Clinical Outcomes Following an Initial Stereotactic Radiosurgery Course for Brain Metastases from Melanoma

Abstract

Brain metastases (BM) are common in melanoma patients. The effect of gene mutations is not well characterized since first-line metastatic therapy has shifted from chemotherapy (CHT) to molecularly targeted therapies (TT) and immunotherapy (IO). We report outcomes of melanoma BM patients stratified by molecular subtype and pre-stereotactic radiosurgery (SRS) systemic therapy. We identified all patients completing an initial SRS course for BM at two institutions between 1/2015 and 12/2020. Patients who had prior WBRT and/or resection were eligible. Demographic and clinical parameters were collected, along with melanoma tumor molecular characteristics. Intracranial progression (ICP) was defined as any radiographic distant and/or in-field progression per multidisciplinary consensus. Overall survival (OS) and freedom from ICP (FFICP) were estimated via the Kaplan Meier method. From a total of 1383 SRS BM patients, we identified 118 (8.5%) with melanoma. Median follow up was 8.7 months, median age 64 years (IQR 51-72), 81% had cutaneous origin, and 55% had a KPS of 90-100. Molecular subtypes included BRAF (45%), NRAS (9.3%), and c-KIT (3.4%). Overall, 61% received IO prior to SRS, while 25% and 9.3% received TT and CHT prior to SRS respectively. 60% of patients harboring a mutation received IO as first line therapy, 10% received TT, and 30% received both TT and IO prior to SRS. BRAFmut patients more likely to have received TT prior to SRS (43% vs 9.2%, p<0.001) compared to BRAFwt patients. Median OS was 9.7 months (95% CI 7.8-13) and was not significantly different from non-melanoma patients (p = 0.6). Median FFICP was worse for melanoma patients (5.9 mos, 95% CI 3.5-8.5) than non-melanoma patients (8.96 mos, 95% CI 8.2-9.7, p = 0.009). A total of 72 ICP events occurred, with 56 (77.8%) distant ICP cases, 3 (4.2%) in-field ICP, and 13 (18%) ICP events that were radionecrosis (RN) only. RN was associated with the presence of a targetable mutation (18% vs 2%, p = 0.006) and receipt of TT pre-SRS (36% vs 9.8%, p = 0.001). BRAFmut patients had significantly worse FFICP (3.8 mos, 95% CI 3.0-6.8) compared to BRAFwt patients (8.5 mos, 95% CI 5.8-30.2, p = 0.006), although median OS was not significantly different (9.6 mos, 95% CI 6.9-16 vs 10.7 mos, 95% CI 6.7-15.5, p = 0.8). NRASmut was associated with better FFICP (29 mos, 95% CI 2.94-NA, p = 0.02). In this modern, multi-institutional cohort of SRS patients, melanoma BM patients had worse FFICP compared to non-melanoma BM patients, and BRAFmut patients had worse FFICP than BRAFwt patients. RN was associated with mutational status and receipt of TT pre-SRS. OS did not vary significantly across groups. This analysis may help inform systemic therapy decisions and future genomic studies for patients with BMs from melanoma.