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Page editor		Section editor
	Ryan Nguyen, DO University of Illinois at Chicago Chicago, IL, USA LinkedIn		Elizabeth Buchbinder, MD Dana-Farber Cancer Institute Boston, MA, USA LinkedIn

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.

13 regimens on this page 12 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	Superior RFS (primary endpoint) RFS36: 58% vs 39% (HR 0.47, 95% CI 0.39-0.58) Superior MFS¹ (secondary endpoint) MFS60: 65% vs 54% (HR 0.55, 95% CI 0.44-0.70)

¹Reported efficacy is based on the 2020 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 contains dosing details in manuscript PubMed NCT01682083
1. 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 PubMed
2. 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 PubMed
3. 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 PubMed

Vemurafenib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Maio et al. 2018 (BRIM8)	2012-2015	Phase 3 (E-esc)	Placebo	Might have superior DFS¹ (primary endpoint) Median 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 contains dosing details in manuscript PubMed NCT01667419

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	Superior PFS (primary endpoint) Median PFS: 14.9 vs 7.3 mo (HR 0.54, 95% CI 0.41-0.71) Superior 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 contains dosing details in abstract PubMed NCT01909453
1. 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 PubMed
2. 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 PubMed
3. 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 PubMed
4. 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 PubMed
5. 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 PubMed

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	Superior PFS¹ (primary endpoint) Median PFS: 12.3 vs 7.2 mo (HR 0.58, 95% CI 0.46-0.72) Superior 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 inferior PFS

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 contains dosing details in manuscript PubMed NCT01689519
1. 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 PubMed
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 PubMed NCT02908672
1. 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 PubMed

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 superior PFS (primary endpoint) Median PFS: 15.1 vs 10.6 mo (HR 0.78, 95% CI 0.63-0.97)

Note: dosing details are from the FDA recommended dosing and are not available in the abstract.

Targeted therapy

Cobimetinib (Cotellic) 60 mg PO once per day on days 1 to 21
Vemurafenib (Zelboraf) 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 PubMed NCT02908672
1. 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 PubMed

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	Superior 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	Inferior PFS
Long et al. 2014 (COMBI-d)	2012-05 to 2013-01	Phase 3 (C)	Dabrafenib & Trametinib	Seems to have inferior OS

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 contains dosing details in manuscript PubMed NCT01227889
1. 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 PubMed
2. 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 PubMed
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 contains dosing details in manuscript link to PMC article PubMed NCT01072175
1. 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 PubMed
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 PubMed NCT01584648
1. 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 PubMed
2. 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 PubMed
3. 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 PubMed
4. 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 PubMed

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	Superior 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	Superior PFS¹ (primary endpoint) PFS36: 22% vs 12% (HR 0.71, 95% CI 0.57-0.88) Seems to have superior 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	Superior 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 inferior PFS Median 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 contains dosing details in manuscript link to PMC article PubMed NCT01072175
1. 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 PubMed
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 PubMed NCT01584648
1. 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 PubMed
2. 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 PubMed
3. 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 PubMed
4. 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 PubMed
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 contains dosing details in manuscript PubMed NCT01597908
1. 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 PubMed
2. 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 PubMed
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 contains dosing details in abstract link to PMC article PubMed 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	Inferior OS
Hauschild et al. 2012 (BREAK-3)	2010-12-23 to 2011-09-01	Phase 3 (C)	Dabrafenib	Inferior PFS
Flaherty et al. 2012 (METRIC)	2010-12 to 2011-07	Phase 3 (C)	Trametinib	Inferior PFS

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 contains dosing details in manuscript link to PMC article PubMed NCT01006980
1. 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 PubMed
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 contains dosing details in manuscript PubMed NCT01227889
1. 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 PubMed
2. 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 PubMed
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 contains dosing details in manuscript PubMed NCT01245062
1. 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 PubMed
2. 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 PubMed

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	Superior 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 cycles 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 PubMed 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	Inferior PFS

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 contains dosing details in manuscript PubMed NCT01245062
1. 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 PubMed
2. 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 PubMed

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. Dacarbazine 1b. Paclitaxel	Superior PFS¹ (primary endpoint) Median PFS: 4.9 vs 1.5 mo (HR 0.54, 95% CI 0.41-0.73) Superior OS (secondary endpoint) OS6: 81% vs 67% (HR 0.54, 95% CI 0.32-0.92)

¹Reported efficacy for PFS in 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 contains dosing details in manuscript PubMed NCT01245062
1. 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 PubMed
2. 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 PubMed
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 contains dosing details in manuscript link to PMC article PubMed 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 contains dosing details in manuscript link to PMC article PubMed NCT01037127

Vemurafenib monotherapy

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Flaherty et al. 2010	NR	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	Superior 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	Inferior OS
Larkin et al. 2014 (coBRIM)	2013-01 to 2014-01	Phase 3 (C)	Cobimetinib & Vemurafenib	Inferior OS²
Dummer et al. 2018 (COLUMBUS)	2013-12-30 to 2015-04-10	Phase 3 (C)	1. Binimetinib & Encorafenib	Inferior OS³
Dummer et al. 2018 (COLUMBUS)	2013-12-30 to 2015-04-10	Phase 3 (C)	2. Encorafenib	Not reported

²Reported 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 contains dosing details in abstract PubMed
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 contains dosing details in manuscript link to PMC article PubMed NCT01006980
1. 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 PubMed
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 PubMed 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 contains dosing details in manuscript PubMed NCT01689519
1. 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 PubMed
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 contains dosing details in manuscript PubMed NCT01597908
1. 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 PubMed
2. 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 PubMed
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 contains dosing details in abstract PubMed NCT01909453
1. 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 PubMed
2. 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 PubMed
3. 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 PubMed
4. 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 PubMed
5. 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 PubMed

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 contains dosing details in manuscript link to PMC article PubMed NCT01037127

