Articles

Focus on the dabrafenib, vemurafenib, and trametinib in clinical outcome of melanoma: a systematic review and meta-analysis

Ida Ayu Widya Anjani , Anak Agung Bagus Putra Indrakusuma, I Gede Krisna Arim Sadeva, Putri Ayu Wulandari, Luh Made Mas Rusyati, Prima Sanjiwani Saraswati Sudarsa, I Gede Putu Supadmanaba, Desak Made Wihandani

Ida Ayu Widya Anjani
Udayana Univesity. Email: widyaanjani98@gmail.com

Anak Agung Bagus Putra Indrakusuma


I Gede Krisna Arim Sadeva


Putri Ayu Wulandari


Luh Made Mas Rusyati


Prima Sanjiwani Saraswati Sudarsa


I Gede Putu Supadmanaba


Desak Made Wihandani

Online First: December 15, 2020 | Cite this Article
Widya Anjani, I., Indrakusuma, A., Arim Sadeva, I., Wulandari, P., Rusyati, L., Sudarsa, P., Supadmanaba, I., Wihandani, D. 2020. Focus on the dabrafenib, vemurafenib, and trametinib in clinical outcome of melanoma: a systematic review and meta-analysis. Bali Dermatology and Venereology Journal 3(2). DOI:10.15562/bdv.v3i2.38


Background: Melanoma is the most serious lethal skin cancer, affects the melanin producer cells (melanocytes). Surgery is the most common treatment, whereas for the advance stage the development of a treatment is recommended. BRAF (Dabrafenib and Vemurafenib) inhibitor or MEK inhibitor (Trametinib) is used as the most frequently targeted therapy of melanoma due to more than 80% patient with positive BRAF mutation. In this review, those treatments will be investigated systematically to identify their clinical outcome.

Method: This systematic literature review (SLR) was performed from Cochrane, Science Direct, Google Scholar, and Pubmed. Cochrane Risk-of-Bias Tool RoB2 is used to assess RCT studies and New-castle Ottawa Scale Assessment to assess cohort studies by 3 different assessors. Data analysis was carried out by using Review Manager (RevMan 5.4). Heterogenicity test was assessed by I2  and Chi2 statistic

Result: There are 20 studies used in this article (13 RCT and 7 cohorts). The overall survival (OS) and progression-free survival (PFS) of study that using targeted therapy (vemurafenib, trametinib, or dabrafenib) compare other therapies (chemotherapy, immunotherapy,etc) showed risk ratio (RR) was 1.12 (95%CI 1.07,1.17;  I2=100%; p<0,00001). The OS and PFS with monotherapy compare of vemurafenib, trametinib, or dabrafenib with combination therapy showed RR was 1.09 (95%CI.06,1.13;I2=99%; p<0,00001).

Conclusion: BRAF and MEK targeted therapy has a good prognosis for a patient with a positive BRAF gene mutation and could be combined with other therapy for a better clinical outcome rather than monotherapy.

Keyword: melanoma, dabrafenib, vemurafenib, and trametinib

References

Guterres AN, Herlyn M, Villanueva J. Melanoma. ASHA Lead. 2018;23(7):1-10. doi:10.1044/leader.ppl.23072018.22

Das PK, Jadon S, Pradhan S, Kar DM. A review article on melanoma. J Pharm Sci Res. 2016;8(2):112-117.

Centers for Disease Control and Prevention. Melanoma Incidence and Mortality, United States—2012–2016. USCS Data Br. 2014;(9):2014-2016. Accessed August 9, 2020

Rastrelli M, Tropea S, Rossi CR, Alaibac M. Melanoma: Epidemiology, risk factors, pathogenesis, diagnosis and classification. in vivo (Brooklyn). 2014;28:1005-1012. doi:10.32388/7xj0gw

Melanoma Survival Rates. https://www.curemelanoma.org/about-melanoma/melanoma-staging/melanoma-survival-rates/. Published 2020. Accessed August 9, 2020.

Memorial Sloan Kettering Cancer Center. Targeted Therapy for Melanoma.

Spathis A, Katoulis AC, Damaskou V, et al. Dermatology Practical & Conceptual BRAF Mutation Status in Primary , Recurrent , and Metastatic Malignant Melanoma and Its Relation to Histopathological Parameters. 2019;9(1):54-62. doi: 10.5826/dpc.0901a13

AIM at Melanoma Foundation. BRAF in Melanoma.; 2020.

