Up to half of all patients with advanced melanoma develop secondary tumours in the brain, known as metastases, and average survival among these patients is just 4 months. Ipilimumab, which has been shown to improve the overall survival in people with advanced melanoma, potentially shrinks some tumours and may slow progression of brain metastasis in some patients, according to results of a phase 2 trial published Online First in the Lancet Oncology.
"Currently, there is no effective systemic treatment for melanoma brain metastases, and patients whose cancer has spread to the brain are frequently excluded from promising clinical trials", explains Kim Margolin from the Seattle Cancer Care Alliance in the USA, lead author of the study. "Our results show that antitumour activity, 2-year survival, and safety are similar to what has been reported in patients without brain metastases."*
Ipilimumab is from a new class of immune-based drugs which change the way the immune system works to attack the cancer. Until now, a prospective study of the drug's level of activity in patients with melanoma and brain metastases has not been done.
In this study, the investigators recruited 72 patients with brain metastases into two cohorts: neurologically asymptomatic patients (cohort A; 51 patients) and symptomatic patients receiving corticosteroids for clinical or radiological control of their brain metastases (cohort B; 21 patients). Patients were given 10 mg/kg of ipilimumab every 3 weeks for four doses, with maintenance treatment every 12 weeks for patients who were clinically stable at week 24.
After 3 months of treatment, nine (18%) of patients in cohort A, who were not corticosteroid-dependent, achieved disease control (partial response or stable disease), while one (5%) patient receiving corticosteroids when they began ipilimumab (cohort B) therapy achieved a complete response.
Long-term survival was similar to that reported for patients without brain metastases, with almost one-third of patients in both cohorts alive at 12 months. In cohort A, 26% of patients were alive at 2 years while only two (10%) patients in cohort B were still alive at 2 years.
The authors hypothesize that steroids might have a negative effect on ipilimumab activity, but caution against overinterpretation of these data: "This study design did not permit the assessment of other potentially unfavourable prognostic factors in cohort B such as tumour size, number and extent of peritumoral oedema and prior therapies."*
Ipilimumab was associated with a number of immune-related side effects including diarrhoea, rash, fatigue, nausea, dehydration, pruritus, and hyperglycaemia comparable to those reported in previous studies at the same dose and schedule. One patient died of ipilimumab-related colitis. Importantly, no excessive or unique CNS toxicities as a result of ipilimumab given to patients with brain metastases were observed.
In an accompanying Comment, Rosalie Fisher and James Larkin from the Royal Marsden Hospital, London, UK, say: "Ipilimumab is now a standard of care for advanced melanoma and, in our view, these data show that the presence of brain metastases should not prevent the use of ipilimumab."
They add: "The era in which patients with brain metastases are excluded from clinical trials must end. Brain metastases are a major problem for patients with advanced melanoma and their families and we need to offer them active drugs as a matter of urgency."
Professor Kim Margolin from the Seattle Cancer Care Alliance, Seattle, USA. T) 206-288-7565 E) kmargoli@seattlecca.org
For Dr James Larkin, Royal Marsden Hospital, London, UK, please contact Belinda Payne, Press Office, Royal Marsden Hospital. T) 44-207-8082605 E) belinda.payne@rmh.nhs.uk
Notes to Editors *Quotes direct from author and cannot be found in text of Article.
Journal
The Lancet Oncology