@@ Line 1: / Line 1: @@
-{| class="wikitable" style="text-align:center; width:50%;"
+<span id="BackToTop"></span>
-! colspan="2" align="center" style="color:white; font-size:125%; background-color:#08519c" |'''Section editor'''
+<div class="noprint" style="background-color:LightGray; position:fixed; bottom:2%; right:0.25%; padding-left:5px; padding-right:5px; margin: 15px; opacity:0.8; border-style: solid; border-color:DarkGray; border-width: 1px">
-|-
+[[#top|Back to Top]]
-| style="background-color:#F0F0F0" |[[File:Bethbuchbinder.jpg|frameless|upright=0.3|center]]
+</div>
-|<big>[[User:Bethbuchbinder|Elizabeth Buchbinder, MD]]<br>Dana-Farber Cancer Institute<br>Boston, MA</big><br>[https://www.linkedin.com/in/beth-buchbinder-2a9b994/ LinkedIn]
+{{#lst:Editorial board transclusions|mel}}
-|-
-|}
 <big>'''Note: these are regimens tested in biomarker-specific populations, please see the [[Melanoma|main melanoma page]] for other regimens.'''</big>
+<br>''For placebo or observational studies in this condition, please visit [[Melanoma, BRAF-mutated - null regimens|this page]].''
 {| class="wikitable" style="float:right; margin-right: 5px;"
 |-
@@ Line 13: / Line 12: @@
 |}
 {{TOC limit|limit=3}}
+=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 [https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1492 NCCN Guidelines - Melanoma: Cutaneous].''
 =Adjuvant therapy=
 ==Dabrafenib & Trametinib {{#subobject:2c672b|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:d808ec|Variant=1}}===
 {| class="wikitable" style="color:white; background-color:#404040"
@@ Line 24: / Line 24: @@
 |-
 |}
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
+!style="width: 20%"|Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Dates of enrollment
-! style="width: 25%" |Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1708539 Long et al. 2017 (COMBI-AD)]
+|[https://doi.org/10.1056/NEJMoa1708539 Long et al. 2017 (COMBI-AD)]
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
-|[[#Placebo|Placebo]]
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-172-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
-| style="background-color:#91cf60" |Seems to have superior OS
+|-
+|} -->
+|2013-01 to 2014-12
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+|[[Melanoma,_BRAF-mutated_-_null_regimens#Placebo|Placebo]]
+| style="background-color:#1a9850" |Superior RFS (primary endpoint)<br>RFS36: 58% vs 39%<br>(HR 0.47, 95% CI 0.39-0.58)<br><br>Superior MFS<sup>1</sup> (secondary endpoint)<br>MFS60: 65% vs 54%<br>(HR 0.55, 95% CI 0.44-0.70)
 |-
 |}
-''Note: per the authors, "the between-group difference (P=0.0006) did not reach the prespecified threshold of P=0.000019 to claim statistical significance in the first interim analysis of overall survival."''
+''<sup>1</sup>Reported efficacy is based on the 2020 update.''
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
 *[[Surgery#Lymphadenectomy|Completion lymphadenectomy]], within 12 weeks
+</div>
-====Chemotherapy====
+<div class="toccolours" style="background-color:#b3e2cd">
+====Targeted therapy====
 *[[Dabrafenib (Tafinlar)]] 150 mg PO twice per day
 *[[Trametinib (Mekinist)]] 2 mg PO once per day
 '''Up to 12-month course'''
+</div></div>
 ===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. [https://doi.org/10.1056/NEJMoa1708539 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28891408/ PubMed] [https://clinicaltrials.gov/study/NCT01682083 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. [https://doi.org/10.1200/JCO.18.01219 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286159/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30343620/ PubMed]
+## '''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. [https://doi.org/10.1016/s1470-2045(18)30940-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30928620/ PubMed]
+## '''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. [https://doi.org/10.1056/nejmoa2005493 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32877599/ PubMed]
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1708539 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28891408 PubMed]
+==Vemurafenib monotherapy {{#subobject:2c7jzb|Regimen=1}}==
-##'''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 Oct 22:JCO1801219. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.18.01219 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286159/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30343620 PubMed]
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:d808ec|Variant=1}}===
-==Placebo==
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-{| class="wikitable" style="float:right; margin-left: 5px;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[[#top|back to top]]
+|[https://doi.org/10.1016/S1470-2045(18)30106-2 Maio et al. 2018 (BRIM8)]
-|}
+|2012-2015
-===Regimen===
+| style="background-color:#1a9851" |Phase 3 (E-esc)
-{| class="wikitable" style="width: 100%; text-align:center;"
+|[[Melanoma,_BRAF-mutated_-_null_regimens#Placebo|Placebo]]
-! style="width: 25%" |Study
+| style="background-color:#d9ef8b" |Might have superior DFS<sup>1</sup> (primary endpoint)<br>Median DFS: 23.1 vs 15.4 mo<br>(HR 0.80, 95% CI 0.54-1.18)
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |Comparator
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1708539 Long et al. 2017 (COMBI-AD)]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#Dabrafenib_.26_Trametinib|Dabrafenib & Trametinib]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
-|-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30106-2/fulltext Maio et al. 2018 (BRIM8)]
-| style="background-color:#1a9851" |Phase III (C)
-|Vemurafenib
-| style="background-color:#fee08b" |Might have inferior DFS
 |-
 |}
-''Note: per Long et al. 2017, "the between-group difference (P=0.0006) did not reach the prespecified threshold of P=0.000019 to claim statistical significance in the first interim analysis of overall survival. No further antineoplastic treatment."''
+''<sup>1</sup>Reported efficacy is based on the results for cohort 2, which was analyzed first as per the prespecified approach.''
+<div class="toccolours" style="background-color:#cbd5e8">
 ====Preceding treatment====
+*[[Surgery#Melanoma_surgery|Complete resection]], timing not specified
-*COMBI-AD: [[Surgery#Lymphadenectomy|Completion lymphadenectomy]], within 12 weeks
+</div>
-*BRIM8: not specified in abstract
+<div class="toccolours" style="background-color:#b3e2cd">
+====Targeted therapy====
+*[[Vemurafenib (Zelboraf)]] 960 mg PO twice per day
+'''28-day cycle for 13 cycles (1 year)'''
+</div></div>
 ===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. [https://doi.org/10.1016/S1470-2045(18)30106-2 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/29477665/ PubMed] [https://clinicaltrials.gov/study/NCT01667419 NCT01667419]
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1708539 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28891408 PubMed]
-##'''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 Oct 22:JCO1801219. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.18.01219 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286159/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30343620 PubMed]
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30106-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29477665 PubMed]
 =Advanced or metastatic disease, BRAF inhibitor-naive=
 ==Binimetinib & Encorafenib {{#subobject:aa3a2b|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:8d6382|Variant=1}}===
 {| class="wikitable" style="color:white; background-color:#404040"
@@ Line 99: / Line 96: @@
 |-
 |}
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
+!style="width: 20%"|Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Dates of enrollment
-! style="width: 25%" |Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+| rowspan="2" |[https://doi.org/10.1016/S1470-2045(18)30142-6 Dummer et al. 2018 (COLUMBUS)]
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-168-1 <span style="color:white;">ESMO-MCBS (A)</span>]'''
 |-
-| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30142-6/fulltext Dummer et al. 2018 (COLUMBUS)]
+|} -->
-| rowspan="2" style="background-color:#1a9851" |Phase III (E-RT-esc)
+|rowspan=2|2013-12-30 to 2015-04-10
-|1. Encorafenib
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+|1. [[Stub#Encorafenib_monotherapy|Encorafenib]]
 | style="background-color:#d3d3d3" |Not reported
 |-
-|2. [[#Vemurafenib_monotherapy|Vemurafenib]]