Croce L, Coperchini F, Magri F, Chiovato L. The multifaceted anti-cancer effects of BRAF-inhibitors. 2019;10(61):6623-6640.doi: 10.18632/oncotarget.27304

Boni A, Cogdill AP, Dang P, et al. Selective BRAF V600E Inhibition Enhances T-Cell Recognition of Melanoma without Affecting Lymphocyte Function. 2010;(9):5213-5220. doi:10.1158/0008-5472.CAN-10-0118

Ascierto PA, Kirkwood JM, Grob JJ, et al. The role of BRAF V600 mutation in melanoma. J Transl Med. 2012;10(1):85. doi:10.1186/1479-5876-10-85

Heistein JB, Acharya U. Cancer, Malignant Melanoma. StatPearls Publishing; 2019.

Hauschild A, Grob JJ, Demidov L V., et al. An update on BREAK-3, a phase III, randomized trial: Dabrafenib (DAB) versus dacarbazine (DTIC) in patients with BRAF V600E-positive mutation metastatic melanoma (MM). J Clin Oncol. 2013;31(15_suppl):9013-9013. doi:10.1200/jco.2013.31.15_suppl.9013

Hauschild A, Grob JJ, Demidov L V., et al. Dabrafenib in BRAF-mutated metastatic melanoma: A multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380(9839):358-365. doi:10.1016/S0140-6736(12)60868-X

McArthur GA, Chapman PB, Robert C, et al. Safety and efficacy of vemurafenib in BRAFV600E and BRAFV600K mutation-positive melanoma (BRIM-3): Extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol. 2014;15(3):323-332. doi:10.1016/S1470-2045(14)70012-9

Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507-2516. doi:10.1056/NEJMoa1103782

Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367(2):107-114. doi:10.1056/NEJMoa1203421

Stjepanovic N, Bedard PL. Ocular toxicities of MEK inhibitors and other targeted therapies. Ann Oncol. 2016;27(6):998-1005. doi:10.1093/annonc/mdw100

Keith T. Flaherty, Caroline Robert, Peter Hersey, Paul Nathan, Claus Garbe, Moahammed Milhem, Lev V. Demidov, Jessica C. Hassel. Piotr Rutkowski, Peter Mohr, Reinhard Dummer, Uwe Trefzer, Mark R. Middleton, Jurgen C. Becker, Michelle Casey, Laurie J. Sher DS. Improved survival with MEK Inhibition in BRAF-mutated melanoma for the METRIC Study Group. 2012;367(2). doi:10.5167/uzh-63198

Schilling B, Sondermann W, Zhao F, et al. Differential influence of vemurafenib and dabrafenib on patients’ lymphocytes despite similar clinical efficacy in melanoma. Ann Oncol. 2014;25(3):747-753. doi:10.1093/annonc/mdt587

Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2014:1-11. doi:10.1056/NEJMoa1412690

Chapman PB, Robert C, Larkin J, et al. Vemurafenib in patients with BRAFV600 mutation-positive metastatic melanoma: Final overall survival results of the randomized BRIM-3 study. Ann Oncol. 2017;28(10):2581-2587.doi:10.1093/annonc/mdx339

Long G V., Flaherty KT, Stroyakovskiy D, et al. Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/ K-mutant melanoma: Long-term survival and safety analysis of a phase 3 study. Ann Oncol. 2017;28(7):1631-1639. doi:10.1093/annonc/mdx176

Amaria RN, Prieto PA, Tetzlaff MT, et al. Neoadjuvant plus adjuvant dabrafenib and trametinib versus standard of care in patients with high-risk, surgically resectable melanoma: a single-centre, open-label, randomised, phase 2 trial. Lancet Oncol. 2018;19(2):181-193. doi:10.1016/S1470-2045(18)30015-9

Brzozowska M, Wierzba W, Śliwczyński A, Świerkowski M, Potemski P, Marczak M. Analysis of survival of patients treated with vemurafenib, ipilimumab and dabrafenib for advanced skin melanoma in daily clinical practice (Real-World Data): Retrospective analysis of patients treated under drug/reimbursement programmes in Poland in 2013-. Melanoma Res. 2018;28(1):52-55.doi:10.1097/CMR.0000000000000408

