Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations.
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.).
From Memorial Sloan Kettering Cancer Center, New York (D.M.H., E.L.D., J.B.); Vanderbilt University Medical Center, Nashville (I.P., E.C.); University of Texas M.D. Anderson Cancer Center, Houston (V.S.); Massachusetts General Hospital, Boston (J.E.F., N.S.R.); Royal Marsden Hospital, Sutton, Surrey, United Kingdom (I.C.); Centre Léon Bérard, Lyon (J.-Y.B.), Institut Gustave Roussy, Villejuif (A.H.), Centre François Baclesse, Centre Hospitalier Universitaire Côte de Nacre, Caen (R.G.), and Institut Bergonié Cancer Center, Bordeaux (A.I.) - all in France; University Hospital of Cologne, Cologne (J.W.), Universitätsmedizin Mannheim, Mannheim (R.-D.H.), West German Cancer Center, University Hospital Essen, Essen (M.S.), and German Cancer Consortium, Heidelberg (M.S.) - all in Germany; Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona (M.E.E.-F., J.T.), and Hospital Universitario Madrid Sanchinarro, Madrid (M.H.) - both in Spain; and F. Hoffmann-La Roche, Basel, Switzerland (S.F.L., M.M., F.S., M.L.V.).
David M
DM
Hyman
Igor
I
Puzanov
Vivek
V
Subbiah
Jason E
JE
Faris
Ian
I
Chau
Jean-Yves
JY
Blay
Jürgen
J
Wolf
Noopur S
NS
Raje
Eli L
EL
Diamond
Antoine
A
Hollebecque
Radj
R
Gervais
Maria Elena
ME
Elez-Fernandez
Antoine
A
Italiano
Ralf-Dieter
RD
Hofheinz
Manuel
M
Hidalgo
Emily
E
Chan
Martin
M
Schuler
Susan Frances
SF
Lasserre
Martina
M
Makrutzki
Florin
F
Sirzen
Maria Luisa
ML
Veronese
Josep
J
Tabernero
José
J
Baselga
D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D015614:Histiocytosis / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use*; D000077484:Vemurafenib
D000970:Antineoplastic Agents; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; D048493:Proto-Oncogene Proteins B-raf