+|2. [[#Vemurafenib_monotherapy_2|Vemurafenib]]
-| style="background-color:#1a9850" |Superior OS (*)
+| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 14.9 vs 7.3 mo<br>(HR 0.54, 95% CI 0.41-0.71)<br><br>Superior OS<sup>1</sup> (secondary endpoint)<br>Median OS: 33.6 vs 16.9 mo<br>(HR 0.61, 95% CI 0.48-0.79)
 |-
 |}
-''Note: reported efficacy is based on the 2018 update.''
+''<sup>1</sup>Reported efficacy is based on the 2020 update.''
-====Chemotherapy====
+<div class="toccolours" style="background-color:#b3e2cd">
+====Targeted therapy====
-*[[Binimetinib (Mektovi)]] 45 mg PO twice per day
+*[[Binimetinib (Mektovi)]] 45 mg PO twice per day on days 1 to 28
-*[[Encorafenib (Braftovi)]] 450 mg PO once per day
+*[[Encorafenib (Braftovi)]] 450 mg PO once per day on days 1 to 28
+'''28-day cycles'''
-'''Continued indefinitely'''
+</div></div>
 ===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. [https://doi.org/10.1016/S1470-2045(18)30142-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/29573941/ PubMed] [https://clinicaltrials.gov/study/NCT01909453 NCT01909453]
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30142-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29573941 PubMed]
+##'''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. [https://doi.org/10.1016/S1470-2045(18)30497-2 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30219628/ PubMed]
-##'''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 Sep 12. [Epub ahead of print] [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30497-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30219628 PubMed]
+## '''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. [https://doi.org/10.1016/j.ejca.2019.11.016 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31901705/ PubMed]
+## '''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. [https://doi.org/10.1200/jco.21.02659 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9916040/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35862871/ PubMed]
+##'''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. [https://doi.org/10.1200/jco.22.02322 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc10564308/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/37506329/ PubMed]
+##'''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. [https://doi.org/10.1016/j.ejca.2024.114073 link to original article] [https://clinical-trials.dimensions.ai/columbus7/ interactive data visualization] [https://pubmed.ncbi.nlm.nih.gov/38723373/ PubMed]
 ==Cobimetinib & Vemurafenib {{#subobject:PYR3|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:PYV3|Variant=1}}===
 {| class="wikitable" style="color:white; background-color:#404040"
@@ Line 137: / Line 139: @@
 |-
 |}
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
+!style="width: 20%"|Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Dates of enrollment
-! style="width: 25%" |Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1408868 Larkin et al. 2014 (coBRIM)]
+|[https://doi.org/10.1056/NEJMoa1408868 Larkin et al. 2014 (coBRIM)]
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
-|[[#Vemurafenib_monotherapy|Vemurafenib]]
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-88-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
-| style="background-color:#1a9850" |Superior OS (*)
+|-
+|} -->
+|2013-01 to 2014-01
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+|[[#Vemurafenib_monotherapy_2|Vemurafenib]]
+| style="background-color:#1a9850" |Superior PFS<sup>1</sup> (primary endpoint)<br>Median PFS: 12.3 vs 7.2 mo<br>(HR 0.58, 95% CI 0.46-0.72)<br><br>Superior OS<sup>1</sup> (secondary endpoint)<br>Median OS: 22.3 vs 17.4 mo<br>(HR 0.70, 95% CI 0.55-0.90)
+|-
+|[https://doi.org/10.1016/s0140-6736(20)30934-x Gutzmer et al. 2020 (IMspire150)]
+|2017-01-13 to 2018-04-26
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Cobimetinib.2C_Vemurafenib.2C_Atezolizumab|Cobimetinib, Vemurafenib, Atezolizumab]]
+| style="background-color:#fc8d59" |Seems to have inferior PFS
 |-
 |}
-''Efficacy reported for coBRIM is based on the 2016 update.''
+''<sup>1</sup>Reported efficacy for coBRIM is based on the 2016 update.''
-====Chemotherapy====
+<div class="toccolours" style="background-color:#b3e2cd">
+====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'''
+</div></div>
 ===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. [https://doi.org/10.1056/NEJMoa1408868 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25265494/ PubMed] [https://clinicaltrials.gov/study/NCT01689519 NCT01689519]
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1408868 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25265494 PubMed]
+##'''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. [https://doi.org/10.1016/S1470-2045(16)30122-X link to original article] [https://pubmed.ncbi.nlm.nih.gov/27480103/ PubMed]
-##'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30122-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27480103 PubMed]
+#'''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. [https://doi.org/10.1016/s0140-6736(20)30934-x link to original article] [https://pubmed.ncbi.nlm.nih.gov/32534646/ PubMed] [https://clinicaltrials.gov/study/NCT02908672 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. [https://doi.org/10.1016/s1470-2045(22)00687-8 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36460017/ PubMed]
-==Dabrafenib monotherapy {{#subobject:8f3562|Regimen=1}}==
+==Cobimetinib, Vemurafenib, Atezolizumab {{#subobject:Pq0vb3|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:P8gajc3|Variant=1}}===
+{| class="wikitable" style="color:white; background-color:#404040"
+|<small>'''FDA-recommended dose'''</small>
+|-
+|}
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+!style="width: 20%"|Study
+!style="width: 20%"|Dates of enrollment
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|[https://doi.org/10.1016/s0140-6736(20)30934-x Gutzmer et al. 2020 (IMspire150)]
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-232-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
+|-
+|} -->
+|2017-01-13 to 2018-04-26
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+|[[#Cobimetinib_.26_Vemurafenib|Cobimetinib & Vemurafenib]]
+| style="background-color:#91cf60" |Seems to have superior PFS (primary endpoint)<br>Median PFS: 15.1 vs 10.6 mo<br>(HR 0.78, 95% CI 0.63-0.97)
 |-
-|[[#top|back to top]]
 |}
+''Note: dosing details are from the FDA recommended dosing and are not available in the abstract.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Targeted therapy====
+*[[Cobimetinib (Cotellic)]] 60 mg PO once per day on days 1 to 21
+*[[Vemurafenib (Zelboraf)]] 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'''
+</div></div>
+===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. [https://doi.org/10.1016/s0140-6736(20)30934-x link to original article] [https://pubmed.ncbi.nlm.nih.gov/32534646/ PubMed] [https://clinicaltrials.gov/study/NCT02908672 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. [https://doi.org/10.1016/s1470-2045(22)00687-8 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36460017/ PubMed]
+==Dabrafenib monotherapy {{#subobject:8f3562|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
 ===Regimen {{#subobject:fa5aa0|Variant=1}}===
 {| class="wikitable" style="color:white; background-color:#404040"
@@ Line 172: / Line 220: @@
 |-
 |}
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
+!style="width: 20%"|Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Dates of enrollment
-! style="width: 25%" |Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60868-X/fulltext Hauschild et al. 2012 (BREAK-3)]
+|[https://doi.org/10.1016/S0140-6736(12)60868-X Hauschild et al. 2012 (BREAK-3)]
-| style="background-color:#1a9851" |Phase III (E-RT-switch-ooc)
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-86-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
+|-
+|} -->
+|2010-12-23 to 2011-09-01
+| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
 |[[#Dacarbazine_monotherapy|Dacarbazine]]
-| style="background-color:#1a9850" |Superior PFS
+| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 5.1 vs 2.7 mo<br>(HR 0.30, 95% CI 0.18-0.51)
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549295/ Flaherty et al. 2012]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549295/ Flaherty et al. 2012 (Novartis 113220)]
-| style="background-color:#1a9851" |Randomized Phase II (C)
+|2010-2011
+| style="background-color:#1a9851" |Randomized Phase 2 (C)