Dummer R, Ascierto PA, Gogas HJ, et al. Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2018;19(10):1315-1327. doi:10.1016/S1470-2045(18)30497-2

Urbonas V, Schadendorf D, Zimmer L, et al. Paclitaxel with or without trametinib or pazopanib in advanced wild-type braf melanoma (pacmel): A multicentre, open-label, randomised, controlled phase II trial. Ann Oncol. 2019;30(2):317-324. doi:10.1093/annonc/mdy500

Robert C, Grob JJ, Stroyakovskiy D, et al. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. N Engl J Med. 2019;381(7):626-636. doi:10.1056/NEJMoa1904059

Robert C, Flaherty K, Nathan P, et al. Five-year outcomes from a phase 3 METRIC study in patients with BRAF V600 E/K–mutant advanced or metastatic melanoma. Eur J Cancer. 2019;109:61-69. doi:10.1016/j.ejca.2018.12.015

Ascierto PA, Dummer R, Gogas HJ, et al. Update on tolerability and overall survival in COLUMBUS: landmark analysis of a randomised phase 3 trial of encorafenib plus binimetinib vs vemurafenib or encorafenib in patients with BRAF V600–mutant melanoma. Eur J Cancer. 2020;126:33-44. doi:10.1016/j.ejca.2019.11.016

Puzanov I, Amaravadi RK, McArthur GA, et al. Long-term outcome in BRAFV600E melanoma patients treated with vemurafenib: Patterns of disease progression and clinical management of limited progression. Eur J Cancer. 2015;51(11):1435-1443. doi:10.1016/j.ejca.2015.04.010

Scholtens A, Geukes Foppen MH, Blank CU, Van Thienen J V., Van Tinteren H, Haanen JB. Vemurafenib for BRAF V600 mutated advanced melanoma: Results of treatment beyond progression. Eur J Cancer. 2015;51(5):642-652. doi:10.1016/j.ejca.2015.01.009

Kim HK, Lee S, Kim K, et al. Efficacy of BRAF inhibitors in Asian metastatic melanoma patients: Potential implications of genomic sequencing in BRAF-mutated melanoma. Transl Oncol. 2016;9(6):557-564. doi:10.1016/j.tranon.2016.09.004

Long G V., Weber JS, Infante JR, et al. Overall survival and durable responses in patients with BRAF V600-mutant metastatic melanoma receiving dabrafenib combined with trametinib. J Clin Oncol. 2016;34(8):871-878. doi:10.1200/JCO.2015.62.9345

Lang BM, Peveling-Oberhag A, Faidt D, et al. Long-term survival with modern therapeutic agents against metastatic melanoma—vemurafenib and ipilimumab in a daily life setting. Med Oncol. 2018;35(3). doi:10.1007/s12032-018-1084-9

Martin-Algarra S, Hinshelwood R, Mesnage S, et al. Effectiveness of dabrafenib in the treatment of patients with braf v600-mutated metastatic melanoma in a named patient program. Melanoma Res. 2019;29(5):527-532. doi:10.1097/CMR.0000000000000608

Lewis KD, Larkin J, Ribas A, et al. Impact of depth of response on survival in patients treated with cobimetinib ± vemurafenib: pooled analysis of BRIM-2, BRIM-3, BRIM-7 and coBRIM. Br J Cancer. 2019;121(7):522-528. doi:10.1038/s41416-019-0546-y

Sullivan RJ, Hamid O, Gonzalez R, et al. Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients. Nat Med. 2019;25(6):929-935. doi:10.1038/s41591-019-0474-7

Yu Q, Lu Y. Clinical outcomes of BRAF plus MEK inhibition in melanoma : A meta ‐ analysis and systematic review. 2019;(April):5414-5424. doi:10.1002/cam4.2248

Amaria RN, Prieto PA, Tetzlaff MT, et al. Vemurafenib in patients with BRAFV600 mutation-positive metastatic melanoma: Final overall survival results of the randomized BRIM-3 study. Lancet Oncol. 2018;28(2):1437-1448.doi:10.1016/j.ejca.2019.11.016


No Supplementary Material available for this article.
Article Views      : 77
PDF Downloads : 35