Abstract PS2-06: First-line (1L) ribociclib (RIB) + endocrine therapy (ET) vs combination chemotherapy (combo CT) in clinically aggressive HR+/HER2- advanced breast cancer (ABC): a subgroup analysis of RIGHT Choice by intrinsic subtype & gene &am

Abstract Background: The phase 2 RIGHT Choice study showed a statistically significant median progression-free survival (mPFS) benefit with 1L RIB + ET vs combo CT (HR, 0.61; 95% CI: 0.43-0.87; P = .003) in pts with clinically aggressive HR+/HER2− ABC (Lu Y-S, et al. J Clin Oncol. Published online May 21, 2024). This exploratory analysis of the RIGHT Choice study examined efficacy of RIB + ET vs combo CT by intrinsic subtype and gene/signature expression levels. Methods: Pre/perimenopausal pts with no prior systemic therapy for aggressive HR+/HER2− ABC were randomized 1:1 to RIB + letrozole/anastrozole + goserelin or physician's choice of combo CT. Baseline tumor samples (n = 49) from pts enrolled in the trial were microdissected and underwent gene expression profiling by NanoString nCounter BC360 and PanCancer IO 360 panels. High and low baseline gene/signature expression levels were defined as greater and less than or equal to the median level, respectively. Results: Of the available samples from the RIB arm (n = 27), 6 (22.2%) were luminal A, 14 (51.9%) were luminal B, 6 (22.2%) were HER2E, and 1 (3.7%) was basal-like; in the CT arm (n = 22), 11 (50.0%) were luminal A, 9 (40.9%) were luminal B, and 2 (9.1%) were HER2E. The mPFS in the RIB vs CT arms was 32.5 mo vs not reached (NR) (HR, 0.88; 95% CI: 0.20-3.91) in luminal A, 38.0 vs 21.7 mo (HR, 0.64; 95% CI: 0.18-2.20) in luminal B, and 17.4 vs 8.0 mo (HR, 0.23; 95% CI: 0.03-1.66) in HER2E subtype. In the combined luminal B/HER2E set, which are known to be associated with poor prognosis, the mPFS was 38.0 vs 18.4 mo with RIB + ET vs combo CT (HR, 0.58; 95% CI: 0.21-1.62). In the RIB arm, pts with high ESR1 expression showed longer mPFS vs pts with low ESR1 expression (high vs low expression, mPFS, HR [95% CI]; 38.0 vs 32.5 mo, 0.52 [0.16-1.66]). Pts in the RIB arm with low expression of tumor inflammation or immune-related genes/cells, such as tumor inflammatory signature (TIS; BC360 panel) and T-cell (IO 360 panel) expression, had a longer mPFS than pts with high expression of these signatures (low vs high expression, mPFS, HR [95% CI]: TIS, NR vs 11.4 mo, 0.17 [0.04-0.76]; T cells, NR vs 10.3 mo, 0.2 [0.05-0.76]). In contrast to the results in the RIB arm, pts with low expression of immune-related genes/cells in the CT arm had a shorter mPFS than those with high expression of these genes (low vs high expression, mPFS, HR [95% CI]: TIS, 15.0 mo vs NR, 2.08 [0.62- 6.93]; T cells, 12.8 vs 18.4 mo, 1.8 [0.57-5.71]). For most other immune-related genes/cells expressions and signatures, a comparable consistent trend in PFS benefit for low vs high expression levels was observed, with a higher PFS benefit for low gene expression in the ribociclib arm, and a higher PFS benefit for high gene expression in the CT arm. Conclusions: This exploratory analysis showed a trend towards PFS benefit with RIB + ET vs combo CT in pts with luminal B/HER2E intrinsic subtypes, which are associated with poor prognosis. This analysis also suggest a more pronounced trend for PFS benefit with RIB + ET in pts with low baseline expression levels of immune-related genes. Contrary results in the CT arm suggest that these signatures warrant further studies on their potential predictive value. These data are hypothesis generating and should be interpreted with caution due to small sample sizes. Citation Format: Yen-Shen Lu, Chia-Lang Hsu, Eznal Izwadi Bin Mohd Mahidin, Sudeep Gupta, Erhan Gökmen, Elena Artamonova, Huang-Chun Lien, Hamdy Azim, Yoon-Sim Yap, Yesim Eralp, Seock-Ah Im, Fei Su, Yogesh Chattar, Estelle Roux, Melissa Gao, Nagi S. El Saghir. First-line (1L) ribociclib (RIB) + endocrine therapy (ET) vs combination chemotherapy (combo CT) in clinically aggressive HR+/HER2- advanced breast cancer (ABC): a subgroup analysis of RIGHT Choice by intrinsic subtype & gene & signature expression [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr PS2-06.