Concurrent vs. Sequential Stereotactic Radiosurgery and Immune Checkpoint Inhibition in Melanoma Brain Metastases: An International Cooperative Group Study.

PURPOSE/OBJECTIVE(S) Multiple single institution retrospective studies have suggested that managing melanoma brain metastases (MBM) with stereotactic radiosurgery (SRS) and immune checkpoint inhibitors (ICI) is associated with improved overall survival (OS) when administered concurrently (within 4 weeks) rather than sequentially (ICI and SRS administered more than 4 weeks apart). However, there is a paucity of data quantifying the risk of developing radiation necrosis (RN) in this setting. MATERIALS/METHODS The International Radiosurgery Research Foundation approved the analysis. The Kaplan Meier method and log-rank test were used to compare OS and local control (LC) at 1- and 2-years post SRS. Factors associated with the development of RN and OS were further analyzed using logistic and Cox proportional hazards regression models. The null hypothesis was rejected for P < 0.05. RESULTS There were 254 patients with 1,322 MBM treated across 10 international institutions. The median follow-up was 12.9 months, median age was 63 years (interquartile range [IQR]: 51-73 years), BRAF mutation was present in 46.6% of patients, active extracranial disease was present in 70% of patients, and the median Karnofsky Performance Status (KPS) was 90. SRS/ICI was administered concurrently in 46.5% of patients. All patients were treated on the stereotactic radiosurgery platform. The median margin dose was 20 Gy (IQR: 18-21 Gy), median number of fractions was 1 (range: 1-4), mean total brain metastasis volume was 3.4 cc and the mean V12 Gy was 8.7 cc. Radiation necrosis occurred in 14.2% of patients (5.9% Grade 1; 5.1% Grade 2; 2.8% Grade 3; 0.4% Grade 4). Overall survival at 1-year was 77.4% vs. 72.1%, and at 2-years was 63.1% vs. 46.1% (P = 0.048) for concurrent and sequential therapy, respectively. Local control at 1-year was 91.5% vs. 84.6%, and at 2-years was 84.9% vs. 75.6% (P = 0.12) for concurrent and sequential therapy, respectively. On multivariate logistic regression total treated brain metastasis volume (odds radio [OR]: 1.11; 95% confidence interval [CI]: 1.03-1.20; P = 0.008) was associated with a higher risk of development of RN; however, sequential therapy (OR: 0.97; 95% CI: 0.46-2.06; P = 0.94), and V12 (OR: 0.98; 95% CI: 0.95-1.01; P = 0.22) were not statistically significant. On multivariate cox regression, sequential therapy (hazard ratio [HR]: 1.58; 95% CI: 1.05-2.42; P = 0.03) and KPS (HR: 0.96; 95% CI: 0.94-0.98; P < 0.001) were prognostic factors for OS, while the presence of extracranial disease (HR: 1.03; 95% CI: 0.66-1.59; P = 0.90) and age (HR: 1.01; 95% CI: 1.00-1.02; P = 0.25) were not prognostic. CONCLUSION In appropriately selected patients with MBM, concurrent administration of SRS/ICI may be associated with improved OS without an increased risk of RN when compared to sequential therapy. The risk of RN appears to increase with irradiated brain volume; therefore, hypofractionated SRS may be considered in patients with high volume disease. Prospective data are needed to further evaluate these findings. AUTHOR DISCLOSURE E.J. Lehrer: None. J. Gurewitz: None. T.D. Malouff: ASTRO Bylaws Committee. K. Bernstein: None. D. Kondziolka: None. P. Bonney: None. S.I. Patel: Independent Contractor; Alberta Health Services. Research Grant; Alberta Cancer Foundation. Travel Expenses; University Hospital Foundation. Chair; Alberta Health Services. Co-Director; Alberta Health Services. Manage and screen wish applications; Make-A-Wish Foundation (Northern Alberta Chapter). J.D. Palmer: Research Grant; Varian Medical Systems, The Kroger Company. Consultant; Huron Consulting. Speaker's Bureau; Varian Medical Systems, Depuy Synthes. Advisory Board; Novocure. Member of panel; NCCN.K. Fakhoury: None. C.G. Rusthoven: Employee; SURVIVEiT (nonprofit cancer patient advocacy). Research Grant; Takeda. Advise regarding patient-facing medical content; SURVIVEiT.D. Mathieu: None. C. Deibert: None. P. Picozzi: None. B. Jones: None. C. Lee: None. S. Sharma: None. A. Niranjan: None. J.P. Sheehan: Neuropoint Alliance. M. Ahluwalia: None. D.M. Trifiletti: None.