Keith Flaherty, MD & George Martin, MD
Vismodegib (ErivedgeTM) for the Treatment of Advanced Basal Cell Carcinoma (BCC)
Dr Keith Flaherty, an oncologist at MGH, spoke on ErivedgeTM for the treatment of advanced and metastatic BCC. Historically, the treatment of patients with advanced BCC with either metastatic or locally advanced disease employed standard chemotherapeutic regimens using agents such as cis-platinum. Reports of success were few and generally limited to individual case reports until the recent FDA approval of Erivedge® a hedgehog pathway inhibitor.
The “hedgehog pathway” (Hh pathway: Figures 1 & 2) and its role in the development of basal cell carcinomas (BCC) has been the subject of intense research over the last decade. Aberrant activation of the Hh pathway (Figures 3 & 4) has been identified in both hereditary BCC syndrome ie Gorlin syndrome (Basal Cell Nevus Syndrome) as well as sporadic BCCs. Gorlin syndrome patients carry a germ-line heterozygous mutation in the PTCH gene and are highly predisposed to developing multiple BCCs. Mutations in the PTCH gene (Figure 3), remove its ability to inhibit the Hh pathway through its inhibition of SMO (Smoothened protein). Approximately 90% of sporadic BCCs have a PTCH gene mutation and an additional 10% of sporadic BCC have activating mutations in the SMO gene (Figure 4), which is downstream of PTCH, and this mutation leads to overstimulation of the Hh pathway.
Vismodegib (Erivedge®) is a hedgehog pathway inhibitor (figure 5), which binds to and inactivates SMO. Its use is indicated for the treatment of adults with metastatic basal cell carcinoma (mBCC), or with locally advanced basal cell carcinoma (laBCC) that has recurred following surgery or who are not candidates for surgery or radiation.
Dr Flaherty presented data evaluating the safety and efficacy of Erivedge in mBCC and laBCC obtained from an international, single-arm, multi-center, open-label, 2-cohort phase II study involving 104 patients (Erivance BCC/SHH447g). Patients with laBCC either had histologically-confirmed BCC that was unresectable or were not appropriate candidates for surgery: >1 cm or 2 or more recurrences after surgery; curative resection unlikely; anticipated substantial morbidity and/or deformity after surgery. mBCC patients had histologic confirmation of mBCC and radiographically measurable tumors. The patient demographics are listed in figure 6. Patients received vismodegib 150 mg/day orally until tumor progression or intolerable drug toxicity.
The objective response rates (ORR) were assessed by an independent review facility (IRF) and were 42.9% for laBCC and 30.3% for mBCC. The median duration of response was 7.6 months and the median progression-free survival was 9.5 months for both cohorts.
The rate of severe toxicities (grade III + IV) for vismodegib is quite low. Mild to moderate toxicity (grades I + II toxicity) seen with vismodegib included fatigue, muscle spasms and dysgeusia (altered taste).
In summary, vismodegib is dramatically effective for BCC treatment in patients with advanced. Approximately 80% of patients with advanced BCC have regression of disease with 30 – 60% of patients having objective responses. Now FDA approved for patients with advanced BCC, it will be interesting to see how this drug will be used both therapeutically and in an adjuvant setting in combination with other surgical and non-surgical modalities.