Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations

David M. Hyman, Igor Puzanov, Vivek Subbiah, Jason E. Faris, Ian Chau, Jean Yves Blay, Jurgen Wolf, Noopur S. Raje, Eli L. Diamond, Antoine Hollebecque, Radj Gervais, Maria Elena Elez Fernandez, Antoine Italiano, Ralf Dieter Hofheinz, Manuel Hidalgo, Emily Chan, Martin Schuler, Susan Frances Lasserre, Martina Makrutzki, Florin Sirzen & 3 others Maria Luisa Veronese, Josep Tabernero, Jose Baselga

Research output: Contribution to journalArticle

Abstract

BACKGROUND BRAF V600 mutations occur in various nonmelanoma cancers. We undertook a histology-independent phase 2 "basket" study of vemurafenib in BRAF V600 mutation- positive nonmelanoma cancers. METHODS We enrolled patients in six prespecified cancer cohorts; patients with all other tumor types were enrolled in a seventh cohort. A total of 122 patients with BRAF V600 mutation-positive cancer were treated, including 27 patients with colorectal cancer who received vemurafenib and cetuximab. The primary end point was the response rate; secondary end points included progression-free and overall survival. RESULTS In the cohort with non-small-cell lung cancer, the response rate was 42% (95% confidence interval [CI], 20 to 67) and median progression-free survival was 7.3 months (95% CI, 3.5 to 10.8). In the cohort with Erdheim-Chester disease or Langerhans'-cell histiocytosis, the response rate was 43% (95% CI, 18 to 71); the median treatment duration was 5.9 months (range, 0.6 to 18.6), and no patients had disease progression during therapy. There were anecdotal responses among patients with pleomorphic xanthoastrocytoma, anaplastic thyroid cancer, cholangiocarcinoma, salivary-duct cancer, ovarian cancer, and clear-cell sarcoma and among patients with colorectal cancer who received vemurafenib and cetuximab. Safety was similar to that in prior studies of vemurafenib for melanoma. CONCLUSIONS BRAF V600 appears to be a targetable oncogene in some, but not all, nonmelanoma cancers. Preliminary vemurafenib activity was observed in non-small-cell lung cancer and in Erdheim-Chester disease and Langerhans'-cell histiocytosis. The histologic context is an important determinant of response in BRAF V600-mutated cancers.

Original languageEnglish (US)
Pages (from-to)726-736
Number of pages11
JournalNew England Journal of Medicine
Volume373
Issue number8
DOIs
StatePublished - Aug 20 2015
Externally publishedYes

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Mutation
Neoplasms
Erdheim-Chester Disease
Langerhans Cell Histiocytosis
Confidence Intervals
Non-Small Cell Lung Carcinoma
Disease-Free Survival
Colorectal Neoplasms
Clear Cell Sarcoma
Salivary Ducts
Cholangiocarcinoma
PLX4032
Oncogenes
Ovarian Neoplasms
Disease Progression
Melanoma
Histology
Safety
Therapeutics
Cetuximab

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Hyman, D. M., Puzanov, I., Subbiah, V., Faris, J. E., Chau, I., Blay, J. Y., ... Baselga, J. (2015). Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. New England Journal of Medicine, 373(8), 726-736. https://doi.org/10.1056/NEJMoa1502309

Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. / Hyman, David M.; Puzanov, Igor; Subbiah, Vivek; Faris, Jason E.; Chau, Ian; Blay, Jean Yves; Wolf, Jurgen; Raje, Noopur S.; Diamond, Eli L.; Hollebecque, Antoine; Gervais, Radj; Fernandez, Maria Elena Elez; Italiano, Antoine; Hofheinz, Ralf Dieter; Hidalgo, Manuel; Chan, Emily; Schuler, Martin; Lasserre, Susan Frances; Makrutzki, Martina; Sirzen, Florin; Veronese, Maria Luisa; Tabernero, Josep; Baselga, Jose.

In: New England Journal of Medicine, Vol. 373, No. 8, 20.08.2015, p. 726-736.

Research output: Contribution to journalArticle

Hyman, DM, Puzanov, I, Subbiah, V, Faris, JE, Chau, I, Blay, JY, Wolf, J, Raje, NS, Diamond, EL, Hollebecque, A, Gervais, R, Fernandez, MEE, Italiano, A, Hofheinz, RD, Hidalgo, M, Chan, E, Schuler, M, Lasserre, SF, Makrutzki, M, Sirzen, F, Veronese, ML, Tabernero, J & Baselga, J 2015, 'Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations', New England Journal of Medicine, vol. 373, no. 8, pp. 726-736. https://doi.org/10.1056/NEJMoa1502309
Hyman DM, Puzanov I, Subbiah V, Faris JE, Chau I, Blay JY et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. New England Journal of Medicine. 2015 Aug 20;373(8):726-736. https://doi.org/10.1056/NEJMoa1502309
Hyman, David M. ; Puzanov, Igor ; Subbiah, Vivek ; Faris, Jason E. ; Chau, Ian ; Blay, Jean Yves ; Wolf, Jurgen ; Raje, Noopur S. ; Diamond, Eli L. ; Hollebecque, Antoine ; Gervais, Radj ; Fernandez, Maria Elena Elez ; Italiano, Antoine ; Hofheinz, Ralf Dieter ; Hidalgo, Manuel ; Chan, Emily ; Schuler, Martin ; Lasserre, Susan Frances ; Makrutzki, Martina ; Sirzen, Florin ; Veronese, Maria Luisa ; Tabernero, Josep ; Baselga, Jose. / Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. In: New England Journal of Medicine. 2015 ; Vol. 373, No. 8. pp. 726-736.
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T1 - Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations

