Abstract
PurposeTo investigate the efficacy and safety of concurrent stereotactic radiosurgery (SRS) and ipilimumab or nivolumab in patients with untreated melanoma brain metastases.Patients and MethodsEighty consecutive patients with 326 melanoma brain metastases receiving SRS in combination with ipilimumab or nivolumab were identified from an institutional database and retrospectively evaluated. Patients started systemic treatment with intravenous nivolumab or ipilimumab within one week of receiving SRS. Nivolumab was given at doses of 3 mg/kg every two weeks. Ipilimumab was administered up to four doses of 10 mg/kg, one every 3 weeks, then patients had a maintenance dose of 10 mg/kg every 12 weeks, until disease progression or inacceptable toxicity. Primary endpoint of the study was intracranial progression-free survival (PFS). Secondary endpoints were extracranial PFS, overall survival (OS), and neurological toxicity.ResultsEighty patients were analyzed. Forty-five patients received SRS and ipilimumab, and 35 patients received SRS and nivolumab. With a median follow-up of 15 months, the 6-month and 12-month intracranial PFS rates were 69% (95%CI,54–87%) and 42% (95%CI,24–65%) for patients receiving SRS and nivolumab and 48% (95%CI,34–64%) and 17% (95%CI,5–31%) for those treated with SRS and ipilimumab (p = 0.02), respectively. Extracranial PFS and OS were 37 and 78% in SRS and nivolumab group, respectively, and 17 and 68% in SRS and ipilimumab group, respectively, at 12 months. Sub-group analysis showed significantly better intracranial PFS for patients receiving multi-fraction SRS (3 × 9 Gy) compared to single-fraction SRS (70% versus 46% at 6 months, p = 0.01), especially in combination with nivolumab. Grade 3 treatment-related adverse events occurred in 11 (24%) patients treated with SRS and ipilimumab and 6 (17%) patients who received SRS and nivolumab. Radiation-induced brain necrosis (RN) occurred in 15% of patients.ConclusionsConcurrent SRS and ipilimumab or nivolumab show meaningful intracranial activity in patients with either asymptomatic and symptomatic melanoma brain metastases, although a subset of patients may develop symptomatic RN. The combination of nivolumab with SRS is associated with better intracranial control.
Highlights
Brain metastases are a common and devastating complication of cancer affecting 25% of patients with advanced melanoma [1]; for these patients, systemic therapy and local treatments, including surgical resection, whole brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS) have been the most common therapeutic options.Systemic chemotherapy has been widely used in the past for patients with melanoma brain metastases, it has shown a limited activity
With a median follow-up of 15 months, the 6-month and 12-month intracranial progression-free survival (PFS) rates were 69% (95%confidence interval (CI),54–87%) and 42% (95%CI,24–65%) for patients receiving SRS and nivolumab and 48% (95%CI,34–64%) and 17% (95%CI,5–31%) for those treated with SRS and ipilimumab (p = 0.02), respectively
The combination of nivolumab with SRS is associated with better intracranial control
Summary
Brain metastases are a common and devastating complication of cancer affecting 25% of patients with advanced melanoma [1]; for these patients, systemic therapy and local treatments, including surgical resection, whole brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS) have been the most common therapeutic options.Systemic chemotherapy has been widely used in the past for patients with melanoma brain metastases, it has shown a limited activity. WBRT has been the cornerstone for treatment of multiple brain metastases, but its use has been progressively replaced by SRS; its efficacy in patients with a limited number of lesions, usually 1-4, has been demonstrated in randomized trials [2, 3], LC in melanoma patients is inferior than that reported for other histologies, especially when considering large tumors [4,5,6,7]. In a randomized phase 2 study of 60 patients with melanoma brain metastases receiving combined nivolumab and ipilimumab or nivolumab alone, Long et al [11] showed an intracranial response of 46% and 20%, respectively; with a median follow-up of 17 months, 6-month intracranial progression-free survival (PFS) and overall survival (OS) rates were 35% and 68% in patients receiving nivolumab, and 53% and 78% in those receiving nivolumab and ipilimumab. In another phase 2 study of 94 patients with melanoma brain metastases treated with combined nivolumab and ipilimumab, Tawbi et al [12] observed an intracranial objective response of 55% lasting at least 6 months, with PFS rates of 70.4% and OS rates of 59.5% at 9 months
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