Abstract PS10-05: Ribociclib + letrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2−) advanced breast cancer (ABC): Expanded safety analysis of the phase IIIb CompLEEment-1 trial
Authors: Lu Janice , Cottu Paul , Martín Miguel , Zamagni Claudio , Prat Aleix , Chia Stephen , Jerusalem Guy , Rajappa Senthil , Timcheva Constanta , Zhukova Lyudmila , Zhou Katie , Wu Jiwen , Menon-Singh Lakshmi , De Laurentiis Michelino 
Published: February 2021

Abstract
Background: CompLEEment-1 (NCT02941926) is an ongoing Phase IIIb trial of ribociclib (RIB) in combination with letrozole (LET) in the first-line setting for patients (pts) with HR+, HER2- ABC, reflecting a real-world clinical setting by including a more diverse pt population than those included in the pivotal MONALEESA trials. Here we report further analyses of the primary endpoint of safety from the completed Core Phase of the trial. 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). Premenopausal women and men received a luteinizing hormone-releasing hormone agonist (3.6 mg goserelin or 7.5 mg leuprolide, Q28D). The primary endpoints were safety and tolerability. Updated analyses included dose reduction/interruption or treatment discontinuation due to adverse events (AEs), clinical impact of AEs of special interest (AESI), and exposure-adjusted incidence/occurrence rates (IRs) for AESI. Results: At data cutoff (November 8, 2019) 3,246 pts had been evaluated (median follow-up of 25.4 months), and median duration of exposure to RIB was 17.5 months; 1,301 (40.1%) pts completed Core Phase treatment, 415 of whom moved to the Extension Phase. Overall, 1,945 (59.9%) pts permanently discontinued treatment, mostly due to progressive disease (34.2%) and AEs (15.5%). Treatment-related AEs were reported in 3,091 (95.2%) pts, leading to dose modification in 2,235 (68.9%) pts. Dose modification occurred most often in pts with grade ≥3 neutropenia (dose interruption, 1,671 [51.5%] pts; dose reduction, 480 [14.8%] pts); treatment discontinuation occurred most frequently in pts with grade ≥3 increased alanine aminotransferase (ALT; 116 [3.6%] pts) or aspartate aminotransferase (AST; 68 [2.1%] pts). Grade ≥3 neutropenia occurred in 1,856 (57.2%) pts, with the median time to first occurrence of 4.1 weeks and median duration of first occurrence of 1.1 weeks. As measured by laboratory values, grade ≥2 increased ALT and AST occurred in 453 (14.0%) and 380 (11.7%) pts, respectively. Grade ≥2 QTcF prolongation was infrequent, occurring in 101 (3.1%) pts, leading 8 (0.2%) pts to discontinue from treatment. AESI rarely led to hospitalization (0 to 0.3%) and none were fatal. Exposure-adjusted IRs for AESI per 100 patient-years of exposure show that with increasing RIB exposure, the IR and the event rates for AESI decreased by a factor of ×2 to ×8 from 0-1 years compared with 1-2 years (Table 1). Conclusions: AEs associated with RIB + LET combination therapy were manageable, consistent with previous Phase III trials of RIB + LET - and adjusted IRs for AESI notably decreased from Year 1 to Year 2 of treatment. These data further support the use of RIB + LET for first-line treatment of HR+, HER2- ABC in both men and women of any menopausal status and in a broader and more diverse patient population.
Table 1. Exposure-adjusted IRs for selected AESI per 100 patient-years of exposure0-1 years1-2 yearsAESIIR per 100 PTYaEvents per 100 PTYbIR per 100 PTYaEvents per 100 PTYbNeutropenia276.76410.2292.43200.83ALT increased20.3741.663.796.32AST increased17.5133.272.944.61QTcF prolongation8.4410.221.081.26aIR per 100 PTY: n/100 PTY, number of patients with an event divided by the corresponding sum of the exposure duration for patients, where duration of exposure in patient treatment-years (PTY) is counted up to the first qualifying event (or duration of exposure in time interval for patients without an event).bEvents per 100 PTY: n/100 PTY, number of events divided by the corresponding sum of the exposure duration, where duration of exposure in patient treatment-years (PTY) is duration of exposure in time interval.
Citation Format: Janice Lu, Paul Cottu, Miguel Martín, Claudio Zamagni, Aleix Prat, Stephen Chia, Guy Jerusalem, Senthil Rajappa, Constanta Timcheva, Lyudmila Zhukova, Katie Zhou, Jiwen Wu, Lakshmi Menon-Singh, Michelino De Laurentiis. Ribociclib + letrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2−) advanced breast cancer (ABC): Expanded safety 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 PS10-05.