CNS melanoma

Section editors
	Seema Nagpal, MD Stanford University Palo Alto, CA		Elizabeth Buchbinder, MD Dana-Farber Cancer Institute Boston, MA LinkedIn

5 regimens on this page 5 variants on this page

Note: these are CNS-specific regimens, please see the main melanoma page for other regimens.

Guidelines

EANO/ESMO

• 2017: Le Rhun et al. EANO–ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with leptomeningeal metastasis from solid tumours

NCCN

• NCCN Guidelines - Central Nervous System Cancers

All lines of therapy

Dabrafenib monotherapy

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Efficacy
Long et al. 2012 (BREAK-MB)	2011	Phase 2 (RT)	ORR: 31-39%

Biomarker eligibility criteria

• BRAF V600 mutant
• Study Inclusion criteria: Val600Glu or Val600Lys

Targeted therapy

• Dabrafenib (Tafinlar) 150 mg PO twice per day

Continued indefinitely

References

1. BREAK-MB: Long GV, Trefzer U, Davies MA, Kefford RF, Ascierto PA, Chapman PB, Puzanov I, Hauschild A, Robert C, Algazi A, Mortier L, Tawbi H, Wilhelm T, Zimmer L, Switzky J, Swann S, Martin AM, Guckert M, Goodman V, Streit M, Kirkwood JM, Schadendorf D. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2012 Nov;13(11):1087-95. Epub 2012 Oct 8. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry

Dabrafenib & Trametinib

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Efficacy
Davies et al. 2017 (COMBI-MB)	2014-2016	Phase 2 (RT)	ORR: 44-59%

Biomarker eligibility criteria

• BRAF V600 mutant
• Clinical Trial Inclusion: BRAF V600 E/K/D/R

Targeted therapy

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

Continued indefinitely

References

1. COMBI-MB: Davies MA, Saiag P, Robert C, Grob JJ, Flaherty KT, Arance A, Chiarion-Sileni V, Thomas L, Lesimple T, Mortier L, Moschos SJ, Hogg D, Márquez-Rodas I, Del Vecchio M, Lebbé C, Meyer N, Zhang Y, Huang Y, Mookerjee B, Long GV. Dabrafenib plus trametinib in patients with BRAF(V600)-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol. 2017 Jul;18(7):863-873. Epub 2017 Jun 4. link to original article contains dosing details in abstract link to PMC article PubMed Clinical Trial Registry

Fotemustine monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Mornex et al. 2003	1991-1997	Phase 3 (C)	Fotemustine & WBRT	Did not meet endpoint of OS
Di Giacomo et al. 2021 (NIBIT-M2)	2013-2018	Phase 3 (C)	1. Fotemustine & Ipilimumab	Did not meet primary endpoint of OS
			2. Ipilimumab & Nivolumab	Inferior OS

Chemotherapy

• Fotemustine (Muphoran)

References

1. Mornex F, Thomas L, Mohr P, Hauschild A, Delaunay MM, Lesimple T, Tilgen W, Bui BN, Guillot B, Ulrich J, Bourdin S, Mousseau M, Cupissol D, Bonneterre ME, De Gislain C, Bensadoun RJ, Clavel M. A prospective randomized multicentre phase III trial of fotemustine plus whole brain irradiation versus fotemustine alone in cerebral metastases of malignant melanoma. Melanoma Res. 2003 Feb;13(1):97-103. link to original article PubMed
2. NIBIT-M2: Di Giacomo AM, Chiarion-Sileni V, Del Vecchio M, Ferrucci PF, Guida M, Quaglino P, Guidoboni M, Marchetti P, Cutaia O, Amato G, Covre A, Camerini R, Calabrò L, Valente M, Giannarelli D, Mandalà M, Maio M. Primary Analysis and 4-Year Follow-Up of the Phase III NIBIT-M2 Trial in Melanoma Patients With Brain Metastases. Clin Cancer Res. 2021 Sep 1;27(17):4737-4745. Epub 2021 Jun 10. link to original article PubMed Clinical Trial Registry

