Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations

By D. Hyman, I. Puzanov, V. Subbiah, J. Faris, I. Chau, J. Blay, J. Wolf, N. Raje, E. Diamond, A. Hollebecque and 13 more. New England Journal of Medicine, 2015

1,621 citations recorded by the source corpus.

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. (Funded by F. Hoffmann–La Roche/Genentech; ClinicalTrials.gov number, NCT01524978.)

Subfields: Cancer Research, Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/abd7e5ae4940f84d6af08e479e67fa7e4788098c

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Citations in the corpus

Cancer chemotherapy and beyond: Current status, drug candidates, associated risks and progress in targeted therapeutics (2022, background): “An oral BRAF inhibitor, namely vemurafenib has been shown to possess a greater affinity for the mutant BRAF than the wildtype BRAF, and therefore was recommended to the patients carrying the above mutation in the tumors.(196) Several potential targets for novel drugs have been identified using high-”
Precision Cancer Medicine: Challenges and Opportunities (2019, background): “In a variety of malignancies, including ovarian, breast, and biliary cancers, this has been shown to be associated with resistance to chemotherapy, including microtubule stabilizers [34], platinum agents [35–37], and topoisomerase inhibitors [35, 36].”
Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. (2016, background): “Rare mutations in other MAPK pathway members including ARAF and MAP3K1 have also been reported.39,40 Finally,mutations affectingother signalingpathway such as PIK3CA, PICK1, and PICK3R2 have also been described in LCH.37,41 The presence of BRAF mutations has been investigated in nonLCHs.”
A framework to rank genomic alterations as targets for cancer precision medicine: the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) (2018, background): “The most relevant example is the limited activity of vemurafenib in BRAF-mutated colorectal cancers [27].”
Current Challenges in Cancer Treatment. (2016, background): “As such, in this trial, encouraging activity in NSCLC subsets receiving vemurafenib (RR 1⁄4 43%) was found, but not in other tumor types, such as colorectal cancers, anaplastic thyroid cancers, cholangiocarcinomas, or ovarian cancers.(45) On the other hand, histology-dependent “umbrella trials” rest”