{
  "abstract": "Background Patients with melanoma brain metastases (MBM) have been observed to respond poorly to immune checkpoint inhibitors (ICIs) compared to those without intracranial disease. 1 2 These patients are frequently underrepresented in pivotal trials due to historically poor prognosis and therapeutic challenges.3 While ICIs have transformed melanoma outcomes overall, their real-world impact on MBM at the population level remains unclear. To address this gap, we conducted a large-scale survival analysis using SEER database, evaluating whether ICI-era survival benefits extend meaningfully to patients with MBM.Methods We used the SEER 18 registry (2010–2022) to identify 7,089 metastatic melanoma patients with complete brain metastasis and survival data. Patients were categorized by MBM status and era of diagnosis: pre-ICI (2010–2014) and ICI era (2016–2022). Overall survival (OS) was analyzed using Kaplan-Meier estimates and Cox proportional hazards models adjusted for age, sex, race/ethnicity, treatment modality (radiation, chemotherapy, surgery), household income, and rural-urban residence. Interaction terms assessed whether MBM modified the survival effect of the ICI era across subgroups.Results MBM was present in 33.5% of patients (n = 2,321). Between the pre-ICI and ICI eras, median OS improved from 14 to 21 months in patients without MBM. For MBM patients, however, median OS improved only marginally, from 5 to 6 months. Adjusted models confirmed MBM as an independent adverse prognostic factor (HR = 1.95; 95% CI: 1.67–2.27; p < 0.001), while the ICI era was associated with improved survival overall (HR = 0.74; 95% CI: 0.66–0.82; p < 0.001). The MBM×ICI interaction term was not statistically significant (HR = 0.96; p = 0.70), indicating limited benefit for MBM patients. 4 5 Subgroup analyses showed no consistent survival modification by race, income, or rurality. A modest trend toward benefit was observed in MBM patients under 45 years (HR interaction = 0.80) (table 1) (figure 1).Conclusions In this national cohort, ICIs significantly improved survival in metastatic melanoma overall but had limited impact in patients with brain metastases. These findings highlight a biologically driven therapeutic gap that persists across sociodemographic strata. The marginal gains in MBM survival underscore the potential biological resistance of intracranial disease to systemic immunotherapy. This gap is unlikely to be addressed by access alone. Future trials should stratify for MBM, incorporate brain-specific endpoints, and prioritize the development of CNS-penetrant, combination immunotherapeutic strategies to address this urgent and under-recognized unmet need. 6 7 References Ellebaek E, Bastholm L, Schmidt H, et al. Survival improvements in patients with melanoma brain metastases and leptomeningeal disease in the modern era: insights from a nationwide study (2015–2022). Eur J Cancer. 2025 Feb 25;217:115253. doi:10.1016/j.ejca.2025.115253Samlowski W, Smith KJ, Bryant R, et al. Timing of brain metastases in relation to outcome during first-line ipilimumab plus nivolumab therapy for metastatic melanoma in a community oncology practice. J Neurooncol. 2025 May;172(3):645–653. doi:10.1007/s11060-025-04951-zAhluwalia MS, Weichselbaum R, Mehta MP. Immunotherapeutic and targeted strategies for managing brain metastases from common cancer origins: a state-of-the-art review. Curr Oncol Rep. 2024 Dec;26(12):1612–1638. doi:10.1007/s11912-024-01593-8Broekman MLD, Smits M, Brandsma D, et al. Hyperprogression of brain metastases following initiation of immune checkpoint inhibitors. J Neurooncol. 2025 May;172(3):667–673. doi:10.1007/s11060-025-04955-9Palmer JD, Ahmed KA, Margalit DN, et al. Delayed and concurrent stereotactic radiosurgery in immunotherapy-naïve melanoma brain metastases. Cancers (Basel). 2024 Nov 5;16(22):3733. doi:10.3390/cancers16223733Mangana J, Dummer R, Lebbé C, et al. Management of metastatic melanoma with combinations including PD-1 inhibitors. Expert Opin Biol Ther. 2025 May;25(5):1–12. doi:10.1080/14712598.2025.2485315Kondziolka D, Niranjan A, Lunsford LD, et al. Outcomes of concurrent versus non-concurrent immune checkpoint inhibition with stereotactic radiosurgery for melanoma brain metastases. J Neurooncol. 2025 Jul;173(3):619–625. doi:10.1007/s11060-025-05026-9Abstract 445 Table 1Impact of brain metastases and immune checkpoint inhibitor era on survival in metastatic melanoma. Abbreviations: HR, hazard ratio; CI, confidence interval; MBM, melanoma brain metastases; ICI, immune checkpoint inhibitorAbstract 445 Figure 1Kaplan-Meier survival curves by brain metastasis status and treatment era. Kaplan-Meier curves showing overall survival in metastatic melanoma by MBM status and treatment era. Survival differed significantly across groups (log-rank p < 0.0001)",
  "authors": [
    {
      "affiliations": [
        "Pakistan Institute of Medical Sciences, Islamabad, Pakistan"
      ],
      "name": "Manzer Ali"
    },
    {
      "affiliations": [
        "Internal Medicine Residency Program, Mercyhealth GME Consortium, Rockford, IL, USA"
      ],
      "name": "Saad Rashid"
    },
    {
      "affiliations": [
        "Oncology Program, Moffitt Cancer Center, Tampa, FL, USA"
      ],
      "name": "Mohammed Al-Jumayli"
    },
    {
      "affiliations": [
        "Rutgers-Trinitas Regional Medical Center, Elizabeth, NJ, USA"
      ],
      "name": "Hanzala Jahangir"
    },
    {
      "affiliations": [
        "Mercy Catholic Medical Center, Darby, PA, USA"
      ],
      "name": "Aftab Ahmed"
    },
    {
      "affiliations": [
        "Cleveland Clinic Akron General, Akron, OH, USA"
      ],
      "name": "Kirti Arora"
    },
    {
      "affiliations": [
        "The New York Medical College Graduate Medical Education Program at St. Mary’s General Hospital and Saint Clare’s Health, Denville, NJ, USA"
      ],
      "name": "Bolivia Fernandes"
    },
    {
      "affiliations": [
        "Memorial HealthCare System, Hollywood, FL, USA"
      ],
      "name": "Hareem Saleem"
    },
    {
      "affiliations": [
        "Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA"
      ],
      "name": "Heena Parkash"
    },
    {
      "affiliations": [
        "Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA"
      ],
      "name": "Zeeshan Muzammil"
    },
    {
      "affiliations": [
        "Mercyhealth GME Consortium, Rockford, IL, USA"
      ],
      "name": "Elizabeth Kaji"
    }
  ],
  "title": "445 Limited survival gains with immune checkpoint inhibitors in melanoma brain metastases: a national SEER analysis of 7,089 patients across a decade of treatment evolution",
  "uid": "70db5446-cce2-517c-8f2d-26e73dc9282a"
}