Kinase protein family that includes MAP, RAS, RAF, MEK and ERK play an important role regulating intracellular and extracellular signaling pathways which control cellular growth, differentiation, transformation and programmed death (apoptosis). In a normal cell line, these kinases work accordingly in a cascade of phosphorylation and dephosphorylation when stimulated by growth factors and eventually leading to regulation of cellular growth and proliferation in an organized manner. However, if the genes coding for these kinases have mutations, this can lead to uninhibited continuous growth of the cell which is manifested clinically by cancer formation.
Rapidly Accelerated Fibrosarcoma (RAF) family was first described in 1983 and was named as such due to its role in inducing fibrosarcoma in certain mice models.[1] The RAF family has three different isoforms (ARAF, BRAF, and CRAF) that have distinct independent genes coding for each one. B-RAF first came into the spotlight of clinical significance in 2002 when its mutations were reported to be present in 66% of malignant melanomas and in other studies it was found that BRAF mutations can reach up to 80%.[2][3] Later, BRAF mutations were found to be present in 40-70% of papillary thyroid carcinomas,[4][5] and also with colorectal cancer, hepatocellular carcinoma and approximately 100% of hairy cell leukemia cells.[6] Moreover, BRAF mutations are associated with more aggressive malignant behavior with increased mortality when present in tumor cells.[7]
The most common activating mutation in BRAF is the substitution of glutamic acid for valine at amino acid codon 600 (V600E mutation) and less commonly is the V600K which is the substitution of lysine for valine. In clinical practice, several medications which inhibit BRAF have been approved for the treatment of malignant melanoma with positive BRAF mutations. These medications did not show similar efficacy in other cancers harboring the BRAF mutation other than malignant melanoma. The first BRAF inhibitor that came into clinical use was Vemurafenib.
Indications:
Vemurafenib has been approved through BRIM trials (phase I, II, III) after showing increased overall survival and progression-free survival in studied patients with malignant melanoma with BRAF V600E positive mutation. The phase I BRIM established the optimal dose of the medication which was found to be 960 mg twice a day taken orally.[8] Phase II BRIM trial showed an overall response rate of 53% ranging between partial and complete response and the median duration of response was 6.7 months.[9] Lastly, phase III BRIM trial was a multicenter randomized controlled trial to compare the efficacy of vemurafenib versus dacarbazine which was the standard of treatment for metastatic melanoma.[10] The study found increased overall survival and progression-free survival in the arm treated with vemurafenib versus dacarbazine. However, this was confounded by the crossover that took place from the dacarbazine group to vemurafenib during an interim analysis that showed greater efficacy and response rate in the arm treated with BRAF inhibitor (vemurafenib). Ultimately, the eventual statistical analysis that accounted for this crossover still showed more favorable response with vemurafenib in patients with Stage IIIC and IV melanoma with BRAF V600E mutation and resulted in an FDA approval of the drug in August 2011.
FDA-labeled Indications:
Non FDA-labeled Indications:
Vemurafenib is a potent highly selective inhibitor of mutated BRAF V600E. By inhibiting the kinase activity of BRAF, this prevents signaling from Mitogen-Activated Pathway (MAP) kinase pathway and blocks proliferation of malignant cells that harbor this specific mutation. The medication does not have activity in wild-type BRAF cells, unlike other drugs like sorafenib which can block both wild-type and mutated BRAF.[13] Interestingly, it was noted that during treatment at some point there would be a progression of the disease and this was attributed to resistance of the MAP kinase pathway to BRAF inhibitor (vemurafenib). The mechanism of resistance is still unknown and is a current subject for investigation. Resistance was described to occur in the MAP kinase pathway to vemurafenib and that what prompted more clinical trials which showed more efficacy of combination therapy with MEK inhibitors like trametinib in the treatment of malignant melanomas with positive BRAF V600E.[14]
BRIM II trial established the effective, nontoxic dose of Vemurafenib to be 960 mg taken twice a day. When taken orally, the medication reaches its peak concentration in plasma within 3 hours. The half-life ranges between 30-120 hours and achieves a plasma steady state within 15 to 22 days. The medication is started twice daily with a 12-hour interval between the two doses and should be stopped if there is a progression of melanoma or high-grade toxicity.[15]
The most common adverse events noticed with the use of vemurafenib are cutaneous manifestations which include but not limited to nonspecific maculopapular eruptions, hyperkeratosis, and photosensitivity especially with radiation therapy.
