FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 361:1164-1172 September 17, 2009 Number 12 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Supplementary Material Purchase this article Editorial by Dlugosz, A. A. Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

ABSTRACT

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 [ClinicalTrials.gov] .)

Source Information

From the Translational Genomics Research Institute and Scottsdale Healthcare, Scottsdale, AZ (D.D.V.H., R.T., G.J.W., M.J.B.); Karmanos Cancer Institute, Detroit (P.M.L.); Johns Hopkins University, Baltimore (C.M.R., C.L.H., J.R.B.); and Genentech, South San Francisco, CA (J.C.R., R.L.Y., H.M.M., B.L.L., W.C.D., J.C.M., F.J.S., J.A.L.).

This article (10.1056/NEJMoa0905360) was published on September 2, 2009, at NEJM.org.

Address reprint requests to Dr. Low at Genentech, 1 DNA Way, South San Francisco, CA 94080, or at low.jennifer{at}gene.com.

Full Text of this Article

This article has been cited by other articles:

• Hidalgo, M., Maitra, A. (2009). The Hedgehog Pathway and Pancreatic Cancer. NEJM 361: 2094-2096 [Full Text]  
• Dlugosz, A. A., Talpaz, M. (2009). Following the Hedgehog to New Cancer Therapies. NEJM 361: 1202-1205 [Full Text]  
• Rudin, C. M., Hann, C. L., Laterra, J., Yauch, R. L., Callahan, C. A., Fu, L., Holcomb, T., Stinson, J., Gould, S. E., Coleman, B., LoRusso, P. M., Von Hoff, D. D., de Sauvage, F. J., Low, J. A. (2009). Treatment of Medulloblastoma with Hedgehog Pathway Inhibitor GDC-0449. NEJM 361: 1173-1178 [Abstract] [Full Text]