Melanoma, BRAF-mutated

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Note: these are regimens tested in biomarker-specific populations, please see the main melanoma page for other regimens.
For placebo or observational studies in this condition, please visit this page.
Last updated on 2024-09-06:13 regimens on this page
13 variants on this page
=Guidelines=
Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.
==NCCN==
*NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Melanoma: Cutaneous.
=Adjuvant therapy=
==Dabrafenib & Trametinib==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Long et al. 2017 (COMBI-AD)	2013-01 to 2014-12 	Phase 3 (E-RT-esc)	Placebo 	Longer RFS1 (primary endpoint)Median RFS: 93.1 vs 16.6 mo(HR 0.52, 95% CI 0.43-0.63)Longer MFS1 (secondary endpoint)MFS120: 63% vs 48%(HR 0.56, 95% CI 0.44-0.71)Might have longer OS1 (secondary endpoint)OS96: 71% vs 65%(HR 0.80, 95% CI 0.62-1.01)
1Reported efficacy is based on the 2024 update.
====Preceding treatment====
*Completion lymphadenectomy, within 12 weeks
====Targeted therapy====
*Dabrafenib (Tafinlar) 150 mg PO twice per day
*Trametinib (Mekinist) 2 mg PO once per day
Up to 12-month course
===References===
#COMBI-AD: Long GV, Hauschild A, Santinami M, Atkinson V, Mandalà M, Chiarion-Sileni V, Larkin J, Nyakas M, Dutriaux C, Haydon A, Robert C, Mortier L, Schachter J, Schadendorf D, Lesimple T, Plummer R, Ji R, Zhang P, Mookerjee B, Legos J, Kefford R, Dummer R, Kirkwood JM. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017 Nov 9;377(19):1813-1823. Epub 2017 Sep 10. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01682083
##Update: Hauschild A, Dummer R, Schadendorf D, Santinami M, Atkinson V, Mandalà M, Chiarion-Sileni V, Larkin J, Nyakas M, Dutriaux C, Haydon A, Robert C, Mortier L, Schachter J, Lesimple T, Plummer R, Dasgupta K, Haas T, Shilkrut M, Gasal E, Kefford R, Kirkwood JM, Long GV. Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in Patients With Resected BRAF V600-Mutant Stage III Melanoma. J Clin Oncol. 2018 Dec 10;36(35):3441-3449. Epub 2018 Oct 22. link to original article link to PMC article EuroPMC
## PRO analysis: Schadendorf D, Hauschild A, Santinami M, Atkinson V, Mandalà M, Chiarion-Sileni V, Larkin J, Nyakas M, Dutriaux C, Haydon A, Robert C, Mortier L, Lesimple T, Plummer R, Schachter J, Dasgupta K, Manson S, Koruth R, Mookerjee B, Kefford R, Dummer R, Kirkwood JM, Long GV. Patient-reported outcomes in patients with resected, high-risk melanoma with BRAFV600E or BRAFV600K mutations treated with adjuvant dabrafenib plus trametinib (COMBI-AD): a randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 May;20(5):701-710. Epub 2019 Mar 27. link to original article EuroPMC
## Update: Dummer R, Hauschild A, Santinami M, Atkinson V, Mandalà M, Kirkwood JM, Chiarion Sileni V, Larkin J, Nyakas M, Dutriaux C, Haydon A, Robert C, Mortier L, Schachter J, Lesimple T, Plummer R, Dasgupta K, Gasal E, Tan M, Long GV, Schadendorf D. Five-Year Analysis of Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma. N Engl J Med. 2020 Sep 17;383(12):1139-1148. Epub 2020 Sep 2. link to original article EuroPMC
##Update: Long GV, Hauschild A, Santinami M, Kirkwood JM, Atkinson V, Mandala M, Merelli B, Sileni VC, Nyakas M, Haydon A, Dutriaux C, Robert C, Mortier L, Schachter J, Schadendorf D, Lesimple T, Plummer R, Larkin J, Tan M, Adnaik SB, Burgess P, Jandoo T, Dummer R. Final Results for Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma. N Engl J Med. 2024 Nov 7;391(18):1709-1720. Epub 2024 Jun 19. link to original article EuroPMC
==Vemurafenib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Maio et al. 2018 (BRIM8)	2012-2015 	Phase 3 (E-esc)	Placebo 	Did not meet primary endpoint of DFS1Median DFS: 23.1 vs 15.4 mo(HR 0.80, 95% CI 0.54-1.18)
1Reported efficacy is based on the results for cohort 2, which was analyzed first as per the prespecified approach.
====Preceding treatment====
*Complete resection, timing not specified
====Targeted therapy====
*Vemurafenib (Zelboraf) 960 mg PO twice per day 
28-day cycle for 13 cycles (1 year)
===References===
#BRIM8: Maio M, Lewis K, Demidov L, Mandalà M, Bondarenko I, Ascierto PA, Herbert C, Mackiewicz A, Rutkowski P, Guminski A, Goodman GR, Simmons B, Ye C, Yan Y, Schadendorf D; BRIM8 Investigators. Adjuvant vemurafenib in resected, BRAF(V600) mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Oncol. 2018 Apr;19(4):510-520. Epub 2018 Feb 21. Erratum in: Lancet Oncol. 2018 Apr;19(4):e184. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01667419
##HRQoL analysis: Schadendorf D, Di Giacomo AM, Demidov L, Merelli B, Bondarenko I, Ascierto PA, Herbert C, Mackiewicz A, Rutkowski P, Guminski A, Goodman GR, Simmons B, Ye C, Hong A, Lewis K; BRIM8 Investigators. Health-related quality of life in patients with fully resected BRAFV600 mutation-positive melanoma receiving adjuvant vemurafenib. Eur J Cancer. 2019 Dec;123:155-161. Epub 2019 Nov 5. link to original article EuroPMC
=Advanced or metastatic disease, BRAF inhibitor-naive=
==Binimetinib & Encorafenib==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Dummer et al. 2018 (COLUMBUS)	2013-12-30 to 2015-04-10	Phase 3 (E-RT-esc)	1. Encorafenib	Not reported
Dummer et al. 2018 (COLUMBUS)	2013-12-30 to 2015-04-10	Phase 3 (E-RT-esc)	2. Vemurafenib	Longer PFS (primary endpoint)Median PFS: 14.9 vs 7.3 mo(HR 0.54, 95% CI 0.41-0.71)Longer OS1 (secondary endpoint)Median OS: 33.6 vs 16.9 mo(HR 0.61, 95% CI 0.48-0.79)
1Reported efficacy is based on the 2020 update.