One of the most significant cutaneous adverse events with the use of vemurafenib is skin cancers including squamous cell carcinoma and keratoacanthoma in approximately up to 30% of cases and less commonly the development of new primary melanoma.[16] This adverse effect usually develops within weeks of starting treatment and is medically managed with surgical resection without discontinuation of the BRAF inhibitors. Also, development of secondary melanoma could happen during therapy and is due to paradoxical activation of the MAP kinase pathway, and clinical trials have shown that combination of BRAF inhibitors with MEK inhibitors associate with a decreased risk of skin tumors but more cutaneous side effects.[17]
Other adverse events include hepatotoxicity, particularly when used when immunotherapy, QT prolongation, arthralgia, and diarrhea are present.
There are some anecdotal reports of Dupuytren’s contracture and acute pancreatitis developing after the use of vemurafenib.
No absolute contraindications exist regarding the use of vemurafenib, and the only mentioned contraindication is hypersensitivity to Vemurafenib which rarely occurs during treatment.
Perform careful skin examination after initiation of therapy to look for any development of skin tumors including (squamous cell carcinoma, keratoacanthoma, and melanoma).
Testing
Medication dose adjustments according to the severity of toxic reactions may be necessary.
The standard dose is 960 mg twice daily and could be reduced to 720 mg twice daily if toxicity occurs for the first time. Further dose reduction is required if toxicity recurs for the second time and with high-grade toxicity with recommendations to reduce the dose to 480 mg twice daily and doses less than that are therapeutically inactive.
Vemurafenib is the first BRAF inhibitor that is used to treated advanced malignant melanoma. Early results show that it may prolong life for several months, but the drug is also prohibitively expensive and has several severe adverse effects. The oncology nurse and the pharmacist must educate the patient on the importance of monitoring their skin for new skin cancers. Additionally, these patients need regular monitoring of their liver and renal function.
[1] | Rapp UR,Goldsborough MD,Mark GE,Bonner TI,Groffen J,Reynolds FH Jr,Stephenson JR, Structure and biological activity of v-raf, a unique oncogene transduced by a retrovirus. Proceedings of the National Academy of Sciences of the United States of America. 1983 Jul [PubMed PMID: 6308607] |
[2] | Davies H,Bignell GR,Cox C,Stephens P,Edkins S,Clegg S,Teague J,Woffendin H,Garnett MJ,Bottomley W,Davis N,Dicks E,Ewing R,Floyd Y,Gray K,Hall S,Hawes R,Hughes J,Kosmidou V,Menzies A,Mould C,Parker A,Stevens C,Watt S,Hooper S,Wilson R,Jayatilake H,Gusterson BA,Cooper C,Shipley J,Hargrave D,Pritchard-Jones K,Maitland N,Chenevix-Trench G,Riggins GJ,Bigner DD,Palmieri G,Cossu A,Flanagan A,Nicholson A,Ho JW,Leung SY,Yuen ST,Weber BL,Seigler HF,Darrow TL,Paterson H,Marais R,Marshall CJ,Wooster R,Stratton MR,Futreal PA, Mutations of the BRAF gene in human cancer. Nature. 2002 Jun 27 [PubMed PMID: 12068308] |
[3] | Lee B,Mukhi N,Liu D, Current management and novel agents for malignant melanoma. Journal of hematology [PubMed PMID: 22333219] |
[4] | Cohen Y,Xing M,Mambo E,Guo Z,Wu G,Trink B,Beller U,Westra WH,Ladenson PW,Sidransky D, BRAF mutation in papillary thyroid carcinoma. Journal of the National Cancer Institute. 2003 Apr 16 [PubMed PMID: 12697856] |
[5] | Huang T,Zhuge J,Zhang WW, Sensitive detection of BRAF V600E mutation by Amplification Refractory Mutation System (ARMS)-PCR. Biomarker research. 2013 Jan 16 [PubMed PMID: 24252159] |
[6] | Ziai J,Hui P, BRAF mutation testing in clinical practice. Expert review of molecular diagnostics. 2012 Mar [PubMed PMID: 22369373] |
