Revision as of 02:58, 28 January 2022

Section editor transclusions Note: these are regimens tested in biomarker-specific populations, please see the main melanoma page for other regimens.

13 regimens on this page 12 variants on this page

Adjuvant therapy

Dabrafenib & Trametinib

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Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Long et al. 2017 (COMBI-AD)	2013-2014	Phase 3 (E-RT-esc)	Placebo	Superior MFS¹ 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 verified protocol 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. 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

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Maio et al. 2018 (BRIM8)	2012-2015	Phase 3 (E-esc)	Placebo	Might have superior DFS¹ (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 verified protocol PubMed NCT01667419

Advanced or metastatic disease, BRAF inhibitor-naive

Binimetinib & Encorafenib

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Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Dummer et al. 2018 (COLUMBUS)	2013-2015	Phase 3 (E-RT-esc)	1. Encorafenib	Not reported
Dummer et al. 2018 (COLUMBUS)	2013-2015	Phase 3 (E-RT-esc)	2. Vemurafenib	Superior OS¹ Median OS: 33.6 mo 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
Encorafenib (Braftovi) 450 mg PO once per day

Continued indefinitely

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 protocol 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

Cobimetinib & Vemurafenib

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Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Larkin et al. 2014 (coBRIM)	2013-2014	Phase 3 (E-RT-esc)	Vemurafenib	Superior OS¹ (HR 0.70, 95% CI 0.55-0.90)
Gutzmer et al. 2020 (IMspire150)	2017-2018	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 verified protocol 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

Cobimetinib, Vemurafenib, Atezolizumab

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Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Gutzmer et al. 2020 (IMspire150)	2017-2018	Phase 3 (E-RT-esc)	Cobimetinib & Vemurafenib	Seems to have superior PFS Median PFS: 15.1 mo 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

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

Dabrafenib monotherapy

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Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Hauschild et al. 2012 (BREAK-3)	2010-2011	Phase 3 (E-RT-switch-ooc)	Dacarbazine	Superior PFS
Flaherty et al. 2012 (Novartis 113220)	2010-2011	Randomized Phase II (C)	Dabrafenib & Trametinib	Inferior PFS
Long et al. 2014 (COMBI-d)	2012-2013	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 verified protocol PubMed NCT01227889
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 verified protocol 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. 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
2. 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
3. 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

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Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Flaherty et al. 2012 (Novartis 113220)	2010-2011	Randomized Phase II (E-esc)	Dabrafenib	Superior PFS
Long et al. 2014 (COMBI-d)	2012-2013	Phase 3 (E-RT-esc)	Dabrafenib	Seems to have superior OS
Robert et al. 2014 (COMBI-v)	2012-2013	Phase 3 (E-RT-esc)	Vemurafenib	Superior OS OS12: 72% vs 65% (HR 0.69, 95% CI 0.53-0.89)

Targeted therapy

Dabrafenib (Tafinlar) 150 mg PO twice per day
Trametinib (Mekinist) 2 mg PO once per day

Continued indefinitely

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 verified protocol 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. 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
2. 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
3. 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 verified protocol PubMed NCT01597908
1. 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

Dacarbazine monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Chapman et al. 2011 (BRIM-3)	2010	Phase 3 (C)	Vemurafenib	Inferior OS
Hauschild et al. 2012 (BREAK-3)	2010-2011	Phase 3 (C)	Dabrafenib	Inferior PFS
Flaherty et al. 2012 (METRIC)	2010-2011	Phase 3 (C)	Trametinib	Seems to have inferior OS

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 verified protocol 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 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 verified protocol PubMed NCT01227889
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 verified protocol PubMed NCT01245062

Ipilimumab & Nivolumab

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"NIVO1+IPI3", flat-dose maintenance before targeted therapy

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Atkins et al. 2021 (DREAMseq)	2015-2021	Phase 3	Dabrafenib & Trametinib followed by Ipilimumab & Nivolumab	Superior OS	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
- Cycle 5 onwards: 240 mg IV once on day 1

21-day cycle for 4 cycles, then 14-day cycles for up to 72 weeks

Upon progressive disease, patients were switched to targeted therapy with Dabrafenib and Trametinib

