Stereotactic Radiosurgery and Anti-PD-1 + CTLA-4 Therapy, Anti-PD-1 Therapy, Anti-CTLA-4 Therapy, BRAF/MEK Inhibitors, BRAF Inhibitor, or Conventional Chemotherapy for the Management of Melanoma Brain Metastases

Abstract

<h3>Purpose/Objective(s)</h3> Immunotherapy and targeted BRAF/MEK inhibition have revolutionized the systemic management of advanced melanoma with sustained intracranial responses noted in prospective clinical trials. Given the role of stereotactic radiosurgery (SRS) in the local management of brain metastases, we sought to evaluate clinical outcomes in patients with melanoma brain metastases (MBM) treated with SRS and anti-PD-1 + CTLA-4 therapy, anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors(i), BRAF inhibitor, or conventional chemotherapy. <h3>Materials/Methods</h3> Patients were included if MBM were diagnosed and treated with SRS within 3 months of receiving anti-PD-1 + CTLA-4 therapy, anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK-i, BRAF-i, or conventional chemotherapy. The assigned regimen was the last course of systemic treatment to avoid the effects of multiple systemic agents influencing clinical end points. The primary endpoint was distant MBM control with secondary endpoints of local MBM control (defined as a sustained less than >20% volume increase on follow-up MRIs) and OS from SRS. <h3>Results</h3> In total, 257 patients with 1048 MBM treated over 368 SRS sessions between 2011 to 2020 were identified: Median SRS dose was 24 Gy (range: 15-24 Gy) all in a single fraction. Median follow-up using the reverse Kaplan-Meier (KM) method was 41.8 months. No significant differences were noted in age (p=0.10), gender (p=0.47), Karnofsky Performance Scale (KPS) (p=0.27), treated gross tumor volume (p=0.07), number of MBM treated per patient (0.08), or Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) (p=0.28) between groups. Twelve-month KM OS rates by DS-GPA were 17%, 33%, 54%, and 69% for scores 0-1, 1.5-2, 2.5-3, 3.5-4, respectively (p=<0.001). Twelve-month KM distant MBM control rates were 42%, 63%, 24%, 44%, 23%, and 16% (p=<0.001) for SRS with anti-PD-1 + CTLA-4, anti-PD-1, anti-CTLA-4, BRAF/MEK inhibitors (i), BRAF-i, or chemotherapy, respectively. The 12-month KM local MBM control rates were 86%, 77%, 79%, 85%, 87%, and 57% (p=<0.001). Twelve-month OS rates from SRS diagnosis were 68%, 59%, 45%, 62%, 21%, and 15% (p=<0.001). On multivariate analysis (MVA), 2-5 MBM (HR 1.72, 95% CI: 1.1-42.7, p=0.02) and >5 MBM being treated (HR 2.65, 95% CI: 1.65-4.25, p=<0.001) was associated with worse distant MBM control. Treatment with anti-PD-1 therapy (HR 0.24, 95% CI:0.14-0.41, p=0.0009) was associated with improved distant MBM control. MVA also showed, treatment with anti-PD-1 (HR 0.27, 95% CI: 0.17-0.41, P=0.0007) and anti-PD-1 + CTLA-4 (HR 0.29, 95% CI: 0.15-0.53, p=0.01) were both associated with increased OS. The rates of symptomatic radiation necrosis were 2%, 2%, 1%, 1%, 2%, and 3% (p=0.93). <h3>Conclusion</h3> To our knowledge, this is the largest series evaluating MBM treated with SRS and various systemic therapy regimens. Our analysis noted significant differences in distant MBM control as well as OS by systemic therapy.