Abstract CT008: Ten-year survival and cell-free DNA methylation profiling of melanoma patients with asymptomatic brain metastases treated with nivolumab plus ipilimumab: The multicenter phase III NIBIT-M2 trial

Abstract Background: The multicenter phase III NIBIT-M2 study, sponsored by the NIBIT Foundation, showed a 41% 7-y overall survival (OS) of melanoma patients (pts) with asymptomatic brain metastases (BM) treated with ipilimumab (I) plus nivolumab (N) (I+N) (Di Giacomo AM, CCR 2021; EJC 2024). In spite of the significant therapeutic efficacy of I+N in this patient population, no biomarkers predictive of response have been identified yet, also due to the limited accessibility of BM. Here, we report the final analysis of the NIBIT-M2 study with the 10-y survival and its correlation with cell free (cf) DNA profiles. Methods: The NIBIT-M2 study recruited melanoma pts with active, untreated, asymptomatic BM from 9 Italian Centers, randomized (1:1:1) to receive fotemustine (F) (Arm A), I+F (Arm B), or I+N (Arm C). Primary endpoint was OS; among secondary was intracranial progression-free survival (iPFS). Exploratory analyses were conducted on cfDNA plasma samples collected at baseline and week (W) 12 on therapy. Tumor fraction (TF) was estimated from low pass WGS using IchorCNA. Tumor-specific methylation Score (T-meth Score) was computed as the ratio between the coverage over methylated regions analyzed by cf-methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) and melanoma-specific methylated regions previously identified in the TCGA melanoma cohort. Results: From Jan 2013 to Sept 2018, 80 pts were enrolled and 76 were treated with F (23), I+F (26), or I+N (27). As of December 1, 2025, with a median follow-up of 125 months (mo), median OS was 8.5 (95% CI: 4.8-12.2), 8.2 (95% CI: 2.1-14.3) and 29.2 (95% CI: 0-73.5) mo for Arm A, B, and C, respectively. The 10-y OS rate was 13.0% (95% CI: 0-26.7) in Arm A, 7.7% (95% CI: 0-17.9) in Arm B, and 31.2% (95% CI: 13.0-49.4) in Arm C. The 10-y melanoma specific survival was 13.0% (95% CI: 0-26.7), 7.7% (95% CI: 0-17.9), and 35.1% (95% CI: 16.3-53.9) in Arm A, B and C, respectively. The 10-year iPFS rate was 4.3% (95% CI: 0-12.7), 7.7% (95% CI: 0-17.9), and 20% (95% CI: 3.9-35.7) in Arm A, B and C, respectively. Patients were stratified at baseline according to the median values of TF (n=57; median 0.022) and of T-meth Score (n=53; median 0.096): a significantly higher median OS was observed in pts with TF (22.3 vs 8.2 mo; p=0.033) and T-meth Score (26.3 vs 7.9 mo; p=0.002) below their median values. Of note, pts with low TF and T-meth Score were enriched at baseline in Arm C. Additionally, a decrease in TF (n=29) and T-meth Score (n=24) was observed at W12 in pts with an OS above the median (26.3 mo for TF and 24.0 mo for T-meth Score). Conclusions: The 10-y results of the NIBIT-M2 study, with the longest follow-up available to date in melanoma pts with asymptomatic BM, continue to show persistent long-term therapeutic efficacy of I+N. Plasma-derived TF and T-meth Score may predict long-term survival of melanoma pts with asymptomatic BM treated with I+N. Citation Format: Anna Maria Di Giacomo, Vanna Chiarion-Sileni, Michele Del Vecchio, Pier Francesco Ferrucci, Michele Guida, Pietro Quaglino, Massimo Guidoboni, Paolo Marchetti, Vincenzo D'Alonzo, Maura Colucci, Giovanni Amato, Roberto Camerini, Maria Fortunata Lofiego, Monica Valente, Valentina Croce, Emma Bello, Maresa Altomonte, Mario Mandalà, Diana Giannarelli, Piera Grisolia, Antonio De Falco, Michele Ceccarelli, Alessia Covre, Michele Maio. Ten-year survival and cell-free DNA methylation profiling of melanoma patients with asymptomatic brain metastases treated with nivolumab plus ipilimumab: The multicenter phase III NIBIT-M2 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT008.