Vemurafenib (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...

, marketed as Zelboraf) is an inhibitor of the B-Raf

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

developed by

Plexxikon Plexxikon is an American drug discovery company based in South San Francisco, California. It was co-founded in 2001 by Joseph Schlessinger of Yale University, and Sung-Hou Kim of the University of California, Berkeley. It uses a proprietary struc ...

(now part of Daiichi-Sankyo) and

Genentech Genentech, Inc., is an American biotechnology corporation headquartered in South San Francisco, California. It became an independent subsidiary of Roche in 2009. Genentech Research and Early Development operates as an independent center within R ...

for the treatment of late-stage

melanoma Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...

.; The name "vemurafenib" comes from V600E mutated BRAF inhibition.

Approvals

Vemurafenib received

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

approval for the treatment of late-stage melanoma on August 17, 2011, making it the first drug designed using

fragment-based lead discovery Fragment-based lead discovery (FBLD) also known as fragment-based drug discovery (FBDD) is a method used for finding lead compounds as part of the drug discovery process. Fragments are small organic molecules which are small in size and low in mol ...

to gain regulatory approval. Vemurafenib later received

Health Canada Health Canada (HC; french: Santé Canada, SC)Health Canada is the applied title under the Federal Identity Program; the legal title is Department of Health (). is the Structure of the Canadian federal government#Departments, with subsidiary unit ...

approval on February 15, 2012. On February 20, 2012, the

European Commission The European Commission (EC) is the executive of the European Union (EU). It operates as a cabinet government, with 27 members of the Commission (informally known as "Commissioners") headed by a President. It includes an administrative body o ...

approved vemurafenib as a monotherapy for the treatment of adult patients with BRAF

V600E V600E is a mutation of the BRAF gene in which valine (V) is substituted by glutamic acid (E) at amino acid 600. It is a driver mutation in a proportion of certain diagnoses, including melanoma, hairy cell leukemia, papillary thyroid carcinoma, ...

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...

positive unresectable or

metastatic melanoma Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye (u ...

, the most aggressive form of skin cancer. On November 6, 2017, the FDA approved Vemurafenib for the treatment of some patients with

Erdheim–Chester disease Erdheim–Chester disease (ECD) is an extremely rare disease characterized by the abnormal multiplication of a specific type of white blood cells called histiocytes, or tissue macrophages (technically, this disease is termed a non- Langerhans-cel ...

(ECD), a rare type of histiocytic neoplasm.

Mechanism of action

Vemurafenib causes

programmed cell death Programmed cell death (PCD; sometimes referred to as cellular suicide) is the death of a cell as a result of events inside of a cell, such as apoptosis or autophagy. PCD is carried out in a biological process, which usually confers advantage durin ...

cell lines. 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 Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

position number 600 on the B-Raf protein, the normal

valine Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α- carboxylic acid group (which is in the deprotonat ...

is replaced by

glutamic acid Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can synt ...

). 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.

Resistance

Three mechanisms of resistance to vemurafenib (covering 40% of cases) have been discovered: * Cancer cells begin to overexpress cell surface protein

PDGFRB Platelet-derived growth factor receptor beta is a protein that in humans is encoded by the ''PDGFRB'' gene. Mutations in PDGFRB are mainly associated with the clonal eosinophilia class of malignancies. Gene The ''PDGFRB'' gene is located on hu ...

, creating an alternative survival pathway. * A second

oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

called NRAS mutates, reactivating the normal BRAF survival pathway. * *

Stromal cell Stromal cells, or mesenchymal stromal cells, are differentiating cells found in abundance within bone marrow but can also be seen all around the body. Stromal cells can become connective tissue cells of any organ, for example in the uterine mucos ...

secretion of

hepatocyte growth factor Hepatocyte growth factor (HGF) or scatter factor (SF) is a paracrine cellular growth, motility and morphogenic factor. It is secreted by mesenchymal cells and targets and acts primarily upon epithelial cells and endothelial cells, but also acts o ...

(HGF).

Clinical trials

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. 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. * In early 2010 a Phase I trial for solid tumors (including

colorectal cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel m ...

), and a phase II study (for metastatic melanoma) were ongoing. A phase III trial (vs

dacarbazine Dacarbazine (DTIC), also known as imidazole carboxamide, is a chemotherapy medication used in the treatment of melanoma and Hodgkin's lymphoma. For Hodgkin's it is often used together with vinblastine, bleomycin, and doxorubicin. It is given by i ...

) in patients with previously untreated metastatic melanoma showed an improved rates of overall and progression-free survival. In June 2011, positive results were reported from the phase III BRIM3 BRAF-mutation melanoma study. The BRIM3 trial reported good updated results in 2012. Further trials are planned including a trial of vemurafenib co-administered with GDC-0973 (

cobimetinib Cobimetinib, sold under the brand name Cotellic, is an anti-cancer medication used in combination with vemurafenib (Zelboraf) alone or with both vemurafenib and atezolizumab (Tecentriq) to treat melanoma. Cobimetinib is a MEK inhibitor. Cotell ...

), a MEK-inhibitor. After good results in 2014 the combination was submitted to the EC and FDA for marketing approval. In January 2015 trial results compared vemurafenib with the combination of

dabrafenib Dabrafenib, sold under the brand name Tafinlar & Rafinlar ( both by Novartis) among others, is a medication for the treatment of cancers associated with a mutated version of the gene BRAF. Dabrafenib acts as an inhibitor of the associated enzym ...

and

trametinib Trametinib, sold under the brand name Mekinist among others, is an anticancer medication used for the treatment of melanoma. It is a MEK inhibitor drug with anti-cancer activity. It inhibits MEK1 and MEK2. Trametinib had good results for metast ...

for metastatic melanoma.

Side effects

At the maximum tolerated dose (MTD) of 960 mg twice a day 31% of patients get skin lesions that may need surgical removal. The BRIM-2 trial investigated 132 patients; the most common adverse events were

arthralgia Arthralgia (from Greek ''arthro-'', joint + ''-algos'', pain) literally means ''joint pain''. Specifically, arthralgia is a symptom of injury, infection, illness (in particular arthritis), or an allergic reaction to medication. According to MeSH, ...

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. A trial combining vemurafenib and ipilimumab was stopped in April 2013 because of signs of

liver toxicity Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdrawn fro ...

References

External links

* {{Portal bar , Medicine Antineoplastic and immunomodulating drugs B-Raf inhibitors Chloroarenes CYP2D6 inhibitors CYP3A4 inducers Fluoroarenes Sulfonamides Chemotherapy Hoffmann-La Roche brands Genentech brands Daiichi Sankyo Diarylketones