281 - Upfront Local Therapy in Melanoma Brain Metastases Treated with Ipilimumab-Nivolumab: An International Multicenter Analysis of Immunotherapy-Naïve Patients
Presenter(s)
J. Lee1, T. Kleber2, X. Fitzgerald3, L. A. Boe1, M. Parker1, K. A. Ahmed4, S. S. Neibart5, J. S. Chiang6, M. Chisam7, M. Gribble8, I. Messing9, T. Seawalt10, W. Shi11, A. W. Lee12, E. Y. Y. Akdemir13, J. D. Palmer14, J. Sia15, K. J. Drummond3, T. Beckham16, and L. R. G. Pike1; 1Memorial Sloan Kettering Cancer Center, New York, NY, 2MD Anderson Cancer Center, Houston, TX, 3Royal Melbourne Hospital, Melbourne, Australia, 4H. Lee Moffitt Cancer Center and Research Institute, Department of Radiation Oncology, Tampa, FL, 5Harvard Radiation Oncology Program, Boston, MA, 6Department of Radiation Oncology, Stanford University, Stanford, CA, 7Duke University, Duke Cancer Institute, Durham, NC, 8University of California San Francisco, San Francisco, CA, 9Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, 10University of Colorado, Aurora, CO, 11Department of Radiation Oncology, Sidney Kimmel Medical College & Cancer Center at Thomas Jefferson University, Philadelphia, PA, 12Department of Radiation Oncology, Columbia University Irving Medical Center, New York, NY, 13Miami Cancer Institute, Miami, FL, 14Department of Radiation Oncology, James Cancer Hospital/Wexner Medical Center, The Ohio State University, Columbus, OH, 15Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia, 16Department of CNS Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
Purpose/Objective(s): Ipilimumab plus nivolumab (IPI+NIVO) has demonstrated activity in melanoma brain metastases (MBM) and is endorsed in current guidelines as the initial therapy in select patients. However, high-quality comparative data justifying the omission of upfront local therapy are lacking, and prospective trials have frequently excluded patients with active brain metastases. Here, we present the largest analysis of immunotherapy-naïve patients directly comparing IPI+NIVO alone versus IPI+NIVO with upfront local therapy.
Materials/Methods: This study included patients treated at 14 high-volume academic medical centers spanning the USA, Canada, and Australia. Immunotherapy-naïve patients starting IPI+NIVO for newly diagnosed MBM were enrolled and stratified by receipt of upfront local therapy, defined as surgery and/or stereotactic radiosurgery (SRS) delivered within 8 weeks of IPI+NIVO initiation. Patients with leptomeningeal disease or whole brain radiation therapy were excluded. The primary endpoint for this analysis was the cumulative incidence of local CNS progression, with death treated as a competing risk. Multivariable hazard ratios (aHR) were calculated using Cox proportional hazards and Fine and Gray competing-risks models for cumulative incidence endpoints.
Results: A total of 466 patients were identified from January 2015 to January 2025. Of these, 302 (65%) received upfront local therapy; 165 (35%) underwent surgery and 275 (59%) underwent SRS, and 138 (30%) received both. Patients receiving upfront local therapy were more likely to be symptomatic (p<0.001), have larger MBM (p<0.001), and be on corticosteroids at the time of IPI+NIVO initiation (p<0.001). Median follow-up was 26.0 months. Overall survival was similar with or without upfront local therapy (p=0.7). However, upfront local therapy was associated with significantly improved local CNS control (aHR: 0.39; 95% CI: 0.22-0.67, p<0.001). This benefit in local control was robust for patients with MBM smaller than 1cm (aHR: 0.31; 95% CI: 0.12-0.85, p=0.023) and greater than or equal to 1cm (aHR: 0.50; 95% CI: 0.28-0.92, p=0.03).
Conclusion: This study represents the largest and highest-quality comparative data on the role of upfront local therapy in immunotherapy-naïve patients receiving IPI+NIVO for melanoma brain metastases. The addition of upfront local therapy to IPI+NIVO confers a robust local control benefit, regardless of lesion size or baseline neurologic symptoms.