Targeted therapy

Dabrafenib (Tafinlar) 150 mg PO twice per day
Trametinib (Mekinist) 2 mg PO once per day

Continued indefinitely

References

DREAMseq: 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. Abstract

Paclitaxel monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Flaherty et al. 2012 (METRIC)	2010-2011	Phase 3 (C)	Trametinib	Seems to have inferior OS

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 verified protocol PubMed NCT01245062

Trametinib monotherapy

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Regimen

Study	Years 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 II		ORR: 25%
Flaherty et al. 2012 (METRIC)	2010-2011	Phase 3 (E-RT-switch-ooc)	1. Dacarbazine 2. Paclitaxel	Seems to have superior OS

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 verified protocol PubMed NCT01245062
1. 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
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. link to original article contains verified protocol 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 verified protocol link to PMC article PubMed NCT01037127

Vemurafenib monotherapy

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Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Flaherty et al. 2010	NR	Phase I/II
Sosman et al. 2012 (BRIM2)	2009-2010	Phase II (RT)		ORR: 53% (95% CI: 44-62)
Chapman et al. 2011 (BRIM-3)	2010	Phase 3 (E-RT-switch-ooc)	Dacarbazine	Superior OS¹ Median OS: 13.6 vs 9.7 mo (HR 0.70, 95% CI 0.57-0.87)
Robert et al. 2014 (COMBI-v)	2012-2013	Phase 3 (C)	Dabrafenib & Trametinib	Inferior OS
Larkin et al. 2014 (coBRIM)	2013-2014	Phase 3 (C)	Cobimetinib & Vemurafenib	Inferior OS²
Dummer et al. 2018 (COLUMBUS)	2013-2015	Phase 3 (C)	1. Binimetinib & Encorafenib	Inferior OS³
Dummer et al. 2018 (COLUMBUS)	2013-2015	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 protocol 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 verified protocol 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 verified protocol 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 verified protocol PubMed NCT01597908
1. 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 protocol 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

Advanced or metastatic disease, BRAF inhibitor-exposed

Trametinib monotherapy

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Regimen

Study	Years of enrollment	Evidence	Efficacy
Kim et al. 2012 (GSK 113583)	2009-2010	Phase II	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 verified protocol link to PMC article PubMed NCT01037127

@@ Line 354: / Line 354: @@
 #'''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://pubmed.ncbi.nlm.nih.gov/22735384 PubMed] NCT01227889
 #'''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://pubmed.ncbi.nlm.nih.gov/22663011 PubMed] NCT01245062
+==Ipilimumab & Nivolumab {{#subobject:51gu10|Regimen=1}}==
+{| class="wikitable" style="float:right; margin-left: 5px;"
+|-
+|[[#top|back to top]]
+|}
+==="NIVO1+IPI3", flat-dose maintenance before targeted therapy {{#subobject:3ab34c|Variant=1}}===
+{| class="wikitable sortable" style="width: 100%; text-align:center;"
+! style="width: 17%" |Study
+! style="width: 15%" |Years 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://ascopubs.org/doi/abs/10.1200/JCO.2021.39.36_suppl.356154 Atkins et al. 2021 (DREAMseq)]
+|2015-2021
+| style="background-color:#1a9851" |Phase 3
+|Dabrafenib & Trametinib followed by Ipilimumab & Nivolumab
+| style="background-color:#1a9850" |Superior OS
+| style="background-color:#d73027" |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
+**Cycle 5 onwards: 240 mg IV once on day 1
+'''21-day cycle for 4 cycles, then 14-day cycles for up to 72 weeks'''
+*'''Upon progressive disease, patients were switched to targeted therapy with Dabrafenib and Trametinib'''
+====Targeted therapy====
+*[[Dabrafenib (Tafinlar)]] 150 mg PO twice per day
+*[[Trametinib (Mekinist)]] 2 mg PO once per day
+'''Continued indefinitely'''
+===References===
+# '''DREAMseq:''' 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]
 ==Paclitaxel monotherapy {{#subobject:bfd5b|Regimen=1}}==

Difference between revisions of "Melanoma, BRAF-mutated"

Revision as of 02:58, 28 January 2022

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

"NIVO1+IPI3", flat-dose maintenance before targeted therapy

Immunotherapy

Targeted therapy

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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