Abstract GS2-10: Nimbus: A phase 2 trial of nivolumab plus ipilimumab for patients with hypermutated her2-negative metastatic breast cancer (MBC)
Authors: Barroso-Sousa Romualdo , Li Tianyu , Reddy Sangeetha , Emens Leisha A. , Overmoyer Beth , Lange Paulina , Dilullo Molly K , Attaya Victoria , Kimmel Jeffrey , Winer Eric P. , Mittendorf Elizabeth A. , Tayob Nabihah , Tolaney Sara M. 
Published: March 2022

Abstract
Background: While high tumor mutational burden (TMB-H) has been used as a tissue-agnostic biomarker for approval of immune checkpoint inhibitors (ICI), there is a paucity of data regarding efficacy of ICI in TMB-H MBC. The aim of this study was to evaluate if patients with TMB-H 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 TMB-H HER2-negative MBC. Eligible patients were required to have measurable HER2-negative MBC, TMB ≥9 Mut/Mb assessed by a cancer-gene panel evaluating &gt; 300 genes and performed in a CLIA-certified laboratory, and 0-3 prior lines of chemotherapy in the advanced setting. The primary objective was overall response rate (ORR) according to RECIST 1.1. Secondary objectives include safety and tolerability, progression-free survival (PFS), and overall survival (OS). The study followed a two-stage design. In the first stage, 14 patients were enrolled. The study required at least 1 objective response in order to continue to the second stage where an additional 16 patients were enrolled. At least 4 objective responses among the 30 patients would suggest the regimen is worthy of further study. If the true response rate is 25%, the chance that the regimen is declared worthy of further study is &gt; 90%. Tumor biopsies, peripheral blood mononuclear cells, circulating tumor DNA, and stool collection were mandatory and were obtained at baseline and on treatment (end of cycle 1). Results: From February 2019 to June 2021, 31 patients were enrolled across 3 different academic institutions. Among 30 patients who initiated study treatment, the median age was 63 yo, 20 had hormone-receptor positive (HR+) breast cancer and 10 had triple-negative breast cancer (TNBC), and median number of prior lines of chemotherapy was 1.5 (0-3). Among the 10 patients with TNBC, PD-L1 status was known in 7 patients (3 positive and 4 negative). Median TMB was 10.9 Mut/Mb and 16.7% (n = 5) of patients had a TMB ≥14 mut/Mb. After a median follow-up of 9.7 (4.4 - 16.4) months, 4 (13.3%) patients achieved a confirmed objective response (all partial responses) meeting the primary endpoint of this study. The median duration of response has not been reached and 3 of these patients are still progression-free for at least 15 months. Two patients have short follow-up, and one has an unconfirmed partial response and the other has a stable disease at the time of the data cut. Median PFS and OS was respectively 1.4 (95% CI 1.3 - 9.5) months and 8.8 (95% CI 4.2 - not reached). Exploratory analysis did not show a difference in response rate according to HR status and PD-L1 status (data not shown) but tumors with TMB ≥14 mut/Mb had a response rate of 60% vs 4% in the group with TMB between ≥9 and &lt;14 mut/Mb (p = 0.01). The treatment was associated with a favorable toxicity profile, with only three patients developing grade 3 immune-related adverse events (1 had adrenal insufficiency and cardiac troponin elevation, and two other had hepatitis). There were no reported grade 4-5 events. Data regarding TIL, PD-L1 and CD8 immunohistochemistry will be presented at the symposium. Conclusion: This study of nivolumab plus ipilimumab in TMB-H MBC achieved the primary endpoint and demonstrated a confirmed ORR of 13.3%. While patients with TMB ≥ 14 Mut/Mb were minority in this study, the 60% of ORR in this subgroup highlights the need to better evaluate the optimal TMB cutoff to predict benefit to immunotherapy in MBC.
Citation Format: Romualdo Barroso-Sousa, Tianyu Li, Sangeetha Reddy, Leisha A. Emens, Beth Overmoyer, Paulina Lange, Molly K Dilullo, Victoria Attaya, Jeffrey Kimmel, Eric P. Winer, Elizabeth A. Mittendorf, Nabihah Tayob, Sara M. Tolaney. Nimbus: A phase 2 trial of nivolumab plus ipilimumab for patients with hypermutated her2-negative metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS2-10.