight loss >5%, muscle cramps, and taste disturbance. Most adverse events were mild or moderate in severity, and no grade 5 events were observed.

Contraindications:

Because of the importance of the Hedgehog pathway in embryogenesis and organ development, vismodegib is contraindicated in pregnancy. Vismodegib has been demonstrated to be teratogenic in rat studies and can result in craniofacial abnormalities, open perineum, retardation in normal growth, and absence or fusion of digits.8⁠ ⁠Patients of reproductive age should be counseled regarding the use of effective contraception while using this drug.

Other Hedgehog Inhibitors:

There have been other Hedgehog pathway inhibitors that have been developed for treatment of BCC besides Vismodegib. There are five other agents (BMS-833923 LDE224, LEQ506, IPI926 and TAK-441) that have shown promise in animal studies and early clinical trials.9⁠ For example, LDE225 is another selective antagonist of SMO protein. In a double-blind, randomized, vehicle-controlled study, twice daily topical treatment with 0.75% LDE25 cream in patients with the basal cell nevus syndrome resulted in partial responses in 9, complete responses in 3, and no clinical response in 1 out of 13 BCCs treated.12⁠


Conclusions:

The use of Vismodegib is an example of selected, targeted molecular biology to treat aggressive basal cell carcinoma. The addition of this drug to the therapeutic armamentarium for recurrent, invasive or metastatic basal cell carcinoma is exciting. Anticipated are even more effective, selective drugs.

References:

1. Taipale J, Beachy PA. The Hedgehog and Wnt signaling pathways in cancer. Nature. 2001; 411(May):349–354.

2. Tao Y, Mao J, Zhang Q, Li L. Overexpression of Hedgehog signaling molecules and its involvement in triple-negative breast cancer. Oncology letters. 2011; 2(5):995–1001.

3. Park K-S, Martelotto LG, Peifer M, et al. A crucial requirement for Hedgehog signaling in small cell lung cancer. Nature Medicine. 2011; 17(11):1504–8.

4. Rudin CM, Hann CL, Laterra J, et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. The New England Journal of Medicine. 2009;361(12):1173–8.

5. Von Hoff DD, Lo Russo PM, Rudin CM, et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. The New England Journal of Medicine. 2009; 361(12):1164–72.

6. Chen JK, Taipale J, Cooper MK, Beachy PA. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. 2002 ;( 410):2743–2748.

7. Sekulic A, Migden M, Oro A, Dirix L. Efficacy and Safety of Vismodegib in Advanced Basal-Cell Carcinoma. The New England Journal of Medicine. 2012; 366(23):2171–2179.

8. Scales S, de Sauvage F. Mechanisms of Hedgehog pathway activation in cancer and implications for therapy. Trends in Pharmacological Sciences. 2009; 30(6):303–12.

9. Tang JY, Marghoob A. Emerging treatments and signaling pathway inhibitors. Seminars in Cutaneous Medicine and Surgery. 2011; 30(4 Suppl):S14–8.

10. Hutchin ME, Kariapper MST, Grachtchouk M, et al. Sustained Hedgehog signaling is required for basal cell carcinoma proliferation and survival: conditional skin tumorigenesis recapitulates the hair growth cycle. Genes & Development. 2005; 19(2):214–23.

11. Tang J, Mackay-Wiggan J, Aszterbaum M, et al. Inhibiting the Hedgehog Pathway in Patients with the Basal-Cell Nevus Syndrome. The New England Journal of Medicine. 2012; 266(23):2180–2188.

12. Skvara H, Kalthoff F, Meingassner JG, et al. Topical treatment of basal cell carcinomas in nevoid basal cell carcinoma syndrome with a smoothened inhibitor. The Journal of Investigative Dermatology. 2011; 131(8):1735–44.