Ipilimumab & Nivolumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Di Giacomo et al. 2021 (NIBIT-M2)	2013-2018	Phase 3 (E-esc)	1. Fotemustine	Superior OS Median OS: 29.2 vs 8.5 mo (HR 0.44, 95% CI 0.22-0.87)
			2. Fotemustine & Ipilimumab	Not reported
Long et al. 2018 (ANZMTG 01.14)	2014-2017	Randomized Phase 2 (E-esc)	Nivolumab	Did not meet primary endpoint of intracranial response from week 12
Tawbi et al. 2018 (CheckMate 204)	2015-2017	Phase 2

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: 3 mg/kg IV over 60 minutes once on day 1

21-day cycle for 4 cycles, then 14-day cycles

References

1. ANZMTG 01.14: Long GV, Atkinson V, Lo S, Sandhu S, Guminski AD, Brown MP, Wilmott JS, Edwards J, Gonzalez M, Scolyer RA, Menzies AM, McArthur GA. Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Lancet Oncol. 2018 Mar 27. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
2. CheckMate 204: Tawbi HA, Forsyth PA, Algazi A, Hamid O, Hodi FS, Moschos SJ, Khushalani NI, Lewis K, Lao CD, Postow MA, Atkins MB, Ernstoff MS, Reardon DA, Puzanov I, Kudchadkar RR, Thomas RP, Tarhini A, Pavlick AC, Jiang J, Avila A, Demelo S, Margolin K. Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain. N Engl J Med. 2018 Aug 23;379(8):722-730. link to original article link to PMC article contains dosing details in manuscript PubMed Clinical Trial Registry
   1. Update: Tawbi HA, Forsyth PA, Hodi FS, Lao CD, Moschos SJ, Hamid O, Atkins MB, Lewis K, Thomas RP, Glaspy JA, Jang S, Algazi AP, Khushalani NI, Postow MA, Pavlick AC, Ernstoff MS, Reardon DA, Puzanov I, Kudchadkar RR, Tarhini AA, Sumbul A, Rizzo JI, Margolin KA. Safety and efficacy of the combination of nivolumab plus ipilimumab in patients with melanoma and asymptomatic or symptomatic brain metastases (CheckMate 204). Neuro Oncol. 2021 Nov 2;23(11):1961-1973. link to original article link to PMC article PubMed
3. NIBIT-M2: Di Giacomo AM, Chiarion-Sileni V, Del Vecchio M, Ferrucci PF, Guida M, Quaglino P, Guidoboni M, Marchetti P, Cutaia O, Amato G, Covre A, Camerini R, Calabrò L, Valente M, Giannarelli D, Mandalà M, Maio M. Primary Analysis and 4-Year Follow-Up of the Phase III NIBIT-M2 Trial in Melanoma Patients With Brain Metastases. Clin Cancer Res. 2021 Sep 1;27(17):4737-4745. Epub 2021 Jun 10. link to original article PubMed Clinical Trial Registry

Vemurafenib monotherapy

Regimen

Study	Dates of enrollment	Evidence
McArthur et al. 2017 (MO25743)	2011-2013	Phase 2 (RT)

Biomarker eligibility criteria

• BRAFV600 mutant

Targeted therapy

• Vemurafenib (Zelboraf)

References

1. MO25743: McArthur GA, Maio M, Arance A, Nathan P, Blank C, Avril MF, Garbe C, Hauschild A, Schadendorf D, Hamid O, Fluck M, Thebeau M, Schachter J, Kefford R, Chamberlain M, Makrutzki M, Robson S, Gonzalez R, Margolin K. Vemurafenib in metastatic melanoma patients with brain metastases: an open-label, single-arm, phase 2, multicentre study. Ann Oncol. 2017 Mar 1;28(3):634-641. link to original article PubMed Clinical Trial Registry