A population-level real-world analysis and single-center validation of melanoma brain metastasis epidemiology following dual-agent immunotherapy

Abstract

Purpose: Melanoma brain metastases (MBM) are common in advanced melanoma and linked to poor prognosis. Preventing MBM can improve survival and reduce morbidity. While dual-agent immunotherapy (dIT) improves survival, its role in MBM prevention is unclear. We compared MBM incidence, overall survival (OS), and brain metastasis-free survival (BMFS) between dIT and single-agent immunotherapies (sIT). Experimental Design: A real-world multi-institutional database identified melanoma patients without MBM at immunotherapy (IT) initiation. Patients were stratified by anti-CTLA4, anti-PD1, and combo anti-CTLA4/anti-PD1 (dIT) treatment. MBM incidences were measured within 5 years post-IT initiation and compared with risk ratios (RR). In a complementary single-institution cohort, median OS and BMFS were compared between dIT, anti-CTLA4, and anti-PD1 via log-rank tests and multivariate Cox proportional-hazards models. Results: TriNetX identified 8,287 patients receiving anti-CTLA (3,205), anti-PD1 (3,218), and dIT (1,864). MBM incidence was significantly lower in dIT (8.6%) and anti-PD1 (7.8%) vs. anti-CTLA4 (12.2%) cohorts, (RR[95% CI], 0.72[0.61-0.86] and 0.63[0.57-0.70], respectively). There was no significant difference in MBM incidence between anti-PD1 (7.8%) and dIT (8.6%) (RR[95% CI], 1.13[0.93-1.36]). In the single-institution analysis (n=119), 2-year OS probabilities were 90%, 80%, and 95%, and 2-year BMFS probabilities were 72.7%, 80%, and 95.7%, in the dIT, anti-CTLA4, and anti-PD1 cohorts, respectively. DIT and anti-PD1 showed improved early-phase protection against MBM development. Number of metastatic sites was significantly associated with MBM development (HR 2.36; 95% CI [1.22-4.58]; p=0.01). Conclusions: These findings highlight dIT’s potential role in primary prophylaxis against MBM, with anti-PD1 as the likely work horse agent. Prospective studies are warranted.