Inhibition of the hedgehog pathway in advanced basal-cell carcinoma.
BACKGROUND
Mutations in hedgehog pathway genes, primarily genes encoding patched homologue 1 (PTCH1) and smoothened homologue (SMO), occur in basal-cell carcinoma. In a phase 1 clinical trial, we assessed the safety and pharmacokinetics of GDC-0449, a small-molecule inhibitor of SMO, and responses of metastatic or locally advanced basal-cell carcinoma to the drug.


METHODS
We selected 33 patients with metastatic or locally advanced basal-cell carcinoma to receive oral GDC-0449 at one of three doses; 17 patients received 150 mg per day, 15 patients received 270 mg per day, and 1 patient received 540 mg per day. We assessed tumor responses with the use of Response Evaluation Criteria in Solid Tumors (RECIST), physical examination, or both. Molecular aspects of the tumors were examined.


RESULTS
The median duration of the study treatment was 9.8 months. Of the 33 patients, 18 had an objective response to GDC-0449, according to assessment on imaging (7 patients), physical examination (10 patients), or both (1 patient). Of the patients who had a response, 2 had a complete response and 16 had a partial response. The other 15 patients had either stable disease (11 patients) or progressive disease (4 patients). Eight grade 3 adverse events that were deemed to be possibly related to the study drug were reported in six patients, including four with fatigue, two with hyponatremia, one with muscle spasm, and one with atrial fibrillation. One grade 4 event, asymptomatic hyponatremia, was judged to be unrelated to GDC-0449. One patient withdrew from the study because of adverse events. We found evidence of hedgehog signaling in tumors that responded to the treatment.


CONCLUSIONS
GDC-0449, an orally active small molecule that targets the hedgehog pathway, appears to have antitumor activity in locally advanced or metastatic basal-cell carcinoma. (ClinicalTrials.gov number, NCT00607724.)
Von Hoff
Daniel D
DD
Translational Genomics Research Institute and Scottsdale Healthcare, Scottsdale, AZ, USA.
LoRusso
Patricia M
PM
Rudin
Charles M
CM
Reddy
Josina C
JC
Yauch
Robert L
RL
Tibes
Raoul
R
Weiss
Glen J
GJ
Borad
Mitesh J
MJ
Hann
Christine L
CL
Brahmer
Julie R
JR
Mackey
Howard M
HM
Lum
Bertram L
BL
Darbonne
Walter C
WC
Marsters
James C
JC
de Sauvage
Frederic J
FJ
Low
Jennifer A
JA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000813:Anilides; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002280:Basal Cell Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D016133:Polymerase Chain Reaction; D011725:Pyridines; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000071676:Zinc Finger Protein GLI1
D000813:Anilides; D000970:Antineoplastic Agents; D001562:Benzimidazoles; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; C538724:HhAntag691; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011725:Pyridines; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1