====Targeted therapy====
*Binimetinib (Mektovi) 45 mg PO twice per day on days 1 to 28
*Encorafenib (Braftovi) 450 mg PO once per day on days 1 to 28
28-day cycles
===References===
#COLUMBUS: Dummer R, Ascierto PA, Gogas HJ, Arance A, Mandala M, Liszkay G, Garbe C, Schadendorf D, Krajsova I, Gutzmer R, Chiarion-Sileni V, Dutriaux C, de Groot JWB, Yamazaki N, Loquai C, Moutouh-de Parseval LA, Pickard MD, Sandor V, Robert C, Flaherty KT. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):603-615. Epub 2018 Mar 21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01909453
##Update: Dummer R, Ascierto PA, Gogas HJ, Arance A, Mandala M, Liszkay G, Garbe C, Schadendorf D, Krajsova I, Gutzmer R, Chiarion Sileni V, Dutriaux C, de Groot JWB, Yamazaki N, Loquai C, Moutouh-de Parseval LA, Pickard MD, Sandor V, Robert C, Flaherty KT. 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 Oct;19(10):1315-1327. Epub 2018 Sep 12. Erratum in: Lancet Oncol. 2018 Oct;19(10):e509. link to original article EuroPMC
## Update: Ascierto PA, Dummer R, Gogas HJ, Flaherty KT, Arance A, Mandala M, Liszkay G, Garbe C, Schadendorf D, Krajsova I, Gutzmer R, de Groot JWB, Loquai C, Gollerkeri A, Pickard MD, Robert C. 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 Feb;126:33-44. Epub 2020 Jan 2. link to original article EuroPMC
## Update: Dummer R, Flaherty KT, Robert C, Arance A, de Groot JWB, Garbe C, Gogas HJ, Gutzmer R, Krajsová I, Liszkay G, Loquai C, Mandalà M, Schadendorf D, Yamazaki N, di Pietro A, Cantey-Kiser J, Edwards M, Ascierto PA. COLUMBUS 5-Year Update: A Randomized, Open-Label, Phase III Trial of Encorafenib Plus Binimetinib Versus Vemurafenib or Encorafenib in Patients With BRAF V600-Mutant Melanoma. J Clin Oncol. 2022 Dec 20;40(36):4178-4188. Epub 2022 Jul 21. link to original article link to PMC article EuroPMC
##Update: Ascierto PA, Dummer R, Gogas HJ, Arance A, Mandala M, Liszkay G, Garbe C, Schadendorf D, Krajsova I, Gutzmer R, Chiarion-Sileni V, Dutriaux C, de Groot JWB, Yamazaki N, Loquai C, Robert C, Flaherty KT. Contribution of MEK Inhibition to BRAF/MEK Inhibitor Combination Treatment of BRAF-Mutant Melanoma: Part 2 of the Randomized, Open-Label, Phase III COLUMBUS Trial. J Clin Oncol. 2023 Oct 10;41(29):4621-4631. Epub 2023 Jul 28. link to original article link to PMC article EuroPMC
##Update: Schadendorf D, Dummer R, Flaherty KT, Robert C, Arance A, de Groot JWB, Garbe C, Gogas HJ, Gutzmer R, Krajsová I, Liszkay G, Loquai C, Mandalà M, Yamazaki N, Queirolo P, Guenzel C, Polli A, Thakur M, di Pietro A, Ascierto PA. COLUMBUS 7-year update: A randomized, open-label, phase III trial of encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF V600E/K-mutant melanoma. Eur J Cancer. 2024 Jun;204:114073. Epub 2024 Apr 24. link to original article interactive data visualization EuroPMC
==Cobimetinib & Vemurafenib==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Larkin et al. 2014 (coBRIM) 	2013-01 to 2014-01 	Phase 3 (E-RT-esc)	Vemurafenib 	Longer PFS1 (primary endpoint)Median PFS: 12.3 vs 7.2 mo(HR 0.58, 95% CI 0.46-0.72)Longer OS1 (secondary endpoint)Median OS: 22.3 vs 17.4 mo(HR 0.70, 95% CI 0.55-0.90)
Gutzmer et al. 2020 (IMspire150)	2017-01-13 to 2018-04-26	Phase 3 (C) 	Cobimetinib, Vemurafenib, Atezolizumab	Seems to have shorter PFSMedian PFS: 10.6 vs 15.1 mo(HR 1.28, 95% CI 1.03-1.59)
1Reported efficacy for coBRIM is based on the 2016 update.