 |[[#Dabrafenib_.26_Trametinib_2|Dabrafenib & Trametinib]]
 | style="background-color:#d73027" |Inferior PFS
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1406037 Long et al. 2014 (COMBI-d)]
+|[https://doi.org/10.1056/NEJMoa1406037 Long et al. 2014 (COMBI-d)]
-| style="background-color:#1a9851" |Phase III (C)
+|2012-05 to 2013-01
+| style="background-color:#1a9851" |Phase 3 (C)
 |[[#Dabrafenib_.26_Trametinib_2|Dabrafenib & Trametinib]]
 | style="background-color:#fc8d59" |Seems to have inferior OS
 |-
 |}
-====Chemotherapy====
+<div class="toccolours" style="background-color:#b3e2cd">
+====Targeted therapy====
 *[[Dabrafenib (Tafinlar)]] 150 mg PO twice per day
 '''Continued indefinitely'''
+</div></div>
 ===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. [https://doi.org/10.1016/S0140-6736(12)60868-X link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22735384/ PubMed] [https://clinicaltrials.gov/study/NCT01227889 NCT01227889]
-#'''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60868-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22735384 PubMed]
+##'''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. [https://doi.org/10.1093/annonc/mdu154 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24769640/ PubMed]
-#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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1210093 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549295/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23020132 PubMed]
+##'''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. [https://doi.org/10.1016/j.ejca.2019.10.033 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8073226/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31864178/ PubMed]
-##'''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. [https://ascopubs.org/doi/full/10.1200/JCO.2015.62.9345 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26811525 PubMed]
+#'''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. [https://doi.org/10.1056/NEJMoa1210093 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549295/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23020132/ PubMed] [https://clinicaltrials.gov/study/NCT01072175 NCT01072175]
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1406037 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25265492 PubMed]
+##'''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. [https://doi.org/10.1200/JCO.2015.62.9345 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26811525/ PubMed]
-##'''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60898-4/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26037941 PubMed]
+#'''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. [https://doi.org/10.1056/NEJMoa1406037 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25265492/ PubMed] [https://clinicaltrials.gov/study/NCT01584648 NCT01584648]
-##'''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. [https://academic.oup.com/annonc/article-lookup/doi/10.1093/annonc/mdx176 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28475671 PubMed]
+##'''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. [https://doi.org/10.1016/j.ejca.2015.03.004 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25794603/ PubMed]
-##'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1904059 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/31166680 PubMed]
+##'''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. [https://doi.org/10.1016/S0140-6736(15)60898-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26037941/ PubMed]
+##'''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. [https://doi.org/10.1093/annonc/mdx176 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834102/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28475671/ PubMed]
+##'''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. [https://doi.org/10.1056/NEJMoa1904059 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31166680/ PubMed]
 ==Dabrafenib & Trametinib {{#subobject:7d3694|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:23212f|Variant=1}}===
 {| class="wikitable" style="color:white; background-color:#404040"
@@ Line 220: / Line 273: @@
 |-
 |}
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
+!style="width: 20%"|Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Dates of enrollment
-! style="width: 25%" |Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549295/ Flaherty et al. 2012]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549295/ Flaherty et al. 2012 (Novartis 113220)]
-| style="background-color:#1a9851" |Randomized Phase II (E-esc)
+|2010-2011
+| style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
 |[[#Dabrafenib_monotherapy|Dabrafenib]]
-| style="background-color:#1a9850" |Superior PFS
+| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 9.4 vs 5.8 mo<br>(HR 0.39, 95% CI 0.25-0.62)
+|-
+|[https://doi.org/10.1056/NEJMoa1406037 Long et al. 2014 (COMBI-d)]
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-85-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1406037 Long et al. 2014 (COMBI-d)]
+|} -->
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
+|2012-05 to 2013-01
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 |[[#Dabrafenib_monotherapy|Dabrafenib]]
-| style="background-color:#91cf60" |Seems to have superior OS
+| style="background-color:#91cf60" |Superior PFS<sup>1</sup> (primary endpoint)<br>PFS36: 22% vs 12%<br>(HR 0.71, 95% CI 0.57-0.88)<br><br>Seems to have superior OS<sup>1</sup> (secondary endpoint)<br>OS36: 44% vs 32%<br>(HR 0.75, 95% CI 0.58-0.96)
+|-
+|[https://doi.org/10.1056/NEJMoa1412690 Robert et al. 2014 (COMBI-v)]
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-87-1 <span style="color:white;">ESMO-MCBS (5)</span>]'''
+|-
+|} -->
+|2012-06 to 2013-10
+| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+|[[#Vemurafenib_monotherapy_2|Vemurafenib]]
+| style="background-color:#1a9850" |Superior OS (primary endpoint)<br>OS12: 72% vs 65% <br>(HR 0.69, 95% CI 0.53-0.89)
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1412690 Robert et al. 2014 (COMBI-v)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9061149/ Dummer et al. 2022 (COMBI-i)]
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
+|2017-09-13 to 2018-07-04
-|[[#Vemurafenib_monotherapy|Vemurafenib]]
+| style="background-color:#1a9851" |Phase 3 (C)
-| style="background-color:#1a9850" |Superior OS
+|[[#Dabrafenib.2C_Trametinib.2C_Spartalizumab_777|sparta-DabTram]]
+| style="background-color:#fee08b" |Might have inferior PFS<br>Median PFS: 12 vs 16.2 mo<br>(HR 1.22, 95% CI 0.97-1.52)
 |-
 |}
-====Chemotherapy====
+''<sup>1</sup>Reported efficacy for COMBI-d is based on the 2017 update.''
+<div class="toccolours" style="background-color:#b3e2cd">
-*[[Dabrafenib (Tafinlar)]] 150 mg PO twice per day
+====Targeted therapy====
-*[[Trametinib (Mekinist)]] 2 mg PO once per day
+*[[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
-'''Continued indefinitely'''
+'''28-day cycles'''
+</div></div>
 ===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. [https://doi.org/10.1056/NEJMoa1210093 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549295/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23020132/ PubMed] [https://clinicaltrials.gov/study/NCT01072175 NCT01072175]
-#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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1210093 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549295/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23020132 PubMed]
+##'''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. [https://doi.org/10.1200/JCO.2015.62.9345 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26811525/ PubMed]
-##'''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. [https://ascopubs.org/doi/full/10.1200/JCO.2015.62.9345 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26811525 PubMed]
+#'''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. [https://doi.org/10.1056/NEJMoa1406037 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25265492/ PubMed] [https://clinicaltrials.gov/study/NCT01584648 NCT01584648]
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1406037 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25265492 PubMed]
+##'''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. [https://doi.org/10.1016/j.ejca.2015.03.004 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25794603/ PubMed]
