Abstract
BACKGROUND: Metastatic sites influence response rates to immune checkpoint inhibitors (ICI) and survival, suggesting anatomical locations impact treatment outcomes. This study examines how baseline metastatic sites affect progression patterns and survival in melanoma patients receiving first-line ICI or BRAF/MEK inhibitors (BRAF/MEKi). METHODS: Metastatic site presence and lesion counts at baseline and progression were captured chronologically for 347 ICI-treated and 210 BRAF/MEKi-treated patients using a novel graph representation. This novel approach enabled systematic comparison of progression patterns post-therapy failure across patients by providing a standardized representation of patterns of progression in patients with distinct clinical histories. Associations of baseline metastatic sites with progression patterns and progression-free survival (PFS) were assessed. RESULTS: Patients with baseline brain metastasis had higher progression rates in the brain (67% for ICI, 61% for BRAF/MEKi) than those without (21% for ICI, 32% for BRAF/MEKi). Among ICI-resistant patients (n = 91), brain progression occurred in 79.4% with baseline brain metastasis (n = 34) versus 19.3% without (n = 57). For both treatment modalities, faster progression in the brain occurred when present at baseline. First-line ICI patients with brain metastasis at baseline had worse PFS than patients without brain metastasis at baseline (hazard ratio 1.9, 95% confidence interval 1.31-2.78, P < 0.01) with patients with more than three brain lesions at baseline having worst 1-year PFS (28%) compared with patients with one to three brain lesions (49%) and with patients with no brain lesions at baseline (62%). CONCLUSIONS: Baseline metastatic sites, treatment modality, and resistance type modulate progression patterns and survival in melanoma patients treated with first-line ICI or BRAF/MEKi.