AU - Hyman, David M.

AU - Puzanov, Igor

AU - Subbiah, Vivek

AU - Faris, Jason E.

AU - Chau, Ian

AU - Blay, Jean Yves

AU - Wolf, Jurgen

AU - Raje, Noopur S.

AU - Diamond, Eli L.

AU - Hollebecque, Antoine

AU - Gervais, Radj

AU - Fernandez, Maria Elena Elez

AU - Italiano, Antoine

AU - Hofheinz, Ralf Dieter

AU - Hidalgo, Manuel

AU - Chan, Emily

AU - Schuler, Martin

AU - Lasserre, Susan Frances

AU - Makrutzki, Martina

AU - Sirzen, Florin

AU - Veronese, Maria Luisa

AU - Tabernero, Josep

AU - Baselga, Jose

PY - 2015/8/20

Y1 - 2015/8/20

N2 - BACKGROUND BRAF V600 mutations occur in various nonmelanoma cancers. We undertook a histology-independent phase 2 "basket" study of vemurafenib in BRAF V600 mutation- positive nonmelanoma cancers. METHODS We enrolled patients in six prespecified cancer cohorts; patients with all other tumor types were enrolled in a seventh cohort. A total of 122 patients with BRAF V600 mutation-positive cancer were treated, including 27 patients with colorectal cancer who received vemurafenib and cetuximab. The primary end point was the response rate; secondary end points included progression-free and overall survival. RESULTS In the cohort with non-small-cell lung cancer, the response rate was 42% (95% confidence interval [CI], 20 to 67) and median progression-free survival was 7.3 months (95% CI, 3.5 to 10.8). In the cohort with Erdheim-Chester disease or Langerhans'-cell histiocytosis, the response rate was 43% (95% CI, 18 to 71); the median treatment duration was 5.9 months (range, 0.6 to 18.6), and no patients had disease progression during therapy. There were anecdotal responses among patients with pleomorphic xanthoastrocytoma, anaplastic thyroid cancer, cholangiocarcinoma, salivary-duct cancer, ovarian cancer, and clear-cell sarcoma and among patients with colorectal cancer who received vemurafenib and cetuximab. Safety was similar to that in prior studies of vemurafenib for melanoma. CONCLUSIONS BRAF V600 appears to be a targetable oncogene in some, but not all, nonmelanoma cancers. Preliminary vemurafenib activity was observed in non-small-cell lung cancer and in Erdheim-Chester disease and Langerhans'-cell histiocytosis. The histologic context is an important determinant of response in BRAF V600-mutated cancers.

AB - BACKGROUND BRAF V600 mutations occur in various nonmelanoma cancers. We undertook a histology-independent phase 2 "basket" study of vemurafenib in BRAF V600 mutation- positive nonmelanoma cancers. METHODS We enrolled patients in six prespecified cancer cohorts; patients with all other tumor types were enrolled in a seventh cohort. A total of 122 patients with BRAF V600 mutation-positive cancer were treated, including 27 patients with colorectal cancer who received vemurafenib and cetuximab. The primary end point was the response rate; secondary end points included progression-free and overall survival. RESULTS In the cohort with non-small-cell lung cancer, the response rate was 42% (95% confidence interval [CI], 20 to 67) and median progression-free survival was 7.3 months (95% CI, 3.5 to 10.8). In the cohort with Erdheim-Chester disease or Langerhans'-cell histiocytosis, the response rate was 43% (95% CI, 18 to 71); the median treatment duration was 5.9 months (range, 0.6 to 18.6), and no patients had disease progression during therapy. There were anecdotal responses among patients with pleomorphic xanthoastrocytoma, anaplastic thyroid cancer, cholangiocarcinoma, salivary-duct cancer, ovarian cancer, and clear-cell sarcoma and among patients with colorectal cancer who received vemurafenib and cetuximab. Safety was similar to that in prior studies of vemurafenib for melanoma. CONCLUSIONS BRAF V600 appears to be a targetable oncogene in some, but not all, nonmelanoma cancers. Preliminary vemurafenib activity was observed in non-small-cell lung cancer and in Erdheim-Chester disease and Langerhans'-cell histiocytosis. The histologic context is an important determinant of response in BRAF V600-mutated cancers.

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