-##'''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60898-4/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26037941 PubMed]
+##'''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. [https://doi.org/10.1016/S0140-6736(15)60898-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26037941/ PubMed]
-##'''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. [https://academic.oup.com/annonc/article-lookup/doi/10.1093/annonc/mdx176 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28475671 PubMed]
+##'''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. [https://doi.org/10.1093/annonc/mdx176 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834102/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28475671/ PubMed]
-##'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1904059 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/31166680 PubMed]
+##'''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. [https://doi.org/10.1056/NEJMoa1904059 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31166680/ PubMed]
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1412690 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25399551 PubMed]
+#'''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. [https://doi.org/10.1056/NEJMoa1412690 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25399551/ PubMed] [https://clinicaltrials.gov/study/NCT01597908 NCT01597908]
-##'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1904059 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/31166680 PubMed]
+##'''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. [https://doi.org/10.1016/s1470-2045(15)00087-x link to original article] [https://pubmed.ncbi.nlm.nih.gov/26433819/ PubMed]
+##'''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. [https://doi.org/10.1056/NEJMoa1904059 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31166680/ PubMed]
+#'''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. [https://doi.org/10.1200/jco.21.01601 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9061149/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35030011/ PubMed] [https://clinicaltrials.gov/study/NCT02967692 NCT02967692]
 ==Dacarbazine monotherapy {{#subobject:d3599b|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:bede4c|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
+!style="width: 20%"|Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Dates of enrollment
-! style="width: 25%" |Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549296/ Chapman et al. 2011 (BRIM-3)]
-| style="background-color:#1a9851" |Phase III (C)
+|2010-01 to 2010-12
-|[[#Vemurafenib_monotherapy|Vemurafenib]]
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Vemurafenib_monotherapy_2|Vemurafenib]]
 | style="background-color:#d73027" |Inferior OS
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60868-X/fulltext Hauschild et al. 2012 (BREAK-3)]
+|[https://doi.org/10.1016/S0140-6736(12)60868-X Hauschild et al. 2012 (BREAK-3)]
-| style="background-color:#1a9851" |Phase III (C)
+|2010-12-23 to 2011-09-01
+| style="background-color:#1a9851" |Phase 3 (C)
 |[[#Dabrafenib_monotherapy|Dabrafenib]]
 | style="background-color:#d73027" |Inferior PFS
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1203421 Flaherty et al. 2012 (METRIC)]
+|[https://doi.org/10.1056/NEJMoa1203421 Flaherty et al. 2012 (METRIC)]
-| style="background-color:#1a9851" |Phase III (C)
+|2010-12 to 2011-07
+| style="background-color:#1a9851" |Phase 3 (C)
 |[[#Trametinib_monotherapy|Trametinib]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
+| style="background-color:#d73027" |Inferior PFS
 |-
 |}
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Dacarbazine (DTIC)]] 1000 mg/m<sup>2</sup> IV once on day 1
 '''21-day cycles'''
+</div></div>
+===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. [https://doi.org/10.1056/NEJMoa1103782 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549296/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21639808/ PubMed] [https://clinicaltrials.gov/study/NCT01006980 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. [https://doi.org/10.1016/s1470-2045(14)70012-9 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382632/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24508103/ PubMed]
+#'''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. [https://doi.org/10.1016/S0140-6736(12)60868-X link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22735384/ PubMed] [https://clinicaltrials.gov/study/NCT01227889 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. [https://doi.org/10.1093/annonc/mdu154 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24769640/ PubMed]
+##'''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. [https://doi.org/10.1016/j.ejca.2019.10.033 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8073226/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31864178/ PubMed]
+#'''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. [https://doi.org/10.1056/NEJMoa1203421 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22663011/ PubMed] [https://clinicaltrials.gov/study/NCT01245062 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. [https://doi.org/10.1093/annonc/mdt580 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc4433512/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24504441/ PubMed]
+##'''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. [https://doi.org/10.1016/j.ejca.2018.12.015 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30690294/ PubMed]
+==Ipilimumab & Nivolumab {{#subobject:51gu10|Regimen=1}}==
+<div class="toccolours" style="background-color:#eeeeee">
+===Regimen {{#subobject:3ab34c|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 17%" |Study
+! style="width: 15%" |Dates of enrollment
+! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
+! style="width: 17%" |Comparator
+! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
+|-
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9839305/ Atkins et al. 2023 (DREAMseq)]
+|2015-07-13 to 2021-09-30
+| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+|[[#Dabrafenib_.26_Trametinib_2|Dabrafenib & Trametinib]], followed by [[#Ipilimumab_.26_Nivolumab|Ipilimumab & Nivolumab]]
+| style="background-color:#1a9850" |Superior OS24 (primary endpoint)<br>OS24: 71.8% vs 51.5%
+| style="background-color:#d73027" |More grade 3 to 5 TRAEs
+|-
+|}
+<div class="toccolours" style="background-color:#b3e2cd">
+====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 cycles for up to 36 cycles (72 weeks)'''
+</div>
+<div class="toccolours" style="background-color:#cbd5e7">
+====Subsequent treatment====
+*DREAMseq, upon progression: Second-line [[#Dabrafenib_.26_Trametinib_2|Dabrafenib & Trametinib]]
+</div></div>
 ===References===
+<!-- # '''Abstract:''' Atkins MB, Lee SJ, Chmielowski B, Ribas A, Tarhini AA, Troung TG, Davar D, O'Rourke MA, Curti BD, Brell JM, Kendra KL, Wolchock JD, Kirkwood JM, Ikeguchi A. Journal of Clinical Oncology 39, no. 36_suppl (December 20, 2021) 356154-356154. [https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.36_suppl.356154 Abstract] -->
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1103782 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549296/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21639808 PubMed]
+#'''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. [https://doi.org/10.1200/JCO.22.01763 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9839305/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/36166727/ PubMed] [https://clinicaltrials.gov/study/NCT02224781 NCT02224781]
-##'''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. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382632/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24508103 PubMed]
-#'''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60868-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22735384 PubMed]
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1203421 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22663011 PubMed]
 ==Paclitaxel monotherapy {{#subobject:bfd5b|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:100b77|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
+!style="width: 20%"|Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Dates of enrollment
-! style="width: 25%" |Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1203421 Flaherty et al. 2012 (METRIC)]
+|[https://doi.org/10.1056/NEJMoa1203421 Flaherty et al. 2012 (METRIC)]
-| style="background-color:#1a9851" |Phase III (C)
