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

Abstract

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).

Fig. 1. Efficacy data of the NIMBUS study.

A Waterfall plot showing change in diameter of target lesions in the full patient population after a median of 30.6 months of follow-up, excluding three unevaluable patients (N = 27). B Kaplan–Meier curves showing progression-free survival in the full population (N = 30), and D among patients with TMB < 14 mut/Mb and patients with TMB ≥ 14 mut/Mb; (N = 30); C Kaplan–Meier curves showing overall survival in the full population (N = 30), and E among patients with TMB < 14 mut/Mb and patients with TMB ≥ 14 mut/Mb (N = 30). P-values are from Log-Rank tests. F Swimmer plot showing time to response and duration of response among the full patient population (N = 30). CI confidence interval, HR hazard ratio, m months, mOS median overall survival, mPFS median progression-free survival, mut/Mb mutations per megabase of DNA, NA not applicable, NE not evaluable, OS overall survival, PD progressive disease, PFS progression-free survival, PR partial response, SD stable disease, TMB tumor mutational burden.

Fig. 2. Factors associated with survival outcomes.

A The mutational landscape of the full patient population for the top 25 mutated genes (N = 29). B Kaplan–Meier curve of the overall survival (OS) outcomes for 20 HR+ patients with or without ESR1 oncogenic mutations showing a significant decrease in survivability. C Progression-free survival (PFS) Kaplan–Meier curve for PTEN showing a negative correlation between PTEN oncogenic mutations and PFS. D Kaplan–Meier curve of OS outcomes for 29 patients showing a negative correlation between PTEN oncogenic mutations with OS. E, F Kaplan–Meier survival curves for the composite immuno-oncology score and TMB ≥ 14 mut/Mb, PFS (E) and OS (F) for high or low composite immuno-oncology (IO) score. PFS (G) and OS (H) for TMB ≥ 14 mut/Mb or TMB < 14 mut/Mb. 21 patients with tissue F1CDx testing are included. P-values are Log-Rank tests of the variables in each Kaplan–Meier curve. Pathogenic/likely pathogenic variants are shown with a black line around the box denoting the variant, while variants of unknown significance are not. HR hormone receptor, NE not evaluable, PD progressive disease, PR partial response, SD stable disease.

Fig. 3. TMB values across different assays and tumor fraction dynamics according to clinical benefit.

A Distribution of the 12 paired tissue and baseline blood samples showing the tissue, blood, and OncoPanel TMB or bTMB, respectively. B Correlation between the tissue TMB and baseline bTMB showing the significant positive correlation with bTMB. C The correlation between baseline bTMB and OncoPanel TMB reveals a significantly higher bTMB. D The correlation between tissue and OncoPanel TMB shows a significant positive correlation between them, and the strongest correlation among the different TMB panels. P-values in (B–D) are two-sided Student t tests for the Pearson correlation coefficient r. E Changes in tumor fraction from seven paired baseline and end of treatment patients reveal a significant correlation based on clinical benefit status. P-value is an unpaired two-sided Wilcoxon rank-sum test between the clinical benefit groups using paired tumor fraction changes per patient. Patients 1 and 7 had similar changes in tumor fraction, and they overlap in the trajectory plot.