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Clinical data | |
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Pronunciation | /ˌvɛməˈræfənɪb/ VEM-ə-RAF-ə-nib |
Trade names | Zelboraf |
Other names | PLX4032, RG7204, PLX4720, RO5185426 |
AHFS/ Drugs.com | Monograph |
MedlinePlus | a612009 |
License data |
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Pregnancy category |
|
Routes of administration | By mouth |
ATC code | |
Legal status | |
Legal status | |
Identifiers | |
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CAS Number | |
PubChem CID | |
IUPHAR/BPS | |
DrugBank | |
ChemSpider | |
UNII | |
KEGG | |
ChEMBL | |
PDB ligand | |
CompTox Dashboard ( EPA) | |
ECHA InfoCard | 100.287.801 |
Chemical and physical data | |
Formula | C23H18ClF2N3O3S |
Molar mass | 489.92 g·mol−1 |
3D model ( JSmol) | |
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(verify) |
vemurafenib | |
---|---|
Drug mechanism | |
![]()
Crystallographic structure of B-Raf (rainbow colored,
N-terminus = blue,
C-terminus = red) complexed with vemurafenib (spheres, carbon = white, oxygen = red, nitrogen = blue, chlorine = green, fluorine = cyan, sulfur = yellow).
[2] | |
Therapeutic use | melanoma |
Biological target | BRAF |
Mechanism of action | protein kinase inhibitor |
External links | |
PDB ligand id | 032: PDBe, RCSB PDB |
LIGPLOT | 3og7 |
Vemurafenib ( INN), sold under the brand name Zelboraf, is a medication used for the treatment of late-stage melanoma. [2] It is an inhibitor of the B-Raf enzyme and was developed by Plexxikon. [2]
Vemurafenib causes programmed cell death in melanoma cell lines. [3] Vemurafenib interrupts the B-Raf/MEK step on the B-Raf/MEK/ERK pathway − if the B-Raf has the common V600E mutation.
Vemurafenib only works in melanoma patients whose cancer has a V600E BRAF mutation (that is, at amino acid position number 600 on the B-Raf protein, the normal valine is replaced by glutamic acid). [4] About 60% of melanomas have this mutation. It also has efficacy against the rarer BRAF V600K mutation. Melanoma cells without these mutations are not inhibited by vemurafenib; the drug paradoxically stimulates normal BRAF and may promote tumor growth in such cases. [5] [6]
Three mechanisms of resistance to vemurafenib (covering 40% of cases) have been discovered:
At the maximum tolerated dose (MTD) of 960 mg twice a day 31% of patients get skin lesions that may need surgical removal. [2] The BRIM-2 trial investigated 132 patients; the most common adverse events were arthralgia in 58% of patients, skin rash in 52%, and photosensitivity in 52%. In order to better manage side effects some form of dose modification was necessary in 45% of patients. The median daily dose was 1750 mg, 91% of the MTD. [10]
In a phase I clinical study, vemurafenib (then known as PLX4032) was able to reduce numbers of cancer cells in over half of a group of 16 patients with advanced melanoma. The treated group had a median increased survival time of 6 months over the control group. [11] [12] [13] [14]
A second phase I study, in patients with a V600E mutation in B-Raf, ~80% showed partial to complete regression. The regression lasted from 2 to 18 months. [15]
In early 2010 a Phase I trial [16] for solid tumors (including colorectal cancer), and a phase II study (for metastatic melanoma) were ongoing. [17]
A phase III trial (vs dacarbazine) in patients with previously untreated metastatic melanoma showed an improved rates of overall and progression-free survival. [18]
In June 2011, positive results were reported from the phase III BRIM3 BRAF-mutation melanoma study. [19] The BRIM3 trial reported good updated results in 2012. [20]
Further trials are planned including a trial of vemurafenib co-administered with GDC-0973 ( cobimetinib), a MEK-inhibitor. [19] After good results in 2014, the combination was submitted to the European Medical Agency and the US Food and Drug Administration for marketing approval. [21]
In January 2015, trial results compared vemurafenib with the combination of dabrafenib and trametinib for metastatic melanoma. [22]
Vemurafenib was approved in the United States for the treatment of late-stage melanoma in August 2011, [23] making it the first drug designed using fragment-based lead discovery to gain regulatory approval. [24]
Vemurafenib was approved for use in Canada in February 2012. [25]
In February 2012, the European Commission approved vemurafenib as a monotherapy for the treatment of adults with BRAF V600E mutation positive unresectable or metastatic melanoma, the most aggressive form of skin cancer. [26]
In November 2017, the US Food and Drug Administration (FDA) approved vemurafenib for the treatment of people with Erdheim–Chester disease (ECD), a rare type of histiocytic neoplasm. [27] [28]
A trial combining vemurafenib and ipilimumab was stopped in April 2013 because of signs of liver toxicity. [29]
In 2012, a grant from the Hairy cell leukemia Foundation supported the discovery of the BRAF mutation in classic HCL. This discovery charted a new path forward for many patients. It improved diagnosis and opened the door for additional therapies to be used in managing HCL. [30] In a phase II clinical trial, Memorial Sloan Kettering is testing Vemurafenib, plus Obinutuzumab, in patients with previously untreated classical hairy cell leukemia. [31] A separate clinical study treatment with only Vemurafenib (or monotherarpy) demonstrated high response rates in relapsed/refractory (R/R) hairy cell leukemia (HCL), achieving an overall response rate of 86%, including 33% complete response (CR) and 53% partial response. However, after a median follow-up of 40 months, 21 of 31 responders (68%) experienced relapse with a median relapse-free survival (RFS) of 19 months (range, 12.5-53.9 months). [32]
![]() | |
![]() | |
Clinical data | |
---|---|
Pronunciation | /ˌvɛməˈræfənɪb/ VEM-ə-RAF-ə-nib |
Trade names | Zelboraf |
Other names | PLX4032, RG7204, PLX4720, RO5185426 |
AHFS/ Drugs.com | Monograph |
MedlinePlus | a612009 |
License data |
|
Pregnancy category |
|
Routes of administration | By mouth |
ATC code | |
Legal status | |
Legal status | |
Identifiers | |
| |
CAS Number | |
PubChem CID | |
IUPHAR/BPS | |
DrugBank | |
ChemSpider | |
UNII | |
KEGG | |
ChEMBL | |
PDB ligand | |
CompTox Dashboard ( EPA) | |
ECHA InfoCard | 100.287.801 |
Chemical and physical data | |
Formula | C23H18ClF2N3O3S |
Molar mass | 489.92 g·mol−1 |
3D model ( JSmol) | |
| |
| |
(verify) |
vemurafenib | |
---|---|
Drug mechanism | |
![]()
Crystallographic structure of B-Raf (rainbow colored,
N-terminus = blue,
C-terminus = red) complexed with vemurafenib (spheres, carbon = white, oxygen = red, nitrogen = blue, chlorine = green, fluorine = cyan, sulfur = yellow).
