Ipilimumab in melanoma with limited brain metastases treated with stereotactic radiosurgery

Abstract

The anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody ipilimumab has been shown to improve survival in patients with metastatic non-CNS melanoma. The purpose of this study was to investigate the efficacy of CTLA-4 inhibitors in the treatment of metastatic melanoma with limited brain metastases treated with stereotactic radiosurgery (SRS). Between January 2008 and June 2011, 58 patients with limited brain metastases from melanoma were treated with SRS with a median dose of 20 Gy delivered to the 50% isodose line (range, 15-20 Gy). In 25 patients, ipilimumab was administered intravenously at a dose of 3 mg/kg over 90 min every 3 weeks for a median of four doses (range, 1-8). Local control (LC), freedom from new brain metastases, and overall survival (OS) were assessed from the date of the SRS procedure. The median LC, freedom from new brain metastases, and OS for the entire group were 8.7, 4.3, and 5.9 months, respectively. The cause of death was CNS progression in all but eight patients. Six-month LC, freedom from new brain metastases, and OS were 65, 35, and 56%, respectively, for those who received ipilimumab and 63, 47, and 46% for those who did not (P=NS). Intracranial hemorrhage was noted in seven patients who received ipilimumab compared with 10 patients who received SRS alone (P=NS). In this retrospective study, administration of ipilimumab neither increased toxicity nor improved intracerebral disease control in patients with limited brain metastases who received SRS.

Possible Interaction of Anti–PD-1 Therapy with the Effects of Radiosurgery on Brain Metastases

“…Pembrolizumab and nivolumab, inhibitors of PD-1, were the first to be approved for melanoma and are being studied in other diseases and in combination with other drugs (nivolumab was recently approved for squamous cells carcinoma of the lung). The interaction between immune checkpoint inhibitors and standard treatments for brain metastases, such as SRS, however, remains underinvestigated (20,21).…”

Irradiation and immunotherapy: From concept to the clinic

“…In total, < 150 patients have been reported. However, most have not reported increased intracranial hemorrhage 65 or other "unexpected toxicities." 67 Although the grade 3 and 4 toxicity rate reported by some appears to be high, this is consistent with some series of SRS alone that included long-term follow-up.…”

“…In contrast to extracranial RT, for which reports are sparse, growing numbers of institutions have reported their experiences combining ipilimumab and SRS. [63][64][65][66][67] Some general principles have come to light. First, the optimal timing of SRS and ipilimumab is unknown.…”

Immuno-radiotherapy for brain metastases

“…Fifteen retrospective studies [23,[28][29][30][31][32][33][34][35][36] reported results of 594 melanoma patients with BM. Only 4 studies (Schoenfeld, Patel,Mathew, Qian) reported active systemic disease in the majority of patients (range 72%-96%).…”