Efficacy and safety of vismodegib in advanced basal-cell carcinoma.
BACKGROUND
Alterations in hedgehog signaling are implicated in the pathogenesis of basal-cell carcinoma. Although most basal-cell carcinomas are treated surgically, no effective therapy exists for locally advanced or metastatic basal-cell carcinoma. A phase 1 study of vismodegib (GDC-0449), a first-in-class, small-molecule inhibitor of the hedgehog pathway, showed a 58% response rate among patients with advanced basal-cell carcinoma.


METHODS
In this multicenter, international, two-cohort, nonrandomized study, we enrolled patients with metastatic basal-cell carcinoma and those with locally advanced basal-cell carcinoma who had inoperable disease or for whom surgery was inappropriate (because of multiple recurrences and a low likelihood of surgical cure, or substantial anticipated disfigurement). All patients received 150 mg of oral vismodegib daily. The primary end point was the independently assessed objective response rate; the primary hypotheses were that the response rate would be greater than 20% for patients with locally advanced basal-cell carcinoma and greater than 10% for those with metastatic basal-cell carcinoma.


RESULTS
In 33 patients with metastatic basal-cell carcinoma, the independently assessed response rate was 30% (95% confidence interval [CI], 16 to 48; P=0.001). In 63 patients with locally advanced basal-cell carcinoma, the independently assessed response rate was 43% (95% CI, 31 to 56; P<0.001), with complete responses in 13 patients (21%). The median duration of response was 7.6 months in both cohorts. Adverse events occurring in more than 30% of patients were muscle spasms, alopecia, dysgeusia (taste disturbance), weight loss, and fatigue. Serious adverse events were reported in 25% of patients; seven deaths due to adverse events were noted.


CONCLUSIONS
Vismodegib is associated with tumor responses in patients with locally advanced or metastatic basal-cell carcinoma. (Funded by Genentech; Erivance BCC ClinicalTrials.gov number, NCT00833417.).
Mayo Clinic, Scottsdale, AZ 85259, USA. sekulic.aleksandar@mayo.edu
Aleksandar
A
Sekulic
Michael R
MR
Migden
Anthony E
AE
Oro
Luc
L
Dirix
Karl D
KD
Lewis
John D
JD
Hainsworth
James A
JA
Solomon
Simon
S
Yoo
Sarah T
ST
Arron
Philip A
PA
Friedlander
Ellen
E
Marmur
Charles M
CM
Rudin
Anne Lynn S
AL
Chang
Jennifer A
JA
Low
Howard M
HM
Mackey
Robert L
RL
Yauch
Richard A
RA
Graham
Josina C
JC
Reddy
Axel
A
Hauschild
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000813:Anilides / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002280:Basal Cell Carcinoma / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D005260:Female; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome
D000813:Anilides; D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; C538724:HhAntag691; D011725:Pyridines