[7] | Xing M,Alzahrani AS,Carson KA,Viola D,Elisei R,Bendlova B,Yip L,Mian C,Vianello F,Tuttle RM,Robenshtok E,Fagin JA,Puxeddu E,Fugazzola L,Czarniecka A,Jarzab B,O'Neill CJ,Sywak MS,Lam AK,Riesco-Eizaguirre G,Santisteban P,Nakayama H,Tufano RP,Pai SI,Zeiger MA,Westra WH,Clark DP,Clifton-Bligh R,Sidransky D,Ladenson PW,Sykorova V, Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer. JAMA. 2013 Apr 10 [PubMed PMID: 23571588] |
[8] | Flaherty KT,Puzanov I,Kim KB,Ribas A,McArthur GA,Sosman JA,O'Dwyer PJ,Lee RJ,Grippo JF,Nolop K,Chapman PB, Inhibition of mutated, activated BRAF in metastatic melanoma. The New England journal of medicine. 2010 Aug 26 [PubMed PMID: 20818844] |
[9] | Sosman JA,Kim KB,Schuchter L,Gonzalez R,Pavlick AC,Weber JS,McArthur GA,Hutson TE,Moschos SJ,Flaherty KT,Hersey P,Kefford R,Lawrence D,Puzanov I,Lewis KD,Amaravadi RK,Chmielowski B,Lawrence HJ,Shyr Y,Ye F,Li J,Nolop KB,Lee RJ,Joe AK,Ribas A, Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. The New England journal of medicine. 2012 Feb 23 [PubMed PMID: 22356324] |
[10] | Chapman PB,Hauschild A,Robert C,Haanen JB,Ascierto P,Larkin J,Dummer R,Garbe C,Testori A,Maio M,Hogg D,Lorigan P,Lebbe C,Jouary T,Schadendorf D,Ribas A,O'Day SJ,Sosman JA,Kirkwood JM,Eggermont AM,Dreno B,Nolop K,Li J,Nelson B,Hou J,Lee RJ,Flaherty KT,McArthur GA, Improved survival with vemurafenib in melanoma with BRAF V600E mutation. The New England journal of medicine. 2011 Jun 30 [PubMed PMID: 21639808] |
[11] | Haroche J,Cohen-Aubart F,Emile JF,Maksud P,Drier A,Tolédano D,Barete S,Charlotte F,Cluzel P,Donadieu J,Benameur N,Grenier PA,Besnard S,Ory JP,Lifermann F,Idbaih A,Granel B,Graffin B,Hervier B,Arnaud L,Amoura Z, Reproducible and sustained efficacy of targeted therapy with vemurafenib in patients with BRAF(V600E)-mutated Erdheim-Chester disease. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2015 Feb 10 [PubMed PMID: 25422482] |
[12] | Planchard D,Kim TM,Mazieres J,Quoix E,Riely G,Barlesi F,Souquet PJ,Smit EF,Groen HJ,Kelly RJ,Cho BC,Socinski MA,Pandite L,Nase C,Ma B,D'Amelio A Jr,Mookerjee B,Curtis CM Jr,Johnson BE, Dabrafenib in patients with BRAF(V600E)-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial. The Lancet. Oncology. 2016 May [PubMed PMID: 27080216] |
[13] | Tsai J,Lee JT,Wang W,Zhang J,Cho H,Mamo S,Bremer R,Gillette S,Kong J,Haass NK,Sproesser K,Li L,Smalley KS,Fong D,Zhu YL,Marimuthu A,Nguyen H,Lam B,Liu J,Cheung I,Rice J,Suzuki Y,Luu C,Settachatgul C,Shellooe R,Cantwell J,Kim SH,Schlessinger J,Zhang KY,West BL,Powell B,Habets G,Zhang C,Ibrahim PN,Hirth P,Artis DR,Herlyn M,Bollag G, Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proceedings of the National Academy of Sciences of the United States of America. 2008 Feb 26 [PubMed PMID: 18287029] |
[14] | Larkin J,Ascierto PA,Dréno B,Atkinson V,Liszkay G,Maio M,Mandalà M,Demidov L,Stroyakovskiy D,Thomas L,de la Cruz-Merino L,Dutriaux C,Garbe C,Sovak MA,Chang I,Choong N,Hack SP,McArthur GA,Ribas A, Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. The New England journal of medicine. 2014 Nov 13 [PubMed PMID: 25265494] |
[15] | Nazarian R,Shi H,Wang Q,Kong X,Koya RC,Lee H,Chen Z,Lee MK,Attar N,Sazegar H,Chodon T,Nelson SF,McArthur G,Sosman JA,Ribas A,Lo RS, Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010 Dec 16 [PubMed PMID: 21107323] |
[16] | Robert C,Soria JC,Spatz A,Le Cesne A,Malka D,Pautier P,Wechsler J,Lhomme C,Escudier B,Boige V,Armand JP,Le Chevalier T, Cutaneous side-effects of kinase inhibitors and blocking antibodies. The Lancet. Oncology. 2005 Jul [PubMed PMID: 15992698] |
[17] | Carlos G,Anforth R,Clements A,Menzies AM,Carlino MS,Chou S,Fernandez-Peñas P, Cutaneous Toxic Effects of BRAF Inhibitors Alone and in Combination With MEK Inhibitors for Metastatic Melanoma. JAMA dermatology. 2015 Oct [PubMed PMID: 26200476] |