Is Dual Agent Immunotherapy Shifting the Epidemiology of Melanoma Brain Metastases? A Population-level Analysis and Single-institution Validation Study

Introduction: Dual agent immunotherapy (dIT) has been paradigm changing in advanced melanoma. Recent clinical trials have supported the role of dIT for upfront management of small, asymptomatic melanoma brain metastases (MBM). However, the potential role of dIT in the prevention of MBM has not been explored.

Methods: A retrospective query of TriNetX, a database collating clinical data from 92 healthcare organizations, was performed. Melanoma patients without MBM at diagnosis were stratified by treatment: 1) ipilimumab alone (single immunotherapy, sIT) and 2) ipilimumab and nivolumab (dIT). The incidence of new asynchronous MBM after initial melanoma diagnosis was compared across cohorts. Median overall survival (OS) was calculated using Kaplan Meier analysis and compared via log-rank tests. A complementary retrospective cohort validation study was performed, analyzing randomly sampled patients treated from 2012-2019 at Penn State Cancer Institute. Electronic medical records were reviewed for demographics, treatment history, and clinical outcomes.

Results: TriNetX identified 8,686 melanoma patients who received immunotherapy (4,585 dIT; 4,101 sIT). Mean ages at MBM diagnosis were 62 and 63 years, respectively. MBM incidence was 9.6% in the dIT cohort and 15.6% in the sIT cohort (p < 0.0001). DIT was associated with a lower likelihood of developing MBM compared to sIT (OR [95%CI], 0.64 [0.61-0.77]). Among those who developed MBM, OS was not statistically different (347 vs. 400 days) between treatment groups after propensity score matching. On validation, 61 patients were included (34 dIT; 27 sIT). Patients were predominantly male (61.5%), stage III (62.5%), and age 65 years at diagnosis. Incidence of MBM in each cohort was 38.2% and 59% in dIT and sIT cohorts, respectively (OR [95%CI], 2.35 [0.84-6.60], p=0.08).

Conclusion : These data highlight the association of combination ipilimumab and nivolumab immunotherapy and lower MBM incidence. The potential prophylactic role of dIT to prevent or delay MBM in advanced melanoma patients warrants prospective exploration.