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Nimbus: A phase II study of nivolumab plus ipilimumab in metastatic hypermutated HER2-negative breast cancer.

TPS1115 Background: A previous study from our group showed that approximately 9% of metastatic breast cancer (MBC) is hypermutated, defined as a tumor mutational burden (TMB) ≥10 Mutations/Megabase (Mut/Mb). The aim of this study is to evaluate if patients with hypermutated HER2-negative MBC benefit from the combination of nivolumab plus ipilimumab. Methods: This is an open-label, single-arm, multicenter, phase 2 study assessing the efficacy of nivolumab 3 mg/Kg intravenously (IV) every 14 days plus Ipilimumab 1 mg/Kg IV every 6 weeks in subjects with hypermutated metastatic HER2-negative breast cancer. Patients with measurable HER2-negative MBC, TMB ≥10 Mut/Mb assessed by a cancer-gene panel evaluating > 300 genes and performed in a CLIA-certified laboratory, and 0-3 prior lines of chemotherapy in the advanced setting are eligible. The primary objective is overall response rate according to RECIST 1.1. Secondary objectives include the safety and tolerability of the combination, progression-free survival, and overall survival. The study will follow a two-stage design. In the first stage 14 patients will be enrolled. If there is at least one patient with objective response, accrual will continue to the second stage where an additional 16 patients will be enrolled. If there are at least 4 patients with an objective response among the 30 patients, the regimen will be considered worthy of further study. If the true response rate is 5%, the chance the regimen is declared worthy of further study is less than 5%. If the true response rate is 25%, the chance that the regimen is declared worthy of further study is > 90%. Tumor biopsies, peripheral blood, and stool collection are mandatory and will be obtained at baseline, on treatment (end of cycle 1), and at disease progression and will be assessed for potential biomarkers of treatment response. The trial was activated in February 2019, and accrual should be completed in 18 months. Clinical trial information: NCT03789110.