====Targeted therapy====
*Cobimetinib (Cotellic) 60 mg PO once per day on days 1 to 21
*Vemurafenib (Zelboraf) 960 mg PO twice per day on days 1 to 28
28-day cycles
===References===
#coBRIM: 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. N Engl J Med. 2014 Nov 13;371(20):1867-76. Epub 2014 Sep 29. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01689519
##Update: Ascierto PA, McArthur GA, Dréno B, Atkinson V, Liszkay G, Di Giacomo AM, Mandalà M, Demidov L, Stroyakovskiy D, Thomas L, de la Cruz-Merino L, Dutriaux C, Garbe C, Yan Y, Wongchenko M, Chang I, Hsu JJ, Koralek DO, Rooney I, Ribas A, Larkin J. Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 2016 Sep;17(9):1248-60. Epub 2016 Jul 30. link to original article EuroPMC
#IMspire150: Gutzmer R, Stroyakovskiy D, Gogas H, Robert C, Lewis K, Protsenko S, Pereira RP, Eigentler T, Rutkowski P, Demidov L, Manikhas GM, Yan Y, Huang KC, Uyei A, McNally V, McArthur GA, Ascierto PA. Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAFV600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020 Jun 13;395(10240):1835-1844. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02908672
##Update: Ascierto PA, Stroyakovskiy D, Gogas H, Robert C, Lewis K, Protsenko S, Pereira RP, Eigentler T, Rutkowski P, Demidov L, Zhukova N, Schachter J, Yan Y, Caro I, Hertig C, Xue C, Kusters L, McArthur GA, Gutzmer R. Overall survival with first-line atezolizumab in combination with vemurafenib and cobimetinib in BRAFV600 mutation-positive advanced melanoma (IMspire150): second interim analysis of a multicentre, randomised, phase 3 study. Lancet Oncol. 2023 Jan;24(1):33-44. Epub 2022 Nov 29. link to original article EuroPMC
==Cobimetinib, Vemurafenib, Atezolizumab==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Gutzmer et al. 2020 (IMspire150)	2017-01-13 to 2018-04-26	Phase 3 (E-RT-esc)	Cobimetinib & Vemurafenib	Seems to have longer PFS (primary endpoint)Median PFS: 15.1 vs 10.6 mo(HR 0.78, 95% CI 0.63-0.97)
====Targeted therapy====
*Cobimetinib (Cotellic) 60 mg PO once per day on days 1 to 21
*Vemurafenib (Zelboraf) as follows:
**Cycle 1: 960 mg PO twice per day on days 1 to 21, then 720 mg PO twice per day on days 22 to 28
**Cycle 2 onwards: 720 mg PO twice per day on days 1 to 28
====Immunotherapy====
*Atezolizumab (Tecentriq) as follows:
**Cycle 2 onwards: 840 mg IV once per day on days 1 & 15
28-day cycles
===References===
#IMspire150: Gutzmer R, Stroyakovskiy D, Gogas H, Robert C, Lewis K, Protsenko S, Pereira RP, Eigentler T, Rutkowski P, Demidov L, Manikhas GM, Yan Y, Huang KC, Uyei A, McNally V, McArthur GA, Ascierto PA. Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAFV600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020 Jun 13;395(10240):1835-1844. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02908672
##Update: Ascierto PA, Stroyakovskiy D, Gogas H, Robert C, Lewis K, Protsenko S, Pereira RP, Eigentler T, Rutkowski P, Demidov L, Zhukova N, Schachter J, Yan Y, Caro I, Hertig C, Xue C, Kusters L, McArthur GA, Gutzmer R. Overall survival with first-line atezolizumab in combination with vemurafenib and cobimetinib in BRAFV600 mutation-positive advanced melanoma (IMspire150): second interim analysis of a multicentre, randomised, phase 3 study. Lancet Oncol. 2023 Jan;24(1):33-44. Epub 2022 Nov 29. link to original article EuroPMC
==Dabrafenib monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Hauschild et al. 2012 (BREAK-3) 	2010-12-23 to 2011-09-01	Phase 3 (E-RT-switch-ooc)	Dacarbazine 	Longer PFS (primary endpoint)Median PFS: 5.1 vs 2.7 mo(HR 0.30, 95% CI 0.18-0.51)
Flaherty et al. 2012 (Novartis 113220)	2010-2011 	Randomized Phase 2 (C) 	Dabrafenib & Trametinib	Shorter PFSMedian PFS: 5.8 vs 9.4 mo(HR 2.56, 95% CI 1.61-4.00)
Long et al. 2014 (COMBI-d) 	2012-05 to 2013-01 	Phase 3 (C) 	Dabrafenib & Trametinib	Seems to have shorter OS1 (secondary endpoint)OS36: 32% vs 44%(HR 1.33, 95% CI 1.04-1.72)Shorter PFS1 (primary endpoint)PFS36: 12% vs 22%(HR 1.41, 95% CI 1.14-1.75)
1Reported efficacy for COMBI-d is based on the 2017 update.
====Targeted therapy====
*Dabrafenib (Tafinlar) 150 mg PO twice per day
Continued indefinitely
===References===
#BREAK-3: Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, Blank CU, Miller WH Jr, Kaempgen E, Martín-Algarra S, Karaszewska B, Mauch C, Chiarion-Sileni V, Martin AM, Swann S, Haney P, Mirakhur B, Guckert ME, Goodman V, Chapman PB. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012 Jul 28;380(9839):358-65. Epub 2012 Jun 25. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01227889
##HRQoL analysis: Grob JJ, Amonkar MM, Martin-Algarra S, Demidov LV, Goodman V, Grotzinger K, Haney P, Kämpgen E, Karaszewska B, Mauch C, Miller WH Jr, Millward M, Mirakhur B, Rutkowski P, Chiarion-Sileni V, Swann S, Hauschild A. Patient perception of the benefit of a BRAF inhibitor in metastatic melanoma: quality-of-life analyses of the BREAK-3 study comparing dabrafenib with dacarbazine. Ann Oncol. 2014 Jul;25(7):1428-1436. Epub 2014 Apr 25. link to original article EuroPMC
##Pooled update: Hauschild A, Ascierto PA, Schadendorf D, Grob JJ, Ribas A, Kiecker F, Dutriaux C, Demidov LV, Lebbé C, Rutkowski P, Blank CU, Gutzmer R, Millward M, Kefford R, Haas T, D'Amelio A Jr, Gasal E, Mookerjee B, Chapman PB. Long-term outcomes in patients with BRAF V600-mutant metastatic melanoma receiving dabrafenib monotherapy: Analysis from phase 2 and 3 clinical trials. Eur J Cancer. 2020 Jan;125:114-120. link to original article link to PMC article EuroPMC
