carcinoma originates in the upper layer
of the skin,
known as the epidermis, which experiences frequent exposure to
sunlight and ultraviolet radiation.
Majority of non-melanoma skin cancers, nearly 80%, are basal-cell carcinomas
in which mutations of hedgehog signaling pathway result in uninhibited
multiplication of basal cells. Generally basal-cell carcinomas are treated by
surgery though some progressive cancers
are not responsive to radiotherapy or surgical treatment
Dysregulated hedgehog signaling is implicated in
basal-cell carcinoma pathogenesis. Although most basal-cell carcinomas are
treated surgically, no effective therapy exists for locally advanced or
metastatic basal-cell carcinoma.
A phase 1 study with vismodegib, a
small-molecule drug from Genentech, comprising of 33 advanced basal-cell
carcinoma patients revealed a 58% response rate for an average of nearly 13 months.
The current phase 2 study, in basal-cell
carcinoma patients, was designed to further assess vismodegib efficacy and safety. Metastatic basal-cell
carcinoma (33) and locally advanced inoperable basal-cell carcinoma (71)
patients were enrolled (total 104)
across multiple centers (31) and countries (3). Eligible patients were ≥18
years with acceptable organ function and an ECOG performance status of ≤2.
About 30%, 58% and 97% metastatic basal-cell carcinoma patients had previously
received systemic, surgical and radiation treatment respectively. Nearly 11%,
27%, 21% and 89% locally advanced basal-cell carcinoma patients had previously
received topical, systemic, surgical and radiation treatment respectively.
was no control group in this study
and all patients were administered daily
dose of 150 mg oral vismodegib for 13 months or until disease progression
(20% increment or new lesion) or toxicity was observed. Simultaneous antitumor
therapy was disallowed.
The primary end point was the response
rate, at least 30% decrease in outward
or radiographic evidence of the carcinoma (tumor shrinkage), such that
response rate was expected to be ≥20% for locally advanced basal-cell carcinoma
patients and ≥10% for metastatic basal-cell carcinoma patients. Response time was a key secondary end point.
radiographically, at week 0 and every 8 weeks, or by physical inspection using
the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. Adverse
events were recorded for 45 days after the final drug dose or discontinuation
from the trials. Expression
of GLI family zinc finger 1 (GLI1) and patched homologue 2
target genes, was evaluated by PCR (polymerase-chain-reaction
per the independent reviewer's assessment, 30%
and 43% response rates were observed in 33 metastatic basal-cell carcinoma and
63 locally advanced basal-cell carcinoma patients, respectively. Nearly 21%
locally advanced basal-cell carcinoma patients demonstrated a complete
response. The average response time was
7.6 months in both patient groups. Hedgehog
pathway activation, based on GLI1 and PTCH2 expression, was higher in the assessed patients as compared with normal skin
50% patients withdrew from the study such that average drug treatment was for
10 months. Adverse events appeared
in all patients with grade 1-2 side effects occurring in 57% treated patients.
Over 30% patients were recorded to have muscle spasms, alopecia (hair loss),
dysgeusia (taste disorder), weight loss and fatigue. Nearly 25% patients suffered from serious adverse events including death in 7
conclusion, vismodegib induces a significant 30% response rate (tumor
shrinkage) in locally advanced and metastatic basal-cell carcinoma patients.
Reference: Efficacy and Safety of Vismodegib in
Advanced Basal-Cell Carcinoma; Aleksandar Sekulic et al; N
Engl J Med 2012; 366:2171-2179.