+|2010-12 to 2011-07
+| style="background-color:#1a9851" |Phase 3 (C)
 |[[#Trametinib_monotherapy|Trametinib]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
+| style="background-color:#d73027" |Inferior PFS
 |-
 |}
-''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.''
+''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.''
+<div class="toccolours" style="background-color:#b3e2cd">
 ====Chemotherapy====
 *[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1
 '''21-day cycles'''
+</div></div>
 ===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. [https://doi.org/10.1056/NEJMoa1203421 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22663011/ PubMed] [https://clinicaltrials.gov/study/NCT01245062 NCT01245062]
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1203421 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22663011 PubMed]
+##'''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. [https://doi.org/10.1093/annonc/mdt580 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc4433512/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24504441/ PubMed]
+##'''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. [https://doi.org/10.1016/j.ejca.2018.12.015 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30690294/ PubMed]
 ==Trametinib monotherapy {{#subobject:9e1876|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:abc29f|Variant=1}}===
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
+!style="width: 20%"|Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Dates of enrollment
-! style="width: 25%" |Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+!style="width: 20%"|Comparator
-|-
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1203421 Flaherty et al. 2012 (METRIC)]
-| style="background-color:#1a9851" |Phase III (E-RT-switch-ooc)
-|[[#Dacarbazine_monotherapy|Dacarbazine]]<br> [[#Paclitaxel_monotherapy|Paclitaxel]]
-| style="background-color:#91cf60" |Seems to have superior OS
 |-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70269-3/fulltext Falchook et al. 2012 (MEK111054)]
+|[https://doi.org/10.1016/S1470-2045(12)70269-3 Falchook et al. 2012 (MEK111054)]
+|2008-2010
 | style="background-color:#91cf61" |Phase 1, >20 pts in this dosing cohort
 | style="background-color:#d3d3d3" |
 | style="background-color:#d3d3d3" |
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878037/ Kim et al. 2012]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878037/ Kim et al. 2012 (GSK 113583)]
-| style="background-color:#91cf61" |Phase II
+|2009-2010
+| style="background-color:#91cf61" |Phase 2
 | style="background-color:#d3d3d3" |
 | style="background-color:#404040; color:white" |ORR: 25%
+|-
+|[https://doi.org/10.1056/NEJMoa1203421 Flaherty et al. 2012 (METRIC)]
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-84-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
+|-
+|} -->
+|2010-12 to 2011-07
+| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
+|1a. [[#Dacarbazine_monotherapy|Dacarbazine]]<br>1b. [[#Paclitaxel_monotherapy|Paclitaxel]]
+| style="background-color:#1a9850" |Superior PFS<sup>1</sup> (primary endpoint)<br>Median PFS: 4.9 vs 1.5 mo<br>(HR 0.54, 95% CI 0.41-0.73)<br><br>Superior OS (secondary endpoint)<br>OS6: 81% vs 67%<br>(HR 0.54, 95% CI 0.32-0.92)
 |-
 |}
-====Chemotherapy====
+''<sup>1</sup>Reported efficacy for PFS in METRIC is based on the 2019 update.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Targeted therapy====
 *[[Trametinib (Mekinist)]] 2 mg PO once per day
+</div></div>
 ===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. [https://doi.org/10.1056/NEJMoa1203421 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22663011/ PubMed] [https://clinicaltrials.gov/study/NCT01245062 NCT01245062]
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1203421 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22663011 PubMed]
+##'''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. [https://doi.org/10.1093/annonc/mdt580 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc4433512/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24504441/ PubMed]
-##'''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. [https://www.ejcancer.com/article/S0959-8049(18)31561-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30690294 PubMed]
+##'''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. [https://doi.org/10.1016/j.ejca.2018.12.015 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30690294/ PubMed]
-#'''Phase 1:''' 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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70269-3/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109286/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22805292 PubMed]
+#'''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. [https://doi.org/10.1016/S1470-2045(12)70269-3 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109286/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22805292/ PubMed] [https://clinicaltrials.gov/study/NCT00687622 NCT00687622]
-#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. [http://jco.ascopubs.org/content/31/4/482.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878037/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23248257 PubMed]
+#'''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. [https://doi.org/10.1200/jco.2012.43.5966 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878037/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23248257/ PubMed] [https://clinicaltrials.gov/study/NCT01037127 NCT01037127]
 ==Vemurafenib monotherapy {{#subobject:7652e9|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:c639c3|Variant=1}}===
 {| class="wikitable" style="color:white; background-color:#404040"
@@ Line 379: / Line 491: @@
 |-
 |}
-{| class="wikitable" style="width: 100%; text-align:center;"
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
-! style="width: 25%" |Study
+!style="width: 20%"|Study
-! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 20%"|Dates of enrollment
-! style="width: 25%" |Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+!style="width: 20%"|Comparator
+!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3724529/ Flaherty et al. 2010]
-| style="background-color:#91cf61" |Phase I/II
+|NR
+| style="background-color:#91cf61" |Phase 1/2
 | style="background-color:#d3d3d3" |
 | style="background-color:#d3d3d3" |
-|-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549296/ Chapman et al. 2011 (BRIM-3)]
-| style="background-color:#1a9851" |Phase III (E-RT-switch-ooc)
-|[[#Dacarbazine_monotherapy|Dacarbazine]]
-| style="background-color:#1a9850" |Superior OS
 |-
 |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3724515/ Sosman et al. 2012 (BRIM2)]
-| style="background-color:#91cf61" |Phase II (RT)
+|2009-10 to 2010-03
+| style="background-color:#91cf61" |Phase 2 (RT)
 | style="background-color:#d3d3d3" |
 | style="background-color:#9ebcda" |ORR: 53% (95% CI: 44-62)
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1408868 Larkin et al. 2014 (coBRIM)]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549296/ Chapman et al. 2011 (BRIM-3)]
-| style="background-color:#1a9851" |Phase III (C)
+<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
-|[[#Cobimetinib_.26_Vemurafenib|Cobimetinib & Vemurafenib]]
+|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-82-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
-| style="background-color:#d73027" |Inferior OS (*)
+|-
+|} -->
+|2010-01 to 2010-12
+| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
+|[[#Dacarbazine_monotherapy|Dacarbazine]]
+| style="background-color:#1a9850" |Superior OS<sup>1</sup> (co-primary endpoint)<br>Median OS: 13.6 vs 9.7 mo<br>(HR 0.70, 95% CI 0.57-0.87)
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa1412690 Robert et al. 2014 (COMBI-v)]
+|[https://doi.org/10.1056/NEJMoa1412690 Robert et al. 2014 (COMBI-v)]
-| style="background-color:#1a9851" |Phase III (C)
+|2012-06 to 2013-10
+| style="background-color:#1a9851" |Phase 3 (C)
 |[[#Dabrafenib_.26_Trametinib_2|Dabrafenib & Trametinib]]
 | style="background-color:#d73027" |Inferior OS
 |-
-| rowspan="2" |[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30142-6/fulltext Dummer et al. 2018 (COLUMBUS)]
+|[https://doi.org/10.1056/NEJMoa1408868 Larkin et al. 2014 (coBRIM)]
-| rowspan="2" style="background-color:#1a9851" |Phase III (C)
+|2013-01 to 2014-01
+| style="background-color:#1a9851" |Phase 3 (C)
+|[[#Cobimetinib_.26_Vemurafenib|Cobimetinib & Vemurafenib]]
