Efficacy and safety of vismodegib in advanced basal-cell carcinoma

Aleksandar Sekulic*, Michael R. Migden, Anthony E. Oro, Luc Dirix, Karl D. Lewis, John D. Hainsworth, James A. Solomon, Simon Yoo, Sarah T. Arron, Philip A. Friedlander, Ellen Marmur, Charles M. Rudin, Anne Lynn S. Chang, Jennifer A. Low, Howard M. Mackey, Robert L. Yauch, Richard A. Graham, Josina C. Reddy, Axel Hauschild

*Corresponding author for this work

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Abstract

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.)

Original languageEnglish (US)
Pages (from-to)2171-2179
Number of pages9
JournalNew England Journal of Medicine
Volume366
Issue number23
DOIs
StatePublished - Jun 7 2012

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HhAntag691
Basal Cell Carcinoma
Safety
Dysgeusia
Confidence Intervals
Alopecia

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Sekulic, A., Migden, M. R., Oro, A. E., Dirix, L., Lewis, K. D., Hainsworth, J. D., ... Hauschild, A. (2012). Efficacy and safety of vismodegib in advanced basal-cell carcinoma. New England Journal of Medicine, 366(23), 2171-2179. https://doi.org/10.1056/NEJMoa1113713
Sekulic, Aleksandar ; Migden, Michael R. ; Oro, Anthony E. ; Dirix, Luc ; Lewis, Karl D. ; Hainsworth, John D. ; Solomon, James A. ; Yoo, Simon ; Arron, Sarah T. ; Friedlander, Philip A. ; Marmur, Ellen ; Rudin, Charles M. ; Chang, Anne Lynn S. ; Low, Jennifer A. ; Mackey, Howard M. ; Yauch, Robert L. ; Graham, Richard A. ; Reddy, Josina C. ; Hauschild, Axel. / Efficacy and safety of vismodegib in advanced basal-cell carcinoma. In: New England Journal of Medicine. 2012 ; Vol. 366, No. 23. pp. 2171-2179.
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title = "Efficacy and safety of vismodegib in advanced basal-cell carcinoma",
abstract = "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.)",
author = "Aleksandar Sekulic and Migden, {Michael R.} and Oro, {Anthony E.} and Luc Dirix and Lewis, {Karl D.} and Hainsworth, {John D.} and Solomon, {James A.} and Simon Yoo and Arron, {Sarah T.} and Friedlander, {Philip A.} and Ellen Marmur and Rudin, {Charles M.} and Chang, {Anne Lynn S.} and Low, {Jennifer A.} and Mackey, {Howard M.} and Yauch, {Robert L.} and Graham, {Richard A.} and Reddy, {Josina C.} and Axel Hauschild",
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Sekulic, A, Migden, MR, Oro, AE, Dirix, L, Lewis, KD, Hainsworth, JD, Solomon, JA, Yoo, S, Arron, ST, Friedlander, PA, Marmur, E, Rudin, CM, Chang, ALS, Low, JA, Mackey, HM, Yauch, RL, Graham, RA, Reddy, JC & Hauschild, A 2012, 'Efficacy and safety of vismodegib in advanced basal-cell carcinoma', New England Journal of Medicine, vol. 366, no. 23, pp. 2171-2179. https://doi.org/10.1056/NEJMoa1113713

Efficacy and safety of vismodegib in advanced basal-cell carcinoma. / Sekulic, Aleksandar; Migden, Michael R.; Oro, Anthony E.; Dirix, Luc; Lewis, Karl D.; Hainsworth, John D.; Solomon, James A.; Yoo, Simon; Arron, Sarah T.; Friedlander, Philip A.; Marmur, Ellen; Rudin, Charles M.; Chang, Anne Lynn S.; Low, Jennifer A.; Mackey, Howard M.; Yauch, Robert L.; Graham, Richard A.; Reddy, Josina C.; Hauschild, Axel.

In: New England Journal of Medicine, Vol. 366, No. 23, 07.06.2012, p. 2171-2179.

Research output: Contribution to journalArticle

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T1 - Efficacy and safety of vismodegib in advanced basal-cell carcinoma

AU - Sekulic, Aleksandar

AU - Migden, Michael R.

AU - Oro, Anthony E.

AU - Dirix, Luc

AU - Lewis, Karl D.

AU - Hainsworth, John D.

AU - Solomon, James A.

AU - Yoo, Simon

AU - Arron, Sarah T.

AU - Friedlander, Philip A.

AU - Marmur, Ellen

AU - Rudin, Charles M.

AU - Chang, Anne Lynn S.

AU - Low, Jennifer A.

AU - Mackey, Howard M.

AU - Yauch, Robert L.

AU - Graham, Richard A.

AU - Reddy, Josina C.

AU - Hauschild, Axel

PY - 2012/6/7

Y1 - 2012/6/7

N2 - 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.)

AB - 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.)

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Sekulic A, Migden MR, Oro AE, Dirix L, Lewis KD, Hainsworth JD et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. New England Journal of Medicine. 2012 Jun 7;366(23):2171-2179. https://doi.org/10.1056/NEJMoa1113713