#Novartis 113220: Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N, Kudchadkar R, Burris HA 3rd, Falchook G, Algazi A, Lewis K, Long GV, Puzanov I, Lebowitz P, Singh A, Little S, Sun P, Allred A, Ouellet D, Kim KB, Patel K, Weber J. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012 Nov;367(18):1694-703. Epub 2012 Sep 29. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01072175
##Update: Long GV, Weber JS, Infante JR, Kim KB, Daud A, Gonzalez R, Sosman JA, Hamid O, Schuchter L, Cebon J, Kefford RF, Lawrence D, Kudchadkar R, Burris HA 3rd, Falchook GS, Algazi A, Lewis K, Puzanov I, Ibrahim N, Sun P, Cunningham E, Kline AS, Del Buono H, McDowell DO, Patel K, Flaherty KT. Overall survival and durable responses in patients with BRAF V600-mutant metastatic melanoma receiving dabrafenib combined with trametinib. J Clin Oncol. 2016 Mar 10;34(8):871-8. Epub 2016 Jan 25. link to original article EuroPMC
#COMBI-d: Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Grob JJ, Chiarion Sileni V, Lebbe C, Mandalà M, Millward M, Arance A, Bondarenko I, Haanen JB, Hansson J, Utikal J, Ferraresi V, Kovalenko N, Mohr P, Probachai V, Schadendorf D, Nathan P, Robert C, Ribas A, DeMarini DJ, Irani JG, Casey M, Ouellet D, Martin AM, Le N, Patel K, Flaherty K. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014 Nov 13;371(20):1877-88. Epub 2014 Sep 29. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01584648
##HRQoL analysis: Schadendorf D, Amonkar MM, Stroyakovskiy D, Levchenko E, Gogas H, de Braud F, Grob JJ, Bondarenko I, Garbe C, Lebbe C, Larkin J, Chiarion-Sileni V, Millward M, Arance A, Mandalà M, Flaherty KT, Nathan P, Ribas A, Robert C, Casey M, DeMarini DJ, Irani JG, Aktan G, Long GV. Health-related quality of life impact in a randomised phase III study of the combination of dabrafenib and trametinib versus dabrafenib monotherapy in patients with BRAF V600 metastatic melanoma. Eur J Cancer. 2015 May;51(7):833-40. Epub 2015 Mar 17. link to original article EuroPMC
##Update: Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Grob JJ, Chiarion-Sileni V, Lebbe C, Mandalà M, Millward M, Arance A, Bondarenko I, Haanen JB, Hansson J, Utikal J, Ferraresi V, Kovalenko N, Mohr P, Probachai V, Schadendorf D, Nathan P, Robert C, Ribas A, DeMarini DJ, Irani JG, Swann S, Legos JJ, Jin F, Mookerjee B, Flaherty K. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015 Aug 1;386(9992):444-51. Epub 2015 May 31. link to original article EuroPMC
##Update: Long GV, Flaherty KT, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Chiarion-Sileni V, Lebbe C, Mandalà M, Millward M, Arance A, Bondarenko I, Haanen JBAG, Hansson J, Utikal J, Ferraresi V, Mohr P, Probachai V, Schadendorf D, Nathan P, Robert C, Ribas A, Davies MA, Lane SR, Legos JJ, Mookerjee B, Grob JJ. 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 Jul 1;28(7):1631-1639. link to original article link to PMC article EuroPMC
##Pooled update: Robert C, Grob JJ, Stroyakovskiy D, Karaszewska B, Hauschild A, Levchenko E, Chiarion Sileni V, Schachter J, Garbe C, Bondarenko I, Gogas H, Mandalá M, Haanen JBAG, Lebbé C, Mackiewicz A, Rutkowski P, Nathan PD, Ribas A, Davies MA, Flaherty KT, Burgess P, Tan M, Gasal E, Voi M, Schadendorf D, Long GV. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. N Engl J Med. 2019 Aug 15;381(7):626-636. Epub 2019 Jun 4. link to original article EuroPMC
==Dabrafenib & Trametinib==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Flaherty et al. 2012 (Novartis 113220)	2010-2011 	Randomized Phase 2 (E-esc)	Dabrafenib 	Longer PFS (primary endpoint)Median PFS: 9.4 vs 5.8 mo(HR 0.39, 95% CI 0.25-0.62)
Long et al. 2014 (COMBI-d) 	2012-05 to 2013-01 	Phase 3 (E-RT-esc) 	Dabrafenib 	Longer PFS1 (primary endpoint)PFS36: 22% vs 12%(HR 0.71, 95% CI 0.57-0.88)Seems to have longer OS1 (secondary endpoint)OS36: 44% vs 32%(HR 0.75, 95% CI 0.58-0.96)
Robert et al. 2014 (COMBI-v) 	2012-06 to 2013-10 	Phase 3 (E-RT-esc) 	Vemurafenib 	Longer OS (primary endpoint)OS12: 72% vs 65% (HR 0.69, 95% CI 0.53-0.89)
Dummer et al. 2022 (COMBI-i) 	2017-09-13 to 2018-07-04	Phase 3 (C) 	sparta-DabTram	Might have shorter PFSMedian PFS: 12 vs 16.2 mo(HR 1.22, 95% CI 0.97-1.52)
1Reported efficacy for COMBI-d is based on the 2017 update.
====Targeted therapy====
*Dabrafenib (Tafinlar) 150 mg PO twice per day on days 1 to 28
*Trametinib (Mekinist) 2 mg PO once per day on days 1 to 28
28-day cycles
===References===
#Novartis 113220: Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N, Kudchadkar R, Burris HA 3rd, Falchook G, Algazi A, Lewis K, Long GV, Puzanov I, Lebowitz P, Singh A, Little S, Sun P, Allred A, Ouellet D, Kim KB, Patel K, Weber J. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012 Nov;367(18):1694-703. Epub 2012 Sep 29. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01072175
##Update: Long GV, Weber JS, Infante JR, Kim KB, Daud A, Gonzalez R, Sosman JA, Hamid O, Schuchter L, Cebon J, Kefford RF, Lawrence D, Kudchadkar R, Burris HA 3rd, Falchook GS, Algazi A, Lewis K, Puzanov I, Ibrahim N, Sun P, Cunningham E, Kline AS, Del Buono H, McDowell DO, Patel K, Flaherty KT. Overall survival and durable responses in patients with BRAF V600-mutant metastatic melanoma receiving dabrafenib combined with trametinib. J Clin Oncol. 2016 Mar 10;34(8):871-8. Epub 2016 Jan 25. link to original article EuroPMC
