Nivolumab with or without ipilimumab in pediatric patients with high-grade CNS malignancies: Safety, efficacy, biomarker, and pharmacokinetics—CheckMate 908

• Published in: Neuro-oncology (Charlottesville, Va.) Va.), 2023-08, Vol.25 (8), p.1530-1545
• Main Authors: Dunkel, Ira J, Doz, François, Foreman, Nicholas K, Hargrave, Darren, Lassaletta, Alvaro, André, Nicolas, Hansford, Jordan R, Hassall, Tim, Eyrich, Matthias, Gururangan, Sridharan, Bartels, Ute, Gajjar, Amar, Howell, Lisa, Warad, Deepti, Pacius, Misena, Tam, Rachel, Wang, Yu, Zhu, Li, Cohen, Kenneth
• Format: Article
• Language: English
• Subjects: Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biomarkers; Child; Humans; Ipilimumab - therapeutic use; Neoplasms - drug therapy; Nivolumab - therapeutic use; Pediatric Neuro-Oncology
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/noad031

Abstract Background Therapeutic options are limited in pediatric CNS malignancies. CheckMate 908 (NCT03130959) is an open-label, sequential-arm, phase 1b/2 study investigating nivolumab (NIVO) and NIVO + ipilimumab (IPI) in pediatric patients with high-grade CNS malignancies. Methods Patients (N = 166) in 5 cohorts received NIVO 3 mg/kg every 2 weeks (Q2W) or NIVO 3 mg/kg + IPI 1 mg/kg every 3 weeks (4 doses) followed by NIVO 3 mg/kg Q2W. Primary endpoints included overall survival (OS; newly diagnosed diffuse intrinsic pontine glioma [DIPG]) and progression-free survival (PFS; other recurrent/progressive or relapsed/resistant CNS cohorts). Secondary endpoints included other efficacy metrics and safety. Exploratory endpoints included pharmacokinetics and biomarker analyses. Results As of January 13, 2021, median OS (80% CI) was 11.7 (10.3–16.5) and 10.8 (9.1–15.8) months with NIVO and NIVO + IPI, respectively, in newly diagnosed DIPG. Median PFS (80% CI) with NIVO and NIVO + IPI was 1.7 (1.4–2.7) and 1.3 (1.2–1.5) months, respectively, in recurrent/progressive high-grade glioma; 1.4 (1.2–1.4) and 2.8 (1.5–4.5) months in relapsed/resistant medulloblastoma; and 1.4 (1.4–2.6) and 4.6 (1.4–5.4) months in relapsed/resistant ependymoma. In patients with other recurrent/progressive CNS tumors, median PFS (95% CI) was 1.2 (1.1–1.3) and 1.6 (1.3–3.5) months, respectively. Grade 3/4 treatment-related adverse-event rates were 14.1% (NIVO) and 27.2% (NIVO + IPI). NIVO and IPI first-dose trough concentrations were lower in youngest and lowest-weight patients. Baseline tumor programmed death ligand 1 expression was not associated with survival. Conclusions NIVO ± IPI did not demonstrate clinical benefit relative to historical data. The overall safety profiles were manageable with no new safety signals.