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Vemurafenib: the first drug approved for BRAF-mutant cancer

Key Points

  • The BRAF oncogene is found in 6–8% of all solid tumours, including about half of all melanomas.

  • Scaffold-based drug discovery was used to discover inhibitors of the BRAF oncogene.

  • Vemurafenib was identified as a selective inhibitor of oncogenic BRAF.

  • Preclinical studies supported the testing of the compound in patients with metastatic melanoma.

  • Significant clinical benefit was documented in patients with metastatic melanoma, validating the BRAF oncogene as a driver of these tumours. This led to regulatory approval of vemurafenib in the United States and Europe for the treatment of BRAF-mutant metastatic melanoma.

  • During the development of vemurafenib, an important unexpected finding was linked to some of the side effects: the RAF inhibitor paradox denotes inhibitor-induced RAF pathway activation in cells with elevated RAS signalling.

  • Future studies will explore the efficacy of vemurafenib in other tumours bearing the BRAF oncogene, and in combinations with other anticancer agents to improve the degree and durability of clinical benefit.

Abstract

The identification of driver oncogenes has provided important targets for drugs that can change the landscape of cancer therapies. One such example is the BRAF oncogene, which is found in about half of all melanomas as well as several other cancers. As a druggable kinase, oncogenic BRAF has become a crucial target of small-molecule drug discovery efforts. Following a rapid clinical development path, vemurafenib (Zelboraf; Plexxikon/Roche) was approved for the treatment of BRAF-mutated metastatic melanoma in the United States in August 2011 and the European Union in February 2012. This Review describes the underlying biology of BRAF, the technology used to identify vemurafenib and its clinical development milestones, along with future prospects based on lessons learned during its development.

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Figure 1: The RAF pathway.
Figure 2: From scaffold to lead compound.
Figure 3: Vemurafenib in xenograft models.
Figure 4: Structural studies of vemurafenib.
Figure 5: Pharmacokinetic analysis of vemurafenib exposure in human plasma.
Figure 6: Vemurafenib-mediated tumour regression.
Figure 7: PET scans of patients treated with vemurafenib.
Figure 8: Paired biopsy data from a Phase I clinical trial.

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Acknowledgements

The authors wish to thank all the employees of Plexxikon who contributed to the work described here. They also thank their colleagues at Roche, the clinical investigators and especially the patients.

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Correspondence to Gideon Bollag.

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All authors are employees of Plexxikon Inc., a member of the Daiichi Sankyo group.

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Glossary

Scaffolds

Moderately small molecules — typically 150–350 Da — discovered through screens that measure biochemical activity or in binding assays. Lead optimization of scaffolds usually involves decorating the scaffold with rationally designed substitutions.

Chemical space

The potential chemical diversity that is spanned by all possible combinations of atomic elements to yield all possible compounds encompassing all sizes and with all potential chemical and physical properties.

Fragment

A very small molecule — typically less than 250 Da — discovered through biophysical screening methods such as nuclear magnetic resonance (NMR) or X-ray technologies. Often, several fragments that represent discrete binding components will be linked together to enhance potency during lead optimization.

DFG motif

A motif (Asp-Phe-Gly) that marks the beginning of the activation loop and can assume one of two conformations based on the side-chain orientation of the central residue in the motif: 'DFG-in' and 'DFG-out'. The conformation of the DFG motif affects ATP substrate binding and the catalytic competency of the kinase.

Anchor and grow

A key design strategy of scaffold-based drug discovery, in which the scaffold serves as the anchor that remains constant throughout chemical exploration, and multiple analogues are synthesized systematically by adding substituents to branch points to access unoccupied sub-sites of the drug target.

αC helix

A structurally conserved helix that is present in one of the two lobes that flank the ATP-binding site of a protein kinase. Its conformation is crucial for ATP binding and kinase activity.

Investigational new drug application

A detailed report of compound characteristics, including synthetic and analytical methods, formulation, pharmacology and toxicology data and clinical plans, that is submitted to the US Food and Drug Administration to request approval to begin clinical testing.

Microprecipitated bulk powder

A stabilized formulation of vemurafenib consisting of amorphous (non-crystalline) microparticles that were prepared by precipitating vemurafenib into a polymer matrix; this process substantially improved the systemic absorption of vemurafenib.

Area under the curve

(AUC). A pharmacokinetic parameter that measures the integrated area under the plasma drug concentration curve as a function of time.

Elimination half-life

A pharmacokinetic parameter that measures the time it takes for half of a drug concentration to be eliminated from circulating plasma.

Preclinical scaling analyses

Methods for predicting the pharmacokinetic properties of a drug in humans by extrapolating from its pharmacokinetic properties in multiple animal species.

Adverse events

Adverse side effects graded, by the common toxicity criteria, from 0 (no adverse event) to 5 (fatal adverse event). Grade 1 adverse events are generally mild in severity.

Cutaneous squamous cell carcinoma

Neoplasm of the skin characterized by epithelial cells with a squamous histology.

Keratoacanthoma

A specific low-grade subtype of cutaneous squamous cell carcinoma with a characteristic morphology, believed to originate from the hair follicle.

Unconfirmed overall response rate

The percentage of patients with a partial or complete response recorded from the tumour-imaging scan that showed the highest tumour reduction.

Confirmed overall response rate

The percentage of patients with a partial or complete response who have shown maintenance of tumour reduction using a second tumour-imaging scan taken at least 4 weeks after the initial scan.

Complete response

Determined using RECIST (response evaluation criteria in solid tumours); indicates a 100% reduction in the combined width and length (two-dimensional measurements) of the target lesions of a tumour and no new tumour growth.

Dacarbazine

A chemotherapeutic that kills dividing cells by alkylating DNA and has been approved to treat metastatic melanoma.

Progression-free survival

The duration of time that a patient with cancer survives, in which a tumour does not increase by more than 20% in size.

Hazard ratio

A statistical analysis that measures the significance of a clinical end point by comparing the rate of events in two different cohorts: for example, patients who are not exposed and those who are exposed to a new agent. A hazard ratio of 1 means that there is no effect; a hazard ratio of 0.6 implies that the treated cohort has 60% of the hazard of the untreated cohort (that is, the agent reduces the hazard by 40%).

Neural crest cells

Immature cells found at the crest of the neural plate that give rise to various differentiated cells, including melanocytes.

RECIST

Response evaluation criteria in solid tumours; a set of standardized criteria that define whether patients with cancer have a partial or complete response and stable or progressive disease during treatments.

Partial response

Determined using RECIST (response evaluation criteria in solid tumours); indicates at least 30% reduction in the combined width and length (two-dimensional measurements) of the target lesions of a tumour and no new tumour growth.

On-target genetic alteration

In the context of resistance to a kinase inhibitor, this term refers to a mutation or other genetic alteration in the intended target of the inhibitor that makes the kinase insensitive to the inhibitor.

Cytotoxic T lymphocyte antigen 4

A receptor on the surface of T cells that mediates downregulation of the immune response.

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Bollag, G., Tsai, J., Zhang, J. et al. Vemurafenib: the first drug approved for BRAF-mutant cancer. Nat Rev Drug Discov 11, 873–886 (2012). https://doi.org/10.1038/nrd3847

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