Responses, Albeit Few, for Ipilimumab-Treated Melanoma Patients with Brain Metastases
Responses, Albeit Few, for Ipilimumab-Treated Melanoma Patients with Brain Metastases
Abstract & Commentary
By William B. Ershler, MD
Synopsis: Ipilimumab has recently been approved for the treatment of advanced melanoma. The current trial was undertaken to determine its safety and efficacy in patients with brain involvement. Toxicity was manageable and not significantly different than observed in treatment of melanoma patients without brain metastases. There were no complete responses but partial response or stable disease was observed in just under 20% of those with limited (asymptomatic) brain involvement. For those with more extensive brain involvement only 1 of 21 showed partial regression.
Source: Margolin K, et al. Ipilimumab in patients with melanoma and brain metastases: An open label, phase 2 trial. Lancet Oncol 2012;13:459-465.
Brain metastases are a common feature of melanoma, occurring in as many as 75% of patients who die with this disease.1 Although patients with brain involvement are often treated with surgery, stereotactic radiosurgery, or whole brain irradiation, median survival is < 6 months.2 Systemic therapy, although commonly attempted, particularly with temozolomide, results in objective responses in only 10% of such patients.3 Immunological approaches have provided benefit for patients without brain involvement, but not convincingly for patients with brain metastases. Among novel immunological approaches, ipilimumab recently was FDA approved for first-line treatment for patients presenting with advanced disease.
Ipilimumab is a monoclonal antibody that blocks the interaction between cytotoxic T-lymphocytic antigen-4 (CTLA-4) and its ligands CD80/86 and thereby augments T-cell activation and proliferation.4,5 In Phase 2 and 3 studies, ipilimumab has proven active in the treatment of advanced melanoma.6-9 The study reported by Hodi et al included 11% (of a total of 540) with brain metastases, and treatment responses in terms of survival were comparable to those without brain metastases.9
The current study was designed to determine the safety and activity of this drug specifically for those patients with brain metastases. Between July 31, 2008, and June 3, 2009, the investigators enrolled adult patients at 10 U.S. centers stratified into two parallel cohorts. Patients in cohort A were neurologically asymptomatic and were not receiving corticosteroid treatment at study entry; those in cohort B were symptomatic and on a stable dose of corticosteroids. Patients were treated with four doses of 10 mg/kg intravenous ipilimumab at 3-week intervals. Individuals who were clinically stable at week 24 were eligible to receive additional ipilimumab treatments (10 mg/kg) every 12 weeks. The primary endpoint was the proportion of patients with disease control, defined as complete response, partial response, or stable disease after 12 weeks. Analyses of safety and efficacy included all treated patients.
In all, 72 patients were enrolled. Of these, 51 were in cohort A and 21 were in cohort B. After 12 weeks, nine patients in cohort A exhibited disease control (18%), as did one patient in cohort B (5%). When the brain alone was assessed, 12 patients in cohort A (24%) and two in cohort B (10%) achieved disease control. Disease outside of the brain was controlled in 14 patients (27%) in cohort A and in one individual (5%) in cohort B.
Adverse events were somewhat different in cohorts A and B. The most common grade 3 adverse events in cohort A were diarrhea (six patients [12%]) and fatigue (six [12%]), whereas in cohort B, they were dehydration (two individuals [10%]), hyperglycaemia (two [10%]), and increased concentrations of serum aspartate aminotransferase (two [10%]). One patient in each cohort had grade 4 confusion. One patient in cohort A died of drug-related complications of immune-related colitis.
Commentary
Effective treatment for patients with metastatic melanoma has proven elusive, and this is particularly true for those with brain involvement. For years, experimental immunotherapeutic approaches have held the greatest promise, but their application in the community has been limited by the complex technical procedures and expense, let alone paucity of randomized clinical trial data to support such an approach. That stated, ipilimumab, a potent but non-specific stimulant of immune processes, has been shown to improve survival for patients with advanced disease and the current report suggests its benefit may extend to those with brain metastases, particularly if the metastatic involvement in the brain is limited (asymptomatic). No doubt, this is a step forward. But a small one. Toxicity, particularly immune-related adverse events, can be remarkable despite careful clinical monitoring; the drug is very expensive; and much less than a majority exhibited "stable disease" measured at 12 weeks.
Thus, ipilimumab has assumed a role in the treatment of advanced melanoma, and no doubt there will be a larger experience reported as community oncologists become familiar and comfortable with its use. Alone, it has some limited activity for patients with brain metastases, and it is hoped that ongoing trials will demonstrate more substantial success when it is combined with chemotherapy or used as an adjunct to surgery or radiation.
References
1. Bafaloukos D, Gogas H. The treatment of brain metastases in melanoma patients. Cancer Treat Rev 2004;30:515-520.
2. Davies MA, et al. Prognostic factors for survival in melanoma patients with brain metastases. Cancer 2011;117:1687-1696.
3. Agarwala SS, et al. Temozolomide for the treatment of brain metastases associated with metastatic melanoma: A phase II study. J Clin Oncol 2004;22:2101-2107.
4. Leach DR, et al. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996;271:1734-1736.
5. Sanderson K, et al. Autoimmunity in a phase I trial of a fully human anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody with multiple melanoma peptides and Montanide ISA 51 for patients with resected stages III and IV melanoma. J Clin Oncol 2005;23:741-750.
6. O'Day SJ, et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: A multicenter single-arm phase II study. Ann Oncol 2010;21:1712-1717.
7. Wolchok JD, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: A randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol 2010;11:155-164.
8. Robert C, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011;364:2517-2526.
9. Hodi FS, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711-723.
Ipilimumab has recently been approved for the treatment of advanced melanoma. The current trial was undertaken to determine its safety and efficacy in patients with brain involvement.Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.