#COMBI-d: Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Grob JJ, Chiarion Sileni V, Lebbe C, Mandalà M, Millward M, Arance A, Bondarenko I, Haanen JB, Hansson J, Utikal J, Ferraresi V, Kovalenko N, Mohr P, Probachai V, Schadendorf D, Nathan P, Robert C, Ribas A, DeMarini DJ, Irani JG, Casey M, Ouellet D, Martin AM, Le N, Patel K, Flaherty K. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014 Nov 13;371(20):1877-88. Epub 2014 Sep 29. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01584648
##HRQoL analysis: Schadendorf D, Amonkar MM, Stroyakovskiy D, Levchenko E, Gogas H, de Braud F, Grob JJ, Bondarenko I, Garbe C, Lebbe C, Larkin J, Chiarion-Sileni V, Millward M, Arance A, Mandalà M, Flaherty KT, Nathan P, Ribas A, Robert C, Casey M, DeMarini DJ, Irani JG, Aktan G, Long GV. Health-related quality of life impact in a randomised phase III study of the combination of dabrafenib and trametinib versus dabrafenib monotherapy in patients with BRAF V600 metastatic melanoma. Eur J Cancer. 2015 May;51(7):833-40. Epub 2015 Mar 17. link to original article EuroPMC
##Update: Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Grob JJ, Chiarion-Sileni V, Lebbe C, Mandalà M, Millward M, Arance A, Bondarenko I, Haanen JB, Hansson J, Utikal J, Ferraresi V, Kovalenko N, Mohr P, Probachai V, Schadendorf D, Nathan P, Robert C, Ribas A, DeMarini DJ, Irani JG, Swann S, Legos JJ, Jin F, Mookerjee B, Flaherty K. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015 Aug 1;386(9992):444-51. Epub 2015 May 31. link to original article EuroPMC
##Update: Long GV, Flaherty KT, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Chiarion-Sileni V, Lebbe C, Mandalà M, Millward M, Arance A, Bondarenko I, Haanen JBAG, Hansson J, Utikal J, Ferraresi V, Mohr P, Probachai V, Schadendorf D, Nathan P, Robert C, Ribas A, Davies MA, Lane SR, Legos JJ, Mookerjee B, Grob JJ. 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 Jul 1;28(7):1631-1639. link to original article link to PMC article EuroPMC
##Pooled update: Robert C, Grob JJ, Stroyakovskiy D, Karaszewska B, Hauschild A, Levchenko E, Chiarion Sileni V, Schachter J, Garbe C, Bondarenko I, Gogas H, Mandalá M, Haanen JBAG, Lebbé C, Mackiewicz A, Rutkowski P, Nathan PD, Ribas A, Davies MA, Flaherty KT, Burgess P, Tan M, Gasal E, Voi M, Schadendorf D, Long GV. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. N Engl J Med. 2019 Aug 15;381(7):626-636. Epub 2019 Jun 4. link to original article EuroPMC
#COMBI-v: Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, Lichinitser M, Dummer R, Grange F, Mortier L, Chiarion-Sileni V, Drucis K, Krajsova I, Hauschild A, Lorigan P, Wolter P, Long GV, Flaherty K, Nathan P, Ribas A, Martin AM, Sun P, Crist W, Legos J, Rubin SD, Little SM, Schadendorf D. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015 Jan 1;372(1):30-9. Epub 2014 Nov 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01597908
##HRQoL analysis: Grob JJ, Amonkar MM, Karaszewska B, Schachter J, Dummer R, Mackiewicz A, Stroyakovskiy D, Drucis K, Grange F, Chiarion-Sileni V, Rutkowski P, Lichinitser M, Levchenko E, Wolter P, Hauschild A, Long GV, Nathan P, Ribas A, Flaherty K, Sun P, Legos JJ, McDowell DO, Mookerjee B, Schadendorf D, Robert C. Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): results of a phase 3, open-label, randomised trial. Lancet Oncol. 2015 Oct;16(13):1389-98. link to original article EuroPMC
##Pooled update: Robert C, Grob JJ, Stroyakovskiy D, Karaszewska B, Hauschild A, Levchenko E, Chiarion Sileni V, Schachter J, Garbe C, Bondarenko I, Gogas H, Mandalá M, Haanen JBAG, Lebbé C, Mackiewicz A, Rutkowski P, Nathan PD, Ribas A, Davies MA, Flaherty KT, Burgess P, Tan M, Gasal E, Voi M, Schadendorf D, Long GV. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. N Engl J Med. 2019 Aug 15;381(7):626-636. Epub 2019 Jun 4. link to original article EuroPMC
#COMBI-i: Dummer R, Long GV, Robert C, Tawbi HA, Flaherty KT, Ascierto PA, Nathan PD, Rutkowski P, Leonov O, Dutriaux C, Mandalà M, Lorigan P, Ferrucci PF, Grob JJ, Meyer N, Gogas H, Stroyakovskiy D, Arance A, Brase JC, Green S, Haas T, Masood A, Gasal E, Ribas A, Schadendorf D. Randomized Phase III Trial Evaluating Spartalizumab Plus Dabrafenib and Trametinib for BRAF V600-Mutant Unresectable or Metastatic Melanoma. J Clin Oncol. 2022 May 1;40(13):1428-1438. Epub 2022 Jan 14. link to original article dosing details in abstract have been reviewed by our editors link to PMC article EuroPMC NCT02967692
==Dacarbazine monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Chapman et al. 2011 (BRIM-3) 	2010-01 to 2010-12 	Phase 3 (C)	Vemurafenib	Shorter OS1Median OS: 9.7 vs 13.6 mo(HR 1.43, 95% CI 1.15-1.75)
Hauschild et al. 2012 (BREAK-3)	2010-12-23 to 2011-09-01	Phase 3 (C)	Dabrafenib 	Shorter PFSMedian PFS: 2.7 vs 5.1 mo(HR 3.33, 95% CI 1.96-5.56)
Flaherty et al. 2012 (METRIC) 	2010-12 to 2011-07 	Phase 3 (C)	Trametinib 	Shorter PFS2Median PFS: 1.5 vs 4.9 mo(HR 1.85, 95% CI 1.37-2.44)Shorter OSOS6: 67% vs 81%(HR 1.85, 95% CI 1.09-3.12)
1Reported efficacy for BRIM-3 is based on the 2014 update.
2Reported PFS efficacy for METRIC is based on the 2019 update.
