A single-arm, open-label, expanded access study of vemurafenib in patients with metastatic melanoma in the United States

Lawrence Flaherty, Omid Hamid, Gerald Linette, Lynn Schuchter, Sigrun Hallmeyer, Rene Gonzalez, C. Lance Cowey, Anna Pavlick, Fred Kudrik, Brendan Curti, David Lawson, Paul B. Chapman, Kim Margolin, Antoni Ribas, David McDermott, Keith Flaherty, Lee D Cranmer, F. Stephen Hodi, Bann Mo Day, Rolf LinkeJohn Hainsworth

Research output: Contribution to journalArticle

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Abstract

PURPOSE: 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). PATIENTS AND 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. DISCUSSION: 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.

Original languageEnglish (US)
Pages (from-to)18-24
Number of pages7
JournalCancer Journal
Volume20
Issue number1
DOIs
StatePublished - Jan 2014

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Melanoma
Neoplasm Metastasis
PLX4032
Brain
Mutation
Drug Approval
Safety
Therapeutics
Nervous System
Multicenter Studies
Radiotherapy

Keywords

  • BRAF protein
  • brain neoplasms/ secondary
  • brain neoplasms/drug therapy
  • clinical trial
  • human
  • humans
  • Melanoma/drug therapy
  • melanoma/genetics
  • neoplasm metastasis/drug therapy
  • vemurafenib/adverse effects
  • vemurafenib/therapeutic use

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Flaherty, L., Hamid, O., Linette, G., Schuchter, L., Hallmeyer, S., Gonzalez, R., ... Hainsworth, J. (2014). A single-arm, open-label, expanded access study of vemurafenib in patients with metastatic melanoma in the United States. Cancer Journal, 20(1), 18-24. https://doi.org/10.1097/PPO.0000000000000024

A single-arm, open-label, expanded access study of vemurafenib in patients with metastatic melanoma in the United States. / Flaherty, Lawrence; Hamid, Omid; Linette, Gerald; Schuchter, Lynn; Hallmeyer, Sigrun; Gonzalez, Rene; Cowey, C. Lance; Pavlick, Anna; Kudrik, Fred; Curti, Brendan; Lawson, David; Chapman, Paul B.; Margolin, Kim; Ribas, Antoni; McDermott, David; Flaherty, Keith; Cranmer, Lee D; Hodi, F. Stephen; Day, Bann Mo; Linke, Rolf; Hainsworth, John.

In: Cancer Journal, Vol. 20, No. 1, 01.2014, p. 18-24.

Research output: Contribution to journalArticle

Flaherty, L, Hamid, O, Linette, G, Schuchter, L, Hallmeyer, S, Gonzalez, R, Cowey, CL, Pavlick, A, Kudrik, F, Curti, B, Lawson, D, Chapman, PB, Margolin, K, Ribas, A, McDermott, D, Flaherty, K, Cranmer, LD, Hodi, FS, Day, BM, Linke, R & Hainsworth, J 2014, 'A single-arm, open-label, expanded access study of vemurafenib in patients with metastatic melanoma in the United States', Cancer Journal, vol. 20, no. 1, pp. 18-24. https://doi.org/10.1097/PPO.0000000000000024
Flaherty, Lawrence ; Hamid, Omid ; Linette, Gerald ; Schuchter, Lynn ; Hallmeyer, Sigrun ; Gonzalez, Rene ; Cowey, C. Lance ; Pavlick, Anna ; Kudrik, Fred ; Curti, Brendan ; Lawson, David ; Chapman, Paul B. ; Margolin, Kim ; Ribas, Antoni ; McDermott, David ; Flaherty, Keith ; Cranmer, Lee D ; Hodi, F. Stephen ; Day, Bann Mo ; Linke, Rolf ; Hainsworth, John. / A single-arm, open-label, expanded access study of vemurafenib in patients with metastatic melanoma in the United States. In: Cancer Journal. 2014 ; Vol. 20, No. 1. pp. 18-24.
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T1 - A single-arm, open-label, expanded access study of vemurafenib in patients with metastatic melanoma in the United States

AU - Flaherty, Lawrence

AU - Hamid, Omid

AU - Linette, Gerald

AU - Schuchter, Lynn

AU - Hallmeyer, Sigrun

AU - Gonzalez, Rene

AU - Cowey, C. Lance

AU - Pavlick, Anna

AU - Kudrik, Fred

AU - Curti, Brendan

AU - Lawson, David

AU - Chapman, Paul B.

AU - Margolin, Kim

AU - Ribas, Antoni

AU - McDermott, David

AU - Flaherty, Keith

AU - Cranmer, Lee D

AU - Hodi, F. Stephen

AU - Day, Bann Mo

AU - Linke, Rolf

AU - Hainsworth, John

PY - 2014/1

Y1 - 2014/1

N2 - PURPOSE: 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). PATIENTS AND 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. DISCUSSION: 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.

AB - PURPOSE: 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). PATIENTS AND 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. DISCUSSION: 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.

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KW - clinical trial

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KW - Melanoma/drug therapy

KW - melanoma/genetics

KW - neoplasm metastasis/drug therapy

KW - vemurafenib/adverse effects

KW - vemurafenib/therapeutic use

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