Inhibition of the Hedgehog Pathway in Advanced Basal-Cell Carcinoma

N Engl J Med. 2009 Sep 17;361(12):1164-72. doi: 10.1056/NEJMoa0905360. Epub 2009 Sep 2.

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.)

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Anilides
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics
  • Benzimidazoles / administration & dosage*
  • Benzimidazoles / adverse effects
  • Benzimidazoles / pharmacokinetics
  • Carcinoma, Basal Cell / drug therapy*
  • Carcinoma, Basal Cell / genetics
  • Carcinoma, Basal Cell / secondary
  • Dose-Response Relationship, Drug
  • Female
  • Gene Expression
  • Hedgehog Proteins / antagonists & inhibitors*
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Patched Receptors
  • Patched-1 Receptor
  • Polymerase Chain Reaction
  • Pyridines
  • RNA, Messenger / metabolism
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Sequence Analysis, DNA
  • Signal Transduction / drug effects
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / genetics
  • Skin Neoplasms / pathology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Zinc Finger Protein GLI1

Substances

  • Anilides
  • Antineoplastic Agents
  • Benzimidazoles
  • GLI1 protein, human
  • Hedgehog Proteins
  • HhAntag691
  • PTCH protein, human
  • Patched Receptors
  • Patched-1 Receptor
  • Pyridines
  • RNA, Messenger
  • Receptors, Cell Surface
  • Transcription Factors
  • Zinc Finger Protein GLI1

Associated data

  • ClinicalTrials.gov/NCT00607724