====Chemotherapy====
*Dacarbazine (DTIC) 1000 mg/m2 IV once on day 1
21-day cycles
===References===
#BRIM-3: 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; BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011 Jun 30;364(26):2507-16. Epub 2011 Jun 5. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01006980
##Update: McArthur GA, Chapman PB, Robert C, Larkin J, Haanen JB, Dummer R, Ribas A, Hogg D, Hamid O, Ascierto PA, Garbe C, Testori A, Maio M, Lorigan P, Lebbé C, Jouary T, Schadendorf D, O'Day SJ, Kirkwood JM, Eggermont AM, Dréno B, Sosman JA, Flaherty KT, Yin M, Caro I, Cheng S, Trunzer K, Hauschild A. Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol. 2014 Mar;15(3):323-32. Epub 2014 Feb 7. link to original article link to PMC article EuroPMC
#BREAK-3: Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, Blank CU, Miller WH Jr, Kaempgen E, Martín-Algarra S, Karaszewska B, Mauch C, Chiarion-Sileni V, Martin AM, Swann S, Haney P, Mirakhur B, Guckert ME, Goodman V, Chapman PB. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012 Jul 28;380(9839):358-65. Epub 2012 Jun 25. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01227889
##HRQoL analysis: Grob JJ, Amonkar MM, Martin-Algarra S, Demidov LV, Goodman V, Grotzinger K, Haney P, Kämpgen E, Karaszewska B, Mauch C, Miller WH Jr, Millward M, Mirakhur B, Rutkowski P, Chiarion-Sileni V, Swann S, Hauschild A. Patient perception of the benefit of a BRAF inhibitor in metastatic melanoma: quality-of-life analyses of the BREAK-3 study comparing dabrafenib with dacarbazine. Ann Oncol. 2014 Jul;25(7):1428-1436. Epub 2014 Apr 25. link to original article EuroPMC
##Pooled update: Hauschild A, Ascierto PA, Schadendorf D, Grob JJ, Ribas A, Kiecker F, Dutriaux C, Demidov LV, Lebbé C, Rutkowski P, Blank CU, Gutzmer R, Millward M, Kefford R, Haas T, D'Amelio A Jr, Gasal E, Mookerjee B, Chapman PB. Long-term outcomes in patients with BRAF V600-mutant metastatic melanoma receiving dabrafenib monotherapy: Analysis from phase 2 and 3 clinical trials. Eur J Cancer. 2020 Jan;125:114-120. link to original article link to PMC article EuroPMC
#METRIC: Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, Hassel JC, Rutkowski P, Mohr P, Dummer R, Trefzer U, Larkin JM, Utikal J, Dreno B, Nyakas M, Middleton MR, Becker JC, Casey M, Sherman LJ, Wu FS, Ouellet D, Martin AM, Patel K, Schadendorf D; METRIC Study Group. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012 Jul 12;367(2):107-14. Epub 2012 Jun 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01245062
##HRQoL analysis: Schadendorf D, Amonkar MM, Milhem M, Grotzinger K, Demidov LV, Rutkowski P, Garbe C, Dummer R, Hassel JC, Wolter P, Mohr P, Trefzer U, Lefeuvre-Plesse C, Rutten A, Steven N, Ullenhag G, Sherman L, Wu FS, Patel K, Casey M, Robert C. Functional and symptom impact of trametinib versus chemotherapy in BRAF V600E advanced or metastatic melanoma: quality-of-life analyses of the METRIC study. Ann Oncol. 2014 Mar;25(3):700-706. Epub 2014 Feb 6. link to original article link to PMC article EuroPMC
##Update: Robert C, Flaherty K, Nathan P, Hersey P, Garbe C, Milhem M, Demidov L, Mohr P, Hassel JC, Rutkowski P, Dummer R, Utikal J, Kiecker F, Larkin J, D'Amelio A Jr, Mookerjee B, Schadendorf D. 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 Mar;109:61-69. Epub 2019 Jan 25. link to original article EuroPMC
==Ipilimumab & Nivolumab==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Atkins et al. 2023 (DREAMseq)	2015-07-13 to 2021-09-30	Phase 3 (E-switch-ic)	Dabrafenib & Trametinib, followed by Ipilimumab & Nivolumab	Higher OS24 (primary endpoint)OS24: 71.8% vs 51.5%	More grade 3 to 5 TRAEs
====Immunotherapy====
*Ipilimumab (Yervoy) as follows:
**Cycles 1 to 4: 3 mg/kg IV once on day 1
*Nivolumab (Opdivo) as follows:
**Cycles 1 to 4: 1 mg/kg IV once on day 1
**Cycles 5 to 40: 240 mg IV once on day 1
21-day cycle for 4 cycles, then 14-day cycle for up to 36 cycles (72 weeks)
====Subsequent treatment====
*DREAMseq, upon progression: Second-line Dabrafenib & Trametinib
===References===
#DREAMseq: Atkins MB, Lee SJ, Chmielowski B, Tarhini AA, Cohen GI, Truong TG, Moon HH, Davar D, O'Rourke M, Stephenson JJ, Curti BD, Urba WJ, Brell JM, Funchain P, Kendra KL, Ikeguchi AP, Jaslowski A, Bane CL, Taylor MA, Bajaj M, Conry RM, Ellis RJ, Logan TF, Laudi N, Sosman JA, Crockett DG, Pecora AL, Okazaki IJ, Reganti S, Chandra S, Guild S, Chen HX, Streicher HZ, Wolchok JD, Ribas A, Kirkwood JM. Combination Dabrafenib and Trametinib Versus Combination Nivolumab and Ipilimumab for Patients With Advanced BRAF-Mutant Melanoma: The DREAMseq Trial-ECOG-ACRIN EA6134. J Clin Oncol. 2023 Jan 10;41(2):186-197. Epub 2022 Sep 27. link to original article link to PMC article EuroPMC NCT02224781
==Paclitaxel monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Flaherty et al. 2012 (METRIC)	2010-12 to 2011-07 	Phase 3 (C)	Trametinib	Shorter PFS1Median PFS: 1.5 vs 4.9 mo(HR 1.85, 95% CI 1.37-2.44)Shorter OSOS6: 67% vs 81%(HR 1.85, 95% CI 1.09-3.12)
1Reported PFS efficacy is based on the 2019 update.
Note: This was a therapy option for patients in the control arm of METRIC. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.
====Chemotherapy====
*Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
21-day cycles
===References===
#METRIC: Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, Hassel JC, Rutkowski P, Mohr P, Dummer R, Trefzer U, Larkin JM, Utikal J, Dreno B, Nyakas M, Middleton MR, Becker JC, Casey M, Sherman LJ, Wu FS, Ouellet D, Martin AM, Patel K, Schadendorf D; METRIC Study Group. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012 Jul 12;367(2):107-14. Epub 2012 Jun 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01245062
##HRQoL analysis: Schadendorf D, Amonkar MM, Milhem M, Grotzinger K, Demidov LV, Rutkowski P, Garbe C, Dummer R, Hassel JC, Wolter P, Mohr P, Trefzer U, Lefeuvre-Plesse C, Rutten A, Steven N, Ullenhag G, Sherman L, Wu FS, Patel K, Casey M, Robert C. Functional and symptom impact of trametinib versus chemotherapy in BRAF V600E advanced or metastatic melanoma: quality-of-life analyses of the METRIC study. Ann Oncol. 2014 Mar;25(3):700-706. Epub 2014 Feb 6. link to original article link to PMC article EuroPMC
##Update: Robert C, Flaherty K, Nathan P, Hersey P, Garbe C, Milhem M, Demidov L, Mohr P, Hassel JC, Rutkowski P, Dummer R, Utikal J, Kiecker F, Larkin J, D'Amelio A Jr, Mookerjee B, Schadendorf D. 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 Mar;109:61-69. Epub 2019 Jan 25. link to original article EuroPMC
==Trametinib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Falchook et al. 2012 (MEK111054)	2008-2010 	Phase 1, >20 pts in this dosing cohort	 	
Kim et al. 2012 (GSK 113583) 	2009-2010 	Phase 2 	 	ORR: 25%
Flaherty et al. 2012 (METRIC) 	2010-12 to 2011-07 	Phase 3 (E-RT-switch-ooc) 	1a. Dacarbazine1b. Paclitaxel	Longer PFS1 (primary endpoint)Median PFS: 4.9 vs 1.5 mo(HR 0.54, 95% CI 0.41-0.73)Longer OS (secondary endpoint)OS6: 81% vs 67%(HR 0.54, 95% CI 0.32-0.92)
1Reported PFS efficacy for METRIC is based on the 2019 update.
