Nivolumab plus low-dose ipilimumab in hypermutated HER2-negative metastatic breast cancer: a phase II trial (NIMBUS)

• Published in: Nature communications Vol. 16; no. 1; pp. 4430 - 13
• Main Authors: Barroso-Sousa, Romualdo, Zanudo, Jorge Gomez Tejeda, Li, Tianyu, Reddy, Sangeetha M., Emens, Leisha A., Kuntz, Thomas M., Silva, Carolina Alves Costa, AlDubayan, Saud H., Chu, Hoyin, Overmoyer, Beth, Lange, Paulina, DiLullo, Molly K., Montesion, Meagan, Kasparian, Julie, Hughes, Melissa E., Attaya, Victoria, Basta, Ameer, Lin, Nancy U., Tayob, Nabihah, Jeselsohn, Rinath, Mittendorf, Elizabeth A., Tolaney, Sara M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.05.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 38/23; 631/67/322; 692/308/2779/109/1941; 692/4028/67/1059/2325; 692/4028/67/1347; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biomarkers; Biomarkers, Tumor - genetics; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - mortality; Breast Neoplasms - pathology; Cancer therapies; Chemotherapy; Diarrhea; ErbB-2 protein; ESR1 protein; Female; Genomic analysis; Growth factors; Humanities and Social Sciences; Humans; Immune checkpoint inhibitors; Immunotherapy; Ipilimumab - administration & dosage; Ipilimumab - adverse effects; Ipilimumab - therapeutic use; Metastases; Metastasis; Microbiomes; Middle Aged; multidisciplinary; Mutation; Neoplasm Metastasis; Nivolumab - administration & dosage; Nivolumab - adverse effects; Nivolumab - therapeutic use; Patients; PD-L1 protein; Progression-Free Survival; PTEN protein; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Response rates; Science; Science (multidisciplinary); Survival; Treatment Outcome; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-025-59695-1

In the phase II NIMBUS trial, patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) and high tumor mutational burden (TMB ≥ 9 mut/Mb) received nivolumab (3 mg/kg biweekly) and low-dose ipilimumab (1 mg/kg every 6 weeks) for 2 years or until progression. The primary endpoint was objective response rate (ORR) per RECIST 1.1 criteria. Among 30 patients enrolled, the median TMB was 10.9 mut/Mb (range: 9–110) and the confirmed objective response rate was 20%. Secondary endpoints included progression-free survival, overall survival, clinical benefit rate, and safety and tolerability, including immune-related adverse events (irAEs). A prespecified correlative outcome was to evaluate the ORR in patients with a TMB ≥ 14 mut/Mb. Patients with TMB ≥ 14 mut/Mb (n = 6) experienced higher response rates (60% vs 12%; p = 0.041) and showed a trend towards improved progression-free survival and overall survival compared to patients with TMB < 14 mut/Mb. Exploratory genomic analyses suggested that ESR1 and PTEN mutations may be associated with poor response, while clinical benefit was associated with a decrease or no change in tumor fraction by serial circulating tumor DNA during treatment. Stool microbiome analysis revealed that baseline blood TMB, PD-L1 positivity, and immune-related diarrhea are associated with distinct taxonomic profiles. In summary, some patients with hypermutated HER2-negative MBC experience extended clinical benefit with a dual immunotherapy regimen; a higher TMB, and additional genomic and microbiome biomarkers may optimize patient selection for therapy with nivolumab plus low-dose ipilimumab. (Funded by Bristol Myers Squibb; ClinicalTrials.gov identifier, NCT03789110). The current use of immune checkpoint inhibitors without chemotherapy on patients with metastatic breast cancer (MBC) has not proven useful. Here this group reports a phase 2 NIMBUS trial evaluating the efficacy/safety of nivolumab + low dose ipilimumab in 30 patients with hypermutated HER2-negative MBC.