In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
Indication
In January 2012, vismodegib (Erivedge) was approved for treatment of adult patients with metastatic basal cell carcinoma who are not candidates for radiation therapy and adult patients with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery or radiation.1
Approval was based on findings in a single-arm trial in which 96 patients with confirmed locally advanced basal cell carcinoma (n = 63) or metastatic basal cell carcinoma (n = 33) received oral vismodegib at 150 mg once daily.2 Patients had a median age of 62 years, 61% were male, and 97% had an ECOG performance status of 0 or 1.
Among metastatic basal cell carcinoma patients, 97% had received prior treatment, including surgery (97%), radiation (58%), and systemic therapies (30%). Among those with locally advanced basal cell carcinoma, 94% had received prior treatment, including surgery (89%), radiation (27%), and systemic or topical treatments (11%).
Objective response rates assessed by an independent review facility were 30.3% in patients with metastatic basal cell carcinoma and 42.9% in those with locally advanced basal cell carcinoma. All responses in patients with metastatic basal cell carcinoma were partial responses. Among patients with locally advanced disease, complete response occurred in 20.6% and partial response occurred in 22.2%. Median duration of response was 7.6 months in both groups.
How It Works
Vismodegib is an inhibitor of the hedgehog signaling pathway, a key regulator of developmental cell growth and differentiation that controls epithelial and mesenchymal interactions in many tissues during embryogenesis.3 The hedgehog pathway is inactive in adult tissues. However, most basal cell tumors have mutations in the pathway that can result in constitutive signaling and unrestrained proliferation of basal cells of the skin.
How It Is Given
Vismodegib is dosed at 150 mg once daily until disease progression or unacceptable toxicity. It can be taken with or without food.
Safety Profile
Safety data from 138 patients receiving vismodegib monotherapy for basal cell carcinoma in clinical trials indicate that the most common adverse events are muscle spasms (72%), alopecia (64%), dysgeusia (55%), weight loss (45%), fatigue (40%), nausea (30%), diarrhea (29%), decreased appetite (25%), constipation (21%), arthralgias (16%), vomiting (14%), and ageusia (11%).2 A total of 3 of 10 premenopausal women developed amenorrhea. Grade 3 adverse events occurring in more than 1% of patients were weight loss (7%), fatigue (5%, plus grade 4 in 1 patient), muscle spasms (4%), and decreased appetite (2%).
Vismodegib carries a boxed warning for embryo/fetal death and severe birth defects. Practitioners should verify pregnancy status prior to initiation of vismodegib, counsel pregnant women on the potential risks to the embryo/fetus, and advise nonpregnant women to use highly effective contraception during treatment and for up to 7 months after the last dose. To avoid exposing an embryo or fetus to vismodegib that may be contained in semen, male patients should use condoms with spermicide during treatment with the drug and for 2 months after the last dose.
Practitioners are encouraged to report to Genentech any cases of vismodegib exposure during pregnancy (direct exposure in female patients or via seminal fluid from male patients) and to advise pregnant women to participate in the Erivedge pregnancy pharmacovigilance program to collect information on pregnancy outcomes. ■
References
1. U.S. Food and Drug Administration: Vismodegib. Available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm289571.htm. Accessed September 28, 2012.
2. ERIVEDGETM (vismodegib) capsules prescribing information. Genentech, Inc, January 2012. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203388lbl.pdf. Accessed September 28, 2012.
3. Von Hoff DD, LoRusso PM, Rudin CM, et al: Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med 361:1164-1172, 2009.
