Abstract PS14-07: Ribociclib + letrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2−) advanced breast cancer (ABC) and central nervous system metastases: Subgroup analysis of the phase IIIb CompLEEment-1 trial
Authors: Cottu Paul , De Laurentiis Michelino , Marchetti Paolo , Coltelli Luigi , Califaretti Nadia , Debled Marc , Patil Shekar , Evron Ella , Duhoux Francois , Menon-Singh Lakshmi , Wu Jiwen , Zhou Katie , Bofill Javier Salvador 
Published: February 2021

Abstract
Background: Approximately 10-30% of patients (pts) with metastatic breast cancer (BC) are diagnosed with central nervous system (CNS) metastases, which are a major cause of morbidity and mortality, and are associated with a poor prognosis. Due to improving diagnostics and treatments in BC, and therefore longer pt survival, more CNS metastases in breast cancer pts are readily detected. However, pts with CNS metastases are often excluded from clinical trials. Ribociclib (RIB), an oral, selective cyclin-dependent kinase 4/6 inhibitor, is approved for use in combination with endocrine therapy (ET) in women with HR+, HER2- ABC. Here, we present a subgroup analysis of pts with CNS metastases at baseline from the Core Phase of CompLEEment-1 (NCT02941926), a Phase IIIb trial of RIB in combination with letrozole (LET) in pts with HR+, HER2- ABC. The eligibility criteria for this study allowed a broader and more diverse pt population than those of previous Phase III trials of RIB + LET, to reflect a typical real-world clinical setting. Methods: CompLEEment-1 included women of any menopausal status and men with HR+, HER2- ABC treated with ≤1 line of prior chemotherapy and no prior hormonal therapy for advanced disease. Pts received RIB (600 mg QD, 3 weeks on/1 week off) in combination with LET (2.5 mg QD, continuous). Men and premenopausal women received a luteinizing hormone-releasing hormone agonist (3.6 mg goserelin or 7.5 mg leuprolide, Q28D). This subgroup analysis assessed the primary outcomes (safety and tolerability) and secondary outcomes of time to progression (TTP), overall response rate (ORR), and clinical benefit rate (CBR) in pts with CNS metastases. Results: At the data cutoff date (November 8, 2019), 51 pts with CNS metastases (1.57%; total pt population N = 3,246) had been evaluated: median age was 56.0 years, 30 (58.8%) pts were postmenopausal, and ECOG PS &lt;2 was observed in 49 (96.1%) pts. Median duration of exposure to RIB was 16.8 months. Adverse events (AEs) were reported in 49 (96.1%) pts; with all but one experiencing a treatment-related AE. Grade ≥ 3 AEs were reported in 38 (74.5%) pts; serious AEs were reported in 8 pts. There was 1 treatment-related fatal AE (sepsis). The most common all-grade AEs were neutropenia (66.7%), nausea (39.2%), and vomiting (29.4%). The most common grade ≥ 3 AEs were neutropenia (51.0%), leukopenia (13.7%), and increased alanine aminotransferase (5.9%), aspartate aminotransferase (5.9%), and gamma-glutamyltransferase (5.9%). Overall, 19 pts (37.3%) had ≥ 1 dose reduction of RIB, 12 (23.5%) due to AEs, and 32 pts (62.7%) permanently discontinued treatment, 6 (11.8%) due to AEs. Median TTP was not estimable (NE) (95% CI, 15.5-NE) in this subgroup analysis; with an event-free probability of 56.1% (95% CI, 39.3-69.8) at 30 months. For the 35 pts with measurable disease and CNS metastases at baseline, ORR was 42.9% (95% CI, 26.3-60.6%) and CBR was 62.9% (95% CI, 44.9-78.5). Conclusions: This subgroup analysis from CompLEEment-1 supports the use of RIB + LET in pts with CNS metastases, who typically have poor outcomes and are frequently excluded from clinical trials. Efficacy results support the use of RIB + LET in HR+, HER2- ABC in a close to real-world setting. The safety profile associated with RIB + LET was manageable, with few pts discontinuing treatment due to AEs, consistent with previous Phase III trials of RIB + LET.
Citation Format: Paul Cottu, Michelino De Laurentiis, Paolo Marchetti, Luigi Coltelli, Nadia Califaretti, Marc Debled, Shekar Patil, Ella Evron, Francois Duhoux, Lakshmi Menon-Singh, Jiwen Wu, Katie Zhou, Javier Salvador Bofill. Ribociclib + letrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2−) advanced breast cancer (ABC) and central nervous system metastases: Subgroup analysis of the phase IIIb CompLEEment-1 trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS14-07.