797 Genomic and transcriptomic profiles associated with response to eribulin and nivolumab combination in HER-2 negative metastatic breast cancer

Background

Combination of eribulin and immune checkpoint inhibitor (ICI) showed durable response for HER-2 negative metastatic breast cancer (MBC) patients, but PD-L1 expression was not associated with efficacy. Here, we report the whole exome sequencing (WES) and whole transcriptome sequencing (WTS) analysis of pretreatment tumor tissues from the phase II clinical trial of the eribulin and nivolumab combination in patients with HER-2 negative MBC to find potential biomarker (KORNELIA trial, ClinicalTrials.gov Identifier: NCT04061863).

Methods

We acquired whole exome sequencing (WES) data from 76 patients, and whole transcriptomic sequencing (WTS) data from 58 patients. Patients achieved progression free survival (PFS) ≥ 6 months were defined as PFS6-responders and otherwise as PFS6-nonresponders. We explored the potential biomarkers from WES and WTS, and analyzed how they are associated with efficacy.

Results

PFS6 rate in this study cohort was 34.5%. PFS6-responders tended to have higher TMB compared with PFS6-nonresponders (median TMB 6.6 vs. 5.1 mut/Mb, p = 0.309). TMB-high patients (≥ 8 mut/Mb) showed showed tendency to higher PFS compared with TMB-low patients (median PFS 8.0 months, 95% confidence interval [CI] 5.6 ~ 14.6 for TMB-high and 4.3 months, 95% CI 3.0 ~ 5.6 for TMB-low, p = 0.07). Comprehensive analysis related to homologous recombination deficiency (HRD), which include mutational signature 3, somatic HRD-related gene mutation, and HRD scores, showed that overall HRD was associated with poor response to the combination regimen. Specifically, when patients were divided into two groups by median HRD score, patients with high HRD score showed significantly lower PFS6 rate (23.7% vs. 50.0%, p = 0.031) and significantly shorter PFS compared to patients with low HRD score (median PFS 4.2 months [95% CI 2.6 ~ 5.6] vs. 6.5 [95% CI 5.3 ~ 14.3], p = 0.025). WTS data showed antigen presentation (AP) gene set enrichment scores were high in PFS6-responders and the patients with high scores showed significantly longer PFS compared with the other patients. In addition, the proportion of naïve B-cell and plasma cell were significantly higher in the long responders (≥ 18 months).

Conclusions

In conclusion, we found that high TMB and B-cell related enrichment were associated with good efficacy while HRD was associated with poor efficacy of eribulin plus nivolumab in patients with HER-2 negative metastatic breast cancer. The implications from our study would need to be considered when designing the clinical trial in terms of biomarker enrichment and inclusion/exclusion criteria.

Trial Registration

NCT04061863

Ethics Approval

Institutional review boards of Seoul National University Bundang Hospital

Number

B-1811–505-004