+| style="background-color:#d73027" |Inferior OS<sup>2</sup>
+|-
+| rowspan="2" |[https://doi.org/10.1016/S1470-2045(18)30142-6 Dummer et al. 2018 (COLUMBUS)]
+|rowspan=2|2013-12-30 to 2015-04-10
+| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
 |1. [[#Binimetinib_.26_Encorafenib|Binimetinib & Encorafenib]]
-| style="background-color:#d73027" |Inferior OS (*)
+| style="background-color:#d73027" |Inferior OS<sup>3</sup>
 |-
-|2. Encorafenib
+|2. [[Stub#Encorafenib_monotherapy|Encorafenib]]
 | style="background-color:#d3d3d3" |Not reported
 |-
 |}
-''Note: Reported efficacy for coBRIM is based on the 2016 update. Reported efficacy for COLUMBUS is based on the 2018 update.''
+''<sup>2</sup>Reported efficacy for BRIM-3 is based on the 2014 update.''<br>
-====Chemotherapy====
+''<sup>2</sup>Reported efficacy for coBRIM is based on the 2016 update.''<br>
+''<sup>3</sup>Reported efficacy for COLUMBUS is based on the 2018 update.''
+<div class="toccolours" style="background-color:#b3e2cd">
+====Targeted therapy====
 *[[Vemurafenib (Zelboraf)]] 960 mg PO twice per day
 '''Continued indefinitely'''
+</div></div>
 ===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. [https://doi.org/10.1056/NEJMoa1002011 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3724529/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/20818844/ PubMed]
-#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. [https://www.nejm.org/doi/10.1056/NEJMoa1002011 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3724529/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20818844 PubMed]
+#'''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. [https://doi.org/10.1056/NEJMoa1103782 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549296/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21639808/ PubMed] [https://clinicaltrials.gov/study/NCT01006980 NCT01006980]
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1103782 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549296/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21639808 PubMed]
+##'''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. [https://doi.org/10.1016/s1470-2045(14)70012-9 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382632/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24508103/ PubMed]
-##'''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. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382632/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24508103 PubMed]
+#'''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. [https://doi.org/10.1056/NEJMoa1112302 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3724515/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22356324/ PubMed] [https://clinicaltrials.gov/study/NCT00949702 NCT00949702]
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1112302 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3724515/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22356324 PubMed]
+#'''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. [https://doi.org/10.1056/NEJMoa1408868 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25265494/ PubMed] [https://clinicaltrials.gov/study/NCT01689519 NCT01689519]
-#'''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.[https://www.nejm.org/doi/full/10.1056/NEJMoa1408868 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25265494 PubMed]
+##'''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. [https://doi.org/10.1016/S1470-2045(16)30122-X link to original article] [https://pubmed.ncbi.nlm.nih.gov/27480103/ PubMed]
-##'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30122-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27480103 PubMed]
+#'''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. [https://doi.org/10.1056/NEJMoa1412690 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25399551/ PubMed] [https://clinicaltrials.gov/study/NCT01597908 NCT01597908]
-#'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1412690 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25399551 PubMed]
+##'''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. [https://doi.org/10.1016/s1470-2045(15)00087-x link to original article] [https://pubmed.ncbi.nlm.nih.gov/26433819/ PubMed]
-##'''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. [https://www.nejm.org/doi/full/10.1056/NEJMoa1904059 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/31166680 PubMed]
+##'''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. [https://doi.org/10.1056/NEJMoa1904059 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31166680/ PubMed]
-#'''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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30142-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29573941 PubMed]
+#'''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. [https://doi.org/10.1016/S1470-2045(18)30142-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/29573941/ PubMed] [https://clinicaltrials.gov/study/NCT01909453 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 Sep 12. [Epub ahead of print] [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30497-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30219628 PubMed]
+##'''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. [https://doi.org/10.1016/S1470-2045(18)30497-2 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30219628/ PubMed]
+## '''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. [https://doi.org/10.1016/j.ejca.2019.11.016 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31901705/ PubMed]
+## '''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. [https://doi.org/10.1200/jco.21.02659 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9916040/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35862871/ PubMed]
+##'''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. [https://doi.org/10.1200/jco.22.02322 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc10564308/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/37506329/ PubMed]
+##'''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. [https://doi.org/10.1016/j.ejca.2024.114073 link to original article] [https://clinical-trials.dimensions.ai/columbus7/ interactive data visualization] [https://pubmed.ncbi.nlm.nih.gov/38723373/ PubMed]
 =Advanced or metastatic disease, BRAF inhibitor-exposed=
 ==Trametinib monotherapy {{#subobject:a1060c|Regimen=1}}==
-{| class="wikitable" style="float:right; margin-left: 5px;"
+<div class="toccolours" style="background-color:#eeeeee">
-|-
-|[[#top|back to top]]
-|}
 ===Regimen {{#subobject:75aeb1|Variant=1}}===
+{| class="wikitable sortable" style="width: 80%; text-align:center;"
+!style="width: 25%"|Study
-'''Biomarker eligibility criteria'''
+!style="width: 25%"|Dates of enrollment
+!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-Gene: BRAF
+!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-Alteration: mutation [BARF V600E, V600K or V600D]
-Acceptable methods of measurement: IHC and FISH
-'''Chemotherapy'''
-* Trametinib 2 mg oral once daily
-<br />
-{| class="wikitable" style="width: 75%; text-align:center;"
-! style="width: 33%" |Study
-! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
-! style="width: 33%" |[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878037/ Kim et al. 2012]
+|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878037/ Kim et al. 2012 (GSK 113583)]
-| style="background-color:#91cf61" |Phase II
+|2009-2010
+| style="background-color:#91cf61" |Phase 2
 | style="background-color:black; color:white" |ORR: 0%
 |-
 |}
-====Chemotherapy====
+<div class="toccolours" style="background-color:#fdcdac">
+====Biomarker eligibility criteria====
+*Gene: BRAF
+*Alteration: V600E, V600K, or V600D
+</div>
+<div class="toccolours" style="background-color:#b3e2cd">
+====Targeted therapy====
 *[[Trametinib (Mekinist)]] 2 mg PO once per day
+</div></div>
 ===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. [https://doi.org/10.1200/jco.2012.43.5966 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878037/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23248257/ PubMed] [https://clinicaltrials.gov/study/NCT01037127 NCT01037127]
-#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. [http://jco.ascopubs.org/content/31/4/482.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878037/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23248257 PubMed]
 [[Category:Melanoma regimens]]
 [[Category:Biomarker-specific pages]]
 [[Category:Skin cancers]]

