Abstract PO2-27-12: Genomic determinants of benefit to nivolumab (NIVO) plus low dose ipilimumab (IPI) among patients (pts) with hypermutated HER2-negative metastatic breast cancer (MBC): results of NIMBUS trial
Authors: Barroso-Sousa Romualdo , Chinsky Tyler , Li Tianyu , Reddy Sangeetha , Emens Leisha , Overmoyer Beth , AlDubayan Saud , Chu Hoyin , Lange Paulina , Kasparian Julie , Basta Ameer , DiLullo Molly , Attaya Victoria , Hughes Melissa , Lin Nancy , Tayob Nabihah , Jeselsohn Rinath , Mittendorf Elizabeth , Tolaney Sara 
Published: May 2024

Abstract
Background: Genomic determinants of benefit to immune checkpoint inhibitors (ICI) among pts with MBC and high tumor mutational burden (TMB-H) are largely unknown. NIMBUS was an open-label, single-arm, multicenter, phase 2 study assessing the efficacy of NIVO 3 mg/kg intravenously every 14 days plus IPI 1 mg/kg IV every 6 weeks in pts with TMB-H HER2-negative MBC. The objective of this current study was to evaluate genomic profiling of pts included in NIMBUS and its association with benefit to ICI. Methods: In NIMBUS, eligible pts 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 progression-free survival (PFS), and overall survival (OS). We performed genomic analyses on the pre-treatment tissue, and on baseline and on treatment plasma from pts run on the Foundation Medicine Inc (Boston, MA) FoundationOne®CDx (F1CDx®) and FoundationOne®Liquid CDx (F1LCDx®) panel, respectively. Results: A total of 30 pts (21 with estrogen receptor (ER)-positive and 9 with triple-negative breast cancer) were included in this study. After a median follow-up of 30.6 months, 6 pts (20%) achieved partial response (PR) for a confirmed ORR of 20% (95% CI: 7.7-38.6%). Exploratory analyses did not reveal differences in ORR based on ER status, PD-L1 status, or stromal TIL. The median PFS was 1.4 months (95% CI: 1.3 – 4.6), and the median OS was 16.9 months (95% CI: 7.1-not reached). Pts who achieved PR had a 3-year OS of 75% versus 25% in non-responders. A total of 29 pts (6 responders and 23 non-responders) had at least one pre-treatment genomic panel performed: 16 had both, 5 had pretreatment F1CDx only and 8 had F1LCDx panel only. Blood TMB (bTMB) was highly correlated with tissue TMB by F1CDx (r = 0.95). Using data from the most recent genomic panel available, (24 for baseline blood, and 5 for pretreatment tissue), the most frequently mutated genes ( &gt; 30%) in this population were: TP53 (66%); PIK3CA (45%), ESR1 (35%), CDH1 (35%), ROS1 (31%). ESR1 and PTEN mutations were associated with absence of PR while PALB2 was associated with objective response. We observed a significant correlation between ESR1 mutations and a decrease in OS among pts with ER+ disease. Among the entire 29 pts, a negative correlation between PTEN with PFS and OS, and positive correlation between PALB2 with PFS was observed (Table). Among the 24 pts with baseline F1LCDx panel evaluable, the median TMB was 7.6 Mut/Mb ([interquartile range 0.0–113.8). Median TMB was 8.9 Mut/Mb and 41.7 Mut/mB among pts without and with PR, respectively. Baseline TMB &gt; 20 mut/Mb was found in all pts with PR and in one of those without response. Paired serial blood samples demonstrated that among responding pts, TMB was significantly reduced from baseline to end of treatment (EOT) compared to those with no clinical benefit [n=16, p=0.0015]. Lastly, the tumor fraction (TF) estimates from 7 paired baseline to EOT samples demonstrated that all responders had a decrease or no change in TF compared to an increase in non-responders [n=7, p=0.017]. Conclusion: In the NIMBUS trial, all pts with PR to NIVO plus low dose IPI had a TMB &gt; 20 Mut/Mb and had a decrease in TMB during treatment. ESR1 and PTEN mutations were associated with lack of benefit, while PALB2 mutation was associated with increased benefit. If validated, these results could help tailor the use of ICI among pts with TMB-H MBC.
Association between genomic alterations in ESR1, PTEN and PALB2 and benefit to nivolumab and low dose ipilimumab among patients with HER2-negative MBC and TMB-H

HR: hazard ratio; MBC: metastatic breast cancer; mOS: median overall survival (months); mPFS: median progression-free survival (months); TMB-H: tumor mutational burden above &gt; 9 mutations/megabase.
Citation Format: Romualdo Barroso-Sousa, Tyler Chinsky, Tianyu Li, Sangeetha Reddy, Leisha Emens, Beth Overmoyer, Saud AlDubayan, Hoyin Chu, Paulina Lange, Julie Kasparian, Ameer Basta, Molly DiLullo, Victoria Attaya, Melissa Hughes, Nancy Lin, Nabihah Tayob, Rinath Jeselsohn, Elizabeth Mittendorf, Sara Tolaney. Genomic determinants of benefit to nivolumab (NIVO) plus low dose ipilimumab (IPI) among patients (pts) with hypermutated HER2-negative metastatic breast cancer (MBC): results of NIMBUS trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-27-12.