Improved Survival Following Immunotherapy in Patients with Lung and Melanoma Primaries Metastatic to the Brain Treated with Upfront Stereotactic Radiosurgery

Abstract

For patients with lung or melanoma primaries metastatic to the brain, immunotherapy has improved extracranial disease control but results on intracranial disease outcomes after stereotactic radiosurgery (SRS) are not well understood. We sought to evaluate survival, risk of neurologic death and risk of distant brain failure (DBF) and to determine the brain metastasis velocity (BMV) in this patient population comparing those treated with and without immunotherapy. We performed a single institution retrospective analysis of 257 consecutive patients with lung or melanoma primaries metastatic to the brain treated with upfront SRS. 170 of these patients did not receive immunotherapy as part of their treatment and 87 of these patients did. Of the patients that received immunotherapy, 42 (48%) received nivolumab, 24 (28%) received pembrolizumab and 15 (17%) received ipilimumab. 1 (1%) used a combination of nivolumab/ipilimumab and 5 (6%) received other or unknown immunotherapy treatments. BMV was calculated as previously described and compared using the Mann-Whitney U test. The cumulative incidences (CI) of DBF were estimated with death as a competing risk. Overall survival was estimated using the Kaplan Meier method. From 2013-2016, 257 patients with lung or melanoma primaries metastatic to the brain and treated with upfront SRS were identified for review. The median age at diagnosis was 66 (IQR: 57-72). Median OS in patients treated with and without immunotherapy was 22.4 and 6.1 months (log-rank p<0.01), respectively. Median freedom from neurologic death in patients treated with and without immunotherapy was 24.8 and 10.2 months (log-rank p=0.04). The one-year CI of DBF in patients with and without immunotherapy was 57% and 36% (p < 0.01). When stratified by primary histology, 1-year DBF rates with and without immunotherapy were 53% vs. 30% for lung (p<0.01) and 65% vs 95% for melanoma (p<0.01). Of the 115 patients with distant brain failure, median BMV at first failure (BMV1) in patients with and without immunotherapy was 9.0 and 11.4 (p=0.85). Median BMV1 was 14.0 and 6.4 in patients who received immunotherapy before and after SRS (p=0.37). This difference was most pronounced in lung cancer patients (42.6 v. 6.2, p=0.14). Median total BMV over the course of follow-up in patients with and without immunotherapy was 6.8 and 7.3 and 8.0 versus 5.9 in patients who received immunotherapy before and after SRS. Univariate linear regression analysis revealed an association between total number of cycles of immunotherapy and total BMV (β=-1.67, SE=0.77, p=0.04). These findings suggest that while immunotherapy improves overall survival and decreases neurologic death in lung cancer and melanoma brain metastasis patients, continued progression in the brain remains an issue.