Immunotherapy
Interleukin-2 (IL-2)
Historically high dose IL-2 has had a limited role in advanced melanoma in patients with good performance status and organ function and no established role in treating brain metastasis. The need for hospitalisation and the propensity to cause serious deleterious side effects including multiorgan failure, fatal cerebral edema and severe neurotoxicity limits its use. A large retrospective study showed some evidence of activity in patients with previously treated brain metastasis with little benefit in the untreated cohort. However a recent retrospective review of eight patients with stable brain metastasis showed progressive disease in 7/8 patients, with several grade three events.
Checkpoint Inhibitors
Ipilimumab. The fully humanised monoclonal antibody against cytotoxic T lymphocyte antigen-4 (CTLA4), ipilimumab, shows activity in melanoma brain metastasis, particularly if asymptomatic and improves OS. A phase 2, multicentre, open-label study administered four doses of 10 mg/kg q3 weekly, followed by maintenance therapy, to 72 metastatic melanoma patients with brain metastasis; cohort A (n=51), asymptomatic patients and cohort B (n=21), symptomatic patients requiring corticosteroids. The global disease control was 18% [modified World Health Organisation (mWHO)] and 26% (immune-related response criteria-irRC) for cohort A and 5% (mWHO) and 10% (irRC) for cohort B. The median OS was 7 months for cohort A and 3.7 months for cohort B. Twelve patients (24%) in cohort A and two patients (10%) in cohort B achieved disease control within the brain. Interestingly, 33% (17/51) in cohort A and 24% (5/21) in cohort B, had prior WBRT. The most common adverse events were fatigue, diarrhoea, nausea, headache, rash and pruritis. A phase 2 study of ipilimumab and fotemustine showed an overall immune disease control rate of rate of 50% and a median progression free survival of 4.3 months, with increased incidence of both haematological and non-haematological toxicity. A phase 3 trial of this combination (EudraCT Number: 2012-004301-27, NIBIT-M2) is currently active.
PD1/PDL1 Inhibitors and Combinations. Long term exposure of T-cells to melanoma antigens leads to expression of programmed cell death 1 (PD-1) receptor (binds to its primary ligand PDL1 within the tumour microenvironment) and second ligand PDL2 by antigen presenting cells, resulting in negative regulation of the effector phase of T-cell responses against melanoma cells. A small study showed marked heterogeneity of PDL1 expression, by immunohistochemistry, between the primary and the metastasis and a positive correlation between PDL1 expression in locoregional metastasis and melanoma specific survival. PDL1 was expressed in about 47% of brain metastasis. Anti-PD1 antibody nivolumab and pembrolizumab have demonstrated highly durable response rates (RR 41% and 38% respectively), with minimal toxicity, in large phase 1 trials and these were further confirmed in subsequent phase 3 trials of these agents versus chemotherapy in the first line and in the second line setting after failure of anti-CTLA4 therapy. These agents in combination with ipilimumab are currently explored in several ongoing phase 2 trials in advanced melanoma patients with (NCT02374242, NCT02320058) and without (NCT01866319, NCT01721772) brain metastasis. A recent phase 1 trial of anti-PDL1 antibody (MPDL3280A) has shown activity in metastatic melanoma.
Anti-PD1 Brain Collaboration (ABC) (NCT02374242) is an Australian Brain randomised phase 2 trial exploring the activity of anti-PD1 antibody alone and in combination with ipilimumab, in melanoma brain metastasis. Eligible patients are those with histologically confirmed metastatic melanoma, measurable brain lesions (5–40 mm) and immunotherapy naïve. Refractoriness to prior BRAF therapy does not preclude participation in the trial. Six patients will initially be enrolled into cohort 1 (asymptomatic and previously untreated brain metastases) and cohort 2 (patients with previously treated brain metastases that have progressed after local treatment, and/or patients who have neurological symptoms related to brain metastases, and/or have leptomeningeal disease). Patients in cohort 1 and 2 will receive nivolumab 3 mg/kg, every 2 weeks. An interim safety analysis will be conducted when six patients from cohort 1 have received 6 weeks of therapy with nivolumab; to assess adverse events related to brain metastases, such as intracranial haemorrhage, seizure or other neurological toxicity. If these adverse events are acceptable (occur in ≤2 of the six patients at a CTCAE grade no higher than 2), then the study will be extended to include an additional cohort of 30 patients with asymptomatic and previously untreated brain metastases to a combination of nivolumab (1 mg/kg, every 2 weeks, for four doses, then continue 3 mg/kg every 2 weeks subsequently) and ipilimumab (3 mg/kg, every 3 weeks for four doses). The primary endpoint is the intracranial response rate (complete and partial response in intracranial metastases as measured using RECIST 1.1 criteria (modified for brain metastasis). Another phase 2 trial (NCT02320058) is also exploring the activity of combination of ipilimumab and nivolumab in active melanoma brain metastases.