====Targeted therapy====
*Trametinib (Mekinist) 2 mg PO once per day
===References===
#METRIC: Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, Hassel JC, Rutkowski P, Mohr P, Dummer R, Trefzer U, Larkin JM, Utikal J, Dreno B, Nyakas M, Middleton MR, Becker JC, Casey M, Sherman LJ, Wu FS, Ouellet D, Martin AM, Patel K, Schadendorf D; METRIC Study Group. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012 Jul 12;367(2):107-14. Epub 2012 Jun 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01245062
##HRQoL analysis: Schadendorf D, Amonkar MM, Milhem M, Grotzinger K, Demidov LV, Rutkowski P, Garbe C, Dummer R, Hassel JC, Wolter P, Mohr P, Trefzer U, Lefeuvre-Plesse C, Rutten A, Steven N, Ullenhag G, Sherman L, Wu FS, Patel K, Casey M, Robert C. Functional and symptom impact of trametinib versus chemotherapy in BRAF V600E advanced or metastatic melanoma: quality-of-life analyses of the METRIC study. Ann Oncol. 2014 Mar;25(3):700-706. Epub 2014 Feb 6. link to original article link to PMC article EuroPMC
##Update: Robert C, Flaherty K, Nathan P, Hersey P, Garbe C, Milhem M, Demidov L, Mohr P, Hassel JC, Rutkowski P, Dummer R, Utikal J, Kiecker F, Larkin J, D'Amelio A Jr, Mookerjee B, Schadendorf D. 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 Mar;109:61-69. Epub 2019 Jan 25. link to original article EuroPMC
#MEK111054: Falchook GS, Lewis KD, Infante JR, Gordon MS, Vogelzang NJ, DeMarini DJ, Sun P, Moy C, Szabo SA, Roadcap LT, Peddareddigari VG, Lebowitz PF, Le NT, Burris HA 3rd, Messersmith WA, O'Dwyer PJ, Kim KB, Flaherty K, Bendell JC, Gonzalez R, Kurzrock R, Fecher LA. Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol. 2012 Aug;13(8):782-9. Epub 2012 Jul 16. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00687622
#GSK 113583: Kim KB, Kefford R, Pavlick AC, Infante JR, Ribas A, Sosman JA, Fecher LA, Millward M, McArthur GA, Hwu P, Gonzalez R, Ott PA, Long GV, Gardner OS, Ouellet D, Xu Y, DeMarini DJ, Le NT, Patel K, Lewis KD. Phase II study of the MEK1/MEK2 inhibitor trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. J Clin Oncol. 2013 Feb 1;31(4):482-9. Epub 2012 Dec 17. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01037127
==Vemurafenib monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Flaherty et al. 2010 	Not reported 	Phase 1/2 	 	
Sosman et al. 2012 (BRIM2) 	2009-10 to 2010-03 	Phase 2 (RT) 	 	ORR: 53% (95% CI: 44-62)
Chapman et al. 2011 (BRIM-3) 	2010-01 to 2010-12 	Phase 3 (E-RT-switch-ooc)	Dacarbazine 	Longer OS1 (co-primary endpoint)Median OS: 13.6 vs 9.7 mo(HR 0.70, 95% CI 0.57-0.87)
Robert et al. 2014 (COMBI-v) 	2012-06 to 2013-10 	Phase 3 (C) 	Dabrafenib & Trametinib 	Shorter OSOS12: 65% vs 72%(HR 1.45, 95% CI 1.12-1.89)
Larkin et al. 2014 (coBRIM) 	2013-01 to 2014-01 	Phase 3 (C) 	Cobimetinib & Vemurafenib 	Shorter PFS2 (primary endpoint)Median PFS: 7.2 vs 12.3 mo(HR 1.72, 95% CI 1.39-2.17)Shorter OS2 (secondary endpoint)Median OS: 17.4 vs 22.3 mo(HR 1.43, 95% CI 1.11-1.82)
Dummer et al. 2018 (COLUMBUS)	2013-12-30 to 2015-04-10	Phase 3 (C) 	1. Binimetinib & Encorafenib	Shorter OS3
Dummer et al. 2018 (COLUMBUS)	2013-12-30 to 2015-04-10	Phase 3 (C) 	2. Encorafenib 	Not reported
1Reported efficacy for BRIM-3 is based on the 2014 update.
2Reported efficacy for coBRIM is based on the 2016 update.
3Reported efficacy for COLUMBUS is based on the 2018 update.