Difference between revisions of "Melanoma, BRAF-mutated"

Latest revision as of 12:18, 23 June 2024

Guidelines

NCCN

Adjuvant therapy

Dabrafenib & Trametinib

Regimen

Preceding treatment

Targeted therapy

References

Vemurafenib monotherapy

Regimen

Preceding treatment

Targeted therapy

References

Advanced or metastatic disease, BRAF inhibitor-naive

Binimetinib & Encorafenib

Regimen

Targeted therapy

References

Cobimetinib & Vemurafenib

Regimen

Targeted therapy

References

Cobimetinib, Vemurafenib, Atezolizumab

Regimen

Targeted therapy

Immunotherapy

References

Dabrafenib monotherapy

Regimen

Targeted therapy

References

Dabrafenib & Trametinib

Regimen

Targeted therapy

References

Dacarbazine monotherapy

Regimen

Chemotherapy

References

Ipilimumab & Nivolumab

Regimen

Immunotherapy

Subsequent treatment

References

Paclitaxel monotherapy

Regimen

Chemotherapy

References

Trametinib monotherapy

Regimen

Targeted therapy

References

Vemurafenib monotherapy

Regimen

Targeted therapy

References

Advanced or metastatic disease, BRAF inhibitor-exposed

Trametinib monotherapy

Regimen

Biomarker eligibility criteria

Targeted therapy

References

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