Inhibition of the hedgehog pathway in advanced basal-cell carcinoma

Daniel D. Von Hoff, Patricia M. LoRusso, Charles M. Rudin, Josina C. Reddy, Robert L. Yauch, Raoul Tibes, Glen J. Weiss, Mitesh J Borad, Christine L. Hann, Julie R. Brahmer, Howard M. Mackey, Bertram L. Lum, Walter C. Darbonne, James C. Marsters, Frederic J. De Sauvage, Jennifer A. Low

Research output: Contribution to journalArticle

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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.)

Original languageEnglish (US)
Pages (from-to)1164-1172
Number of pages9
JournalNew England Journal of Medicine
Volume361
Issue number12
DOIs
StatePublished - Sep 17 2009
Externally publishedYes

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Basal Cell Carcinoma
HhAntag691
Hyponatremia
Physical Examination
Neoplasms
Clinical Trials, Phase I
Spasm
Pharmaceutical Preparations
Atrial Fibrillation
Genes
Fatigue
Pharmacokinetics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Von Hoff, D. D., LoRusso, P. M., Rudin, C. M., Reddy, J. C., Yauch, R. L., Tibes, R., ... Low, J. A. (2009). Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. New England Journal of Medicine, 361(12), 1164-1172. https://doi.org/10.1056/NEJMoa0905360

Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. / Von Hoff, Daniel D.; LoRusso, Patricia M.; Rudin, Charles M.; Reddy, Josina C.; Yauch, Robert L.; Tibes, Raoul; Weiss, Glen J.; Borad, Mitesh J; Hann, Christine L.; Brahmer, Julie R.; Mackey, Howard M.; Lum, Bertram L.; Darbonne, Walter C.; Marsters, James C.; De Sauvage, Frederic J.; Low, Jennifer A.

In: New England Journal of Medicine, Vol. 361, No. 12, 17.09.2009, p. 1164-1172.

Research output: Contribution to journalArticle

Von Hoff, DD, LoRusso, PM, Rudin, CM, Reddy, JC, Yauch, RL, Tibes, R, Weiss, GJ, Borad, MJ, Hann, CL, Brahmer, JR, Mackey, HM, Lum, BL, Darbonne, WC, Marsters, JC, De Sauvage, FJ & Low, JA 2009, 'Inhibition of the hedgehog pathway in advanced basal-cell carcinoma', New England Journal of Medicine, vol. 361, no. 12, pp. 1164-1172. https://doi.org/10.1056/NEJMoa0905360
Von Hoff DD, LoRusso PM, Rudin CM, Reddy JC, Yauch RL, Tibes R et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. New England Journal of Medicine. 2009 Sep 17;361(12):1164-1172. https://doi.org/10.1056/NEJMoa0905360
Von Hoff, Daniel D. ; LoRusso, Patricia M. ; Rudin, Charles M. ; Reddy, Josina C. ; Yauch, Robert L. ; Tibes, Raoul ; Weiss, Glen J. ; Borad, Mitesh J ; Hann, Christine L. ; Brahmer, Julie R. ; Mackey, Howard M. ; Lum, Bertram L. ; Darbonne, Walter C. ; Marsters, James C. ; De Sauvage, Frederic J. ; Low, Jennifer A. / Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. In: New England Journal of Medicine. 2009 ; Vol. 361, No. 12. pp. 1164-1172.
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T1 - Inhibition of the hedgehog pathway in advanced basal-cell carcinoma

AU - Von Hoff, Daniel D.

AU - LoRusso, Patricia M.

AU - Rudin, Charles M.

AU - Reddy, Josina C.

AU - Yauch, Robert L.

AU - Tibes, Raoul

AU - Weiss, Glen J.

AU - Borad, Mitesh J

AU - Hann, Christine L.

AU - Brahmer, Julie R.

AU - Mackey, Howard M.

AU - Lum, Bertram L.

AU - Darbonne, Walter C.

AU - Marsters, James C.

AU - De Sauvage, Frederic J.

AU - Low, Jennifer A.

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N2 - 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.)

AB - 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.)

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