A single-arm, open-label, expanded access study of vemurafenib in patients with metastatic melanoma in the United States.
OBJECTIVE
This open-label, multicenter study was designed to allow access to vemurafenib for patients with metastatic melanoma, bridging the time between end of enrollment in the phase III registration trial (December 2010) and commercial availability following US Food and Drug Administration approval of vemurafenib for the treatment of unresectable or metastatic BRAF-mutated melanoma (August 2011).


METHODS
Eligible patients had metastatic melanoma with a BRAF mutation (detected by the cobas 4800 BRAF V600 Mutation Test). Unlike previous vemurafenib trials, patients with poor performance status (PS) and treated brain metastases were permitted. Enrolled patients received oral vemurafenib 960 mg twice daily.


RESULTS
Of 374 patients enrolled at 29 US sites (December 2010 to October 2011), 371 patients received vemurafenib and were followed up for a median of 2.8 months (the study had a prespecified end upon vemurafenib approval and commercial availability). At baseline, most patients (75%) had stage M1c disease, and 19% had an Eastern Cooperative Oncology Group PS of 2 or 3; 72% of patients had received prior systemic therapy for metastatic melanoma, 27% received prior ipilimumab, and 29% radiotherapy for prior brain metastases. Because reassessment data to confirm response were not available for most patients, point estimates of objective response rate (ORR) are reported. Among 241 efficacy-evaluable patients, the ORR was 54% (median time to response, 1.9 months). The ORR in non-central nervous system sites in patients with previously treated brain metastases (n = 68) was 53%. The ORR in prior ipilimumab-treated patients (n = 68) was 52%. For patients with PS of 0 or 1 (n = 210) and 2 or 3 (n = 31), the ORRs were 55%, and 42%, respectively. The safety profile observed was consistent with that reported in previous studies. The number of patients with grade 3 or 4 treatment-related adverse events was higher in patients with PS 2 or 3 than in those with PS 0 or 1 (10% vs. 5%, respectively). Adverse events requiring a dose reduction (at least 1 level) occurred in 11% of patients, and 9 patients (2%) experienced events leading to vemurafenib withdrawal, including 2 with repeated QT interval prolongation.


CONCLUSIONS
This study confirmed the established rapid and high tumor response rate achievable with vemurafenib in BRAF mutation-positive metastatic melanoma. Several groups not included in previous studies, including patients with previously treated brain metastases, Eastern Cooperative Oncology Group PS 2 to 3, or previous ipilimumab treatment had benefitted from vemurafenib similar to the overall population. No new safety signals were detected.
From the *Karmanos Cancer Center, Wayne State University, Detroit, MI; †The Angeles Clinic and Research Institute, Los Angeles, CA; ‡Washington University, St Louis, MO; §University of Pennsylvania, Philadelphia, PA; ∥Oncology Specialists S.C., Park Ridge, IL; ¶University of Colorado Cancer Center, Aurora, CO; #Baylor Sammons Cancer Center, Texas Oncology, PA, Dallas, TX; **NYU Medical Center, New York, NY; ††South Carolina Oncology Associates, Columbia, SC; ‡‡Providence Portland Medical Center, Portland, OR; §§Winship Cancer Institute, Emory University, Atlanta, GA; ∥∥Memorial Sloan Kettering Cancer Center, New York, NY; ¶¶Seattle Cancer Care Alliance, Seattle, WA; ##UCLA School of Medicine, Los Angeles, CA; ***Beth Israel Deaconess Medical Center and †††Massachusetts General Hospital, Boston, MA; ‡‡‡University of Arizona Cancer Center, Tucson, AZ; §§§Dana Farber Cancer Institute, Boston, MA; ∥∥∥Genentech, San Francisco, CA; ¶¶¶The SFJ Pharma Group, Pleasanton, CA; and ###Sarah Cannon Research Institute, Nashville, TN.
Lawrence
L
Flaherty
Omid
O
Hamid
Gerald
G
Linette
Lynn
L
Schuchter
Sigrun
S
Hallmeyer
Rene
R
Gonzalez
C Lance
CL
Cowey
Anna
A
Pavlick
Fred
F
Kudrik
Brendan
B
Curti
David
D
Lawson
Paul B
PB
Chapman
Kim
K
Margolin
Antoni
A
Ribas
David
D
McDermott
Keith
K
Flaherty
Lee
L
Cranmer
F Stephen
FS
Hodi
Bann-Mo
BM
Day
Rolf
R
Linke
John
J
Hainsworth
D005260:Female; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D009362:Neoplasm Metastasis; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use*; D014481:United States; D000077484:Vemurafenib
D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib