Systemic drug therapy in the management of patients with advanced melanoma brain metastases

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Clinical practice guidelines for the diagnosis and management of melanoma > Systemic drug therapy in the management of patients with advanced melanoma brain metastases



Evidence

What is the role of systemic drug therapy in the management of patients with advanced melanoma brain metastases?

Brain metastases are diagnosed in more than 50% of patients with advanced melanoma and are associated with a poor prognosis, with a median overall survival (OS) of 2.8 to 4 months.[1][2] Phase III trials of effective drug therapies have excluded patients with active central nervous system (CNS) metastases, except for specifically designed phase II studies, summarised below. There were no new toxicities observed in this population of active melanoma brain metastases.

A phase 2 trial of the anti-CTLA-4 checkpoint inhibitor ipilimumab (10mg/kg for four doses) demonstrated an intracranial response of 16% (8/51) in neurologically asymptomatic patients (cohort A) but only a 5% (1/21) intracranial response rate in symptomatic (cohort B) patients requiring corticosteroids.[3]

In a small study patients with active melanoma brain metastases treated with the anti-PD-1 checkpoint inhibitor pembrolizumab, the intracranial response was 22% (4/18).[4] Similarly, in the larger randomised phase II Australian Brain Collaboration (ABC) study the intracranial response rate in asymptomatic patients with untreated brain metastases was 21% (5/25) with nivolumab monotherapy, but 46% (16/35) with ipilimumab combined with nivolumab, and 56% for the combination when patients had no prior BRAF and MEK inhibitors.[5] The 12-month progression-free survival (PFS) for the two cohorts were 20% and 53%, respectively, with a plateau in the Kaplan Meier survival curve at approximately 6 months, raising the possibility that a significant proportion of patients may experience long-term disease control. A single-arm study of the combination of ipilimumab and nivolumab in patients with asymptomatic melanoma brain metastases showed an intracranial response rate of 55% in the brain and a 6-month PFS of 67%,[6] although the burden of brain metastases in this trial was lower than that of the ABC trial (proportion of patients with >3 brain metastases was 21% versus 46% with >4 brain metastases in ABC).[5]

Phase II trials of BRAF inhibitor monotherapy for V600 mutant melanoma demonstrated an intracranial response of 39% for dabrafenib and 29% for vemurafenib as assessed by the investigators.[7][8] The combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib was assessed in a phase II trial of four different cohorts of V600 BRAF-mutation positive patients with active melanoma brain metastases.[9] The intracranial response rate was 58% in the largest cohort (n=76, cohort A), which included neurologically asymptomatic patients without previous local (brain) therapy. In contrast to the results with anti-PD-1-based immunotherapy, the PFS decreased from 44% at 6 months to 19% at 12 months, suggesting that responses are short-lived as patients develop resistance.

As there are now many treatment options for the management of melanoma brain metastases, it is strongly recommended that patients be discussed by an expert multidisciplinary team of clinicians including a neurosurgeon, radiation oncologist and medical oncologist to determine the optimal combination or sequencing of both local therapy (surgery and stereotactic radiosurgery) and systemic therapies. Whole brain radiotherapy is now rarely used to treat brain metastases, usually reserved as last-line palliative therapy.

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Evidence summary

Evidence summary Level References
Combined therapy with BRAF and MEK inhibitors induces an intracranial response of 58% in patients with asymptomatic untreated brain metastases whose melanoma has a V600E BRAF mutation. III-1 [9]
Anti-PD-1 monotherapy in drug treatment-naïve patients induces an intracranial response in at least 20% of patients with active melanoma brain metastases. III-1 [4], [5]
Combined ipilimumab and nivolumab in drug treatment-naïve patients induces an intracranial response in approximately 55% of patients with active brain metastases. (In drug treatment-naïve patients, phase II studies demonstrated 56% and 55% intracranial response rates in the Australian Brain Collaboration and the CheckMate 204 studies, respectively, with 6-month progression-free survival rates of 53% and 67%, respectively). III-1 [5], [6]


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Systemic drug therapy is effective in untreated melanoma brain metastases and can be considered as first-line treatment (as an alternative to local brain therapy) in asymptomatic patients, with multidisciplinary support from a radiation oncologist and a neurosurgeon.


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References

  1. Davies MA, Liu P, McIntyre S, Kim KB, Papadopoulos N, Hwu WJ, et al. Prognostic factors for survival in melanoma patients with brain metastases. Cancer 2011 Apr 15;117(8):1687-96 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20960525.
  2. Fife KM, Colman MH, Stevens GN, Firth IC, Moon D, Shannon KF, et al. Determinants of outcome in melanoma patients with cerebral metastases. J Clin Oncol 2004 Apr 1;22(7):1293-300 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15051777.
  3. Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol 2012 May;13(5):459-65 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22456429.
  4. 4.0 4.1 Goldberg SB, Gettinger SN, Mahajan A, Chiang AC, Herbst RS, Sznol M, et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol 2016 Jul;17(7):976-983 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/27267608.
  5. 5.0 5.1 5.2 5.3 Long GV, Atkinson V, Lo S, Sandhu S, Guminski AD, Brown MP, et al. Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Lancet Oncol 2018 Mar 27 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/29602646.
  6. 6.0 6.1 Tawbi HA-H, Forsyth PAJ, Algazi AP, Hamid O, Hodi FS, Moschos SJ, et al. Efficacy and safety of nivolumab (NIVO) plus ipilimumab (IPI) in patients with melanoma (MEL) metastatic to the brain: Results of the phase II study CheckMate 204. J Clin Oncol 2017;35:(suppl; abstr 9507).
  7. Long GV, Trefzer U, Davies MA, Kefford RF, Ascierto PA, Chapman PB, et al. 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 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23051966.
  8. McArthur GA, Maio M, Arance A, Nathan P, Blank C, Avril MF, et al. 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 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/27993793.
  9. 9.0 9.1 Davies MA, Saiag P, Robert C, Grob JJ, Flaherty KT, Arance A, et al. Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol 2017 Jul;18(7):863-873 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/28592387.

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