[2] | |
Therapeutic use | melanoma |
Biological target | BRAF |
Mechanism of action | protein kinase inhibitor |
External links | |
PDB ligand id | 032: PDBe, RCSB PDB |
LIGPLOT | 3og7 |
Vemurafenib ( INN), sold under the brand name Zelboraf, is a medication used for the treatment of late-stage melanoma. [2] It is an inhibitor of the B-Raf enzyme and was developed by Plexxikon. [2]
Vemurafenib causes programmed cell death in melanoma cell lines. [3] Vemurafenib interrupts the B-Raf/MEK step on the B-Raf/MEK/ERK pathway − if the B-Raf has the common V600E mutation.
Vemurafenib only works in melanoma patients whose cancer has a V600E BRAF mutation (that is, at amino acid position number 600 on the B-Raf protein, the normal valine is replaced by glutamic acid). [4] About 60% of melanomas have this mutation. It also has efficacy against the rarer BRAF V600K mutation. Melanoma cells without these mutations are not inhibited by vemurafenib; the drug paradoxically stimulates normal BRAF and may promote tumor growth in such cases. [5] [6]
Three mechanisms of resistance to vemurafenib (covering 40% of cases) have been discovered:
At the maximum tolerated dose (MTD) of 960 mg twice a day 31% of patients get skin lesions that may need surgical removal. [2] The BRIM-2 trial investigated 132 patients; the most common adverse events were arthralgia in 58% of patients, skin rash in 52%, and photosensitivity in 52%. In order to better manage side effects some form of dose modification was necessary in 45% of patients. The median daily dose was 1750 mg, 91% of the MTD. [10]
In a phase I clinical study, vemurafenib (then known as PLX4032) was able to reduce numbers of cancer cells in over half of a group of 16 patients with advanced melanoma. The treated group had a median increased survival time of 6 months over the control group. [11] [12] [13] [14]
A second phase I study, in patients with a V600E mutation in B-Raf, ~80% showed partial to complete regression. The regression lasted from 2 to 18 months. [15]
In early 2010 a Phase I trial [16] for solid tumors (including colorectal cancer), and a phase II study (for metastatic melanoma) were ongoing. [17]
A phase III trial (vs dacarbazine) in patients with previously untreated metastatic melanoma showed an improved rates of overall and progression-free survival. [18]
In June 2011, positive results were reported from the phase III BRIM3 BRAF-mutation melanoma study. [19] The BRIM3 trial reported good updated results in 2012. [20]
Further trials are planned including a trial of vemurafenib co-administered with GDC-0973 ( cobimetinib), a MEK-inhibitor. [19] After good results in 2014, the combination was submitted to the European Medical Agency and the US Food and Drug Administration for marketing approval. [21]
In January 2015, trial results compared vemurafenib with the combination of dabrafenib and trametinib for metastatic melanoma. [22]
Vemurafenib was approved in the United States for the treatment of late-stage melanoma in August 2011, [23] making it the first drug designed using fragment-based lead discovery to gain regulatory approval. [24]
Vemurafenib was approved for use in Canada in February 2012. [25]
In February 2012, the European Commission approved vemurafenib as a monotherapy for the treatment of adults with BRAF V600E mutation positive unresectable or metastatic melanoma, the most aggressive form of skin cancer. [26]
In November 2017, the US Food and Drug Administration (FDA) approved vemurafenib for the treatment of people with Erdheim–Chester disease (ECD), a rare type of histiocytic neoplasm. [27] [28]
A trial combining vemurafenib and ipilimumab was stopped in April 2013 because of signs of liver toxicity. [29]
In 2012, a grant from the Hairy cell leukemia Foundation supported the discovery of the BRAF mutation in classic HCL. This discovery charted a new path forward for many patients. It improved diagnosis and opened the door for additional therapies to be used in managing HCL. [30] In a phase II clinical trial, Memorial Sloan Kettering is testing Vemurafenib, plus Obinutuzumab, in patients with previously untreated classical hairy cell leukemia. [31] A separate clinical study treatment with only Vemurafenib (or monotherarpy) demonstrated high response rates in relapsed/refractory (R/R) hairy cell leukemia (HCL), achieving an overall response rate of 86%, including 33% complete response (CR) and 53% partial response. However, after a median follow-up of 40 months, 21 of 31 responders (68%) experienced relapse with a median relapse-free survival (RFS) of 19 months (range, 12.5-53.9 months). [32]