====Targeted therapy====
*Vemurafenib (Zelboraf) 960 mg PO twice per day
Continued indefinitely
===References===
#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. N Engl J Med. 2010 Aug 26;363(9):809-19. link to original article link to PMC article dosing details in abstract have been reviewed by our editors EuroPMC
#BRIM-3: 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; BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011 Jun 30;364(26):2507-16. Epub 2011 Jun 5. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01006980
##Update: McArthur GA, Chapman PB, Robert C, Larkin J, Haanen JB, Dummer R, Ribas A, Hogg D, Hamid O, Ascierto PA, Garbe C, Testori A, Maio M, Lorigan P, Lebbé C, Jouary T, Schadendorf D, O'Day SJ, Kirkwood JM, Eggermont AM, Dréno B, Sosman JA, Flaherty KT, Yin M, Caro I, Cheng S, Trunzer K, Hauschild A. Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol. 2014 Mar;15(3):323-32. Epub 2014 Feb 7. link to original article link to PMC article EuroPMC
#BRIM2: 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. N Engl J Med. 2012 Feb 23;366(8):707-14. link to original article link to PMC article EuroPMC NCT00949702
#coBRIM: 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. N Engl J Med. 2014 Nov 13;371(20):1867-76. Epub 2014 Sep 29. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01689519
##Update: Ascierto PA, McArthur GA, Dréno B, Atkinson V, Liszkay G, Di Giacomo AM, Mandalà M, Demidov L, Stroyakovskiy D, Thomas L, de la Cruz-Merino L, Dutriaux C, Garbe C, Yan Y, Wongchenko M, Chang I, Hsu JJ, Koralek DO, Rooney I, Ribas A, Larkin J. Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 2016 Sep;17(9):1248-60. Epub 2016 Jul 30. link to original article EuroPMC
#COMBI-v: Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, Lichinitser M, Dummer R, Grange F, Mortier L, Chiarion-Sileni V, Drucis K, Krajsova I, Hauschild A, Lorigan P, Wolter P, Long GV, Flaherty K, Nathan P, Ribas A, Martin AM, Sun P, Crist W, Legos J, Rubin SD, Little SM, Schadendorf D. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015 Jan 1;372(1):30-9. Epub 2014 Nov 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01597908
##HRQoL analysis: Grob JJ, Amonkar MM, Karaszewska B, Schachter J, Dummer R, Mackiewicz A, Stroyakovskiy D, Drucis K, Grange F, Chiarion-Sileni V, Rutkowski P, Lichinitser M, Levchenko E, Wolter P, Hauschild A, Long GV, Nathan P, Ribas A, Flaherty K, Sun P, Legos JJ, McDowell DO, Mookerjee B, Schadendorf D, Robert C. Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): results of a phase 3, open-label, randomised trial. Lancet Oncol. 2015 Oct;16(13):1389-98. link to original article EuroPMC
##Pooled update: Robert C, Grob JJ, Stroyakovskiy D, Karaszewska B, Hauschild A, Levchenko E, Chiarion Sileni V, Schachter J, Garbe C, Bondarenko I, Gogas H, Mandalá M, Haanen JBAG, Lebbé C, Mackiewicz A, Rutkowski P, Nathan PD, Ribas A, Davies MA, Flaherty KT, Burgess P, Tan M, Gasal E, Voi M, Schadendorf D, Long GV. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. N Engl J Med. 2019 Aug 15;381(7):626-636. Epub 2019 Jun 4. link to original article EuroPMC
#COLUMBUS: Dummer R, Ascierto PA, Gogas HJ, Arance A, Mandala M, Liszkay G, Garbe C, Schadendorf D, Krajsova I, Gutzmer R, Chiarion-Sileni V, Dutriaux C, de Groot JWB, Yamazaki N, Loquai C, Moutouh-de Parseval LA, Pickard MD, Sandor V, Robert C, Flaherty KT. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):603-615. Epub 2018 Mar 21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01909453
##Update: Dummer R, Ascierto PA, Gogas HJ, Arance A, Mandala M, Liszkay G, Garbe C, Schadendorf D, Krajsova I, Gutzmer R, Chiarion Sileni V, Dutriaux C, de Groot JWB, Yamazaki N, Loquai C, Moutouh-de Parseval LA, Pickard MD, Sandor V, Robert C, Flaherty KT. 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 Oct;19(10):1315-1327. Epub 2018 Sep 12. Erratum in: Lancet Oncol. 2018 Oct;19(10):e509. link to original article EuroPMC
## Update: Ascierto PA, Dummer R, Gogas HJ, Flaherty KT, Arance A, Mandala M, Liszkay G, Garbe C, Schadendorf D, Krajsova I, Gutzmer R, de Groot JWB, Loquai C, Gollerkeri A, Pickard MD, Robert C. 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 Feb;126:33-44. Epub 2020 Jan 2. link to original article EuroPMC
## Update: Dummer R, Flaherty KT, Robert C, Arance A, de Groot JWB, Garbe C, Gogas HJ, Gutzmer R, Krajsová I, Liszkay G, Loquai C, Mandalà M, Schadendorf D, Yamazaki N, di Pietro A, Cantey-Kiser J, Edwards M, Ascierto PA. COLUMBUS 5-Year Update: A Randomized, Open-Label, Phase III Trial of Encorafenib Plus Binimetinib Versus Vemurafenib or Encorafenib in Patients With BRAF V600-Mutant Melanoma. J Clin Oncol. 2022 Dec 20;40(36):4178-4188. Epub 2022 Jul 21. link to original article link to PMC article EuroPMC
##Update: Ascierto PA, Dummer R, Gogas HJ, Arance A, Mandala M, Liszkay G, Garbe C, Schadendorf D, Krajsova I, Gutzmer R, Chiarion-Sileni V, Dutriaux C, de Groot JWB, Yamazaki N, Loquai C, Robert C, Flaherty KT. Contribution of MEK Inhibition to BRAF/MEK Inhibitor Combination Treatment of BRAF-Mutant Melanoma: Part 2 of the Randomized, Open-Label, Phase III COLUMBUS Trial. J Clin Oncol. 2023 Oct 10;41(29):4621-4631. Epub 2023 Jul 28. link to original article link to PMC article EuroPMC
##Update: Schadendorf D, Dummer R, Flaherty KT, Robert C, Arance A, de Groot JWB, Garbe C, Gogas HJ, Gutzmer R, Krajsová I, Liszkay G, Loquai C, Mandalà M, Yamazaki N, Queirolo P, Guenzel C, Polli A, Thakur M, di Pietro A, Ascierto PA. COLUMBUS 7-year update: A randomized, open-label, phase III trial of encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF V600E/K-mutant melanoma. Eur J Cancer. 2024 Jun;204:114073. Epub 2024 Apr 24. link to original article interactive data visualization EuroPMC
=Advanced or metastatic disease, BRAF inhibitor-exposed=
==Trametinib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence	Efficacy
Kim et al. 2012 (GSK 113583)	2009-2010 	Phase 2 	ORR: 0%
====Biomarker eligibility criteria====
*Gene: BRAF
*Alteration: V600E, V600K, or V600D
====Targeted therapy====
*Trametinib (Mekinist) 2 mg PO once per day
===References===
#GSK 113583: Kim KB, Kefford R, Pavlick AC, Infante JR, Ribas A, Sosman JA, Fecher LA, Millward M, McArthur GA, Hwu P, Gonzalez R, Ott PA, Long GV, Gardner OS, Ouellet D, Xu Y, DeMarini DJ, Le NT, Patel K, Lewis KD. Phase II study of the MEK1/MEK2 inhibitor trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. J Clin Oncol. 2013 Feb 1;31(4):482-9. Epub 2012 Dec 17. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01037127
Category:Melanoma regimens
Category:Biomarker-specific pages
Category:Skin cancers