Abstract P1-19-21: Ribociclib + letrozole in patients with HR+, HER2− advanced breast cancer: Safety analysis of the phase 3b CompLEEment-1 trial
Authors: Lu Janice , Cottu Paul , Martin Miguel , Zamagni Claudio , Zhou Katie , Wu Jiwen , Ankrah Nii , De Laurentiis Michelino 
Published: March 2020

Abstract
Background: CompLEEment-1 (NCT02941926) is an ongoing phase 3b trial of ribociclib (RIB), a cyclin-dependent kinase 4/6 inhibitor, in combination with letrozole (LET) in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC). The eligibility criteria for this study were less restrictive than those of previous phase 3 trials of RIB + LET (eg, Eastern Cooperative Oncology Group performance status ≤2) to reflect typical clinical settings. A preliminary analysis of CompLEEment-1 has been reported showing safety and efficacy outcomes consistent with the pivotal MONALEESA studies, but the diversity of the patient population in CompLEEment-1 warrants a closer examination of adverse events of special interest (AESIs).
Methods: Men and women of any menopausal status with HR+, HER2- ABC and no prior hormonal therapy received RIB (600 mg QD, 3 weeks on/1 week off) in combination with LET (2.5 mg QD, continuous). Premenopausal women received a luteinizing hormone-releasing hormone agonist (3.6 mg goserelin or 7.5 mg leuprolide, q28d). The primary endpoints were safety and tolerability. Analyses included the incidence of adverse events leading to dose reduction/interruption or treatment discontinuation and clinical impact of AESIs.
Results: At the data cutoff date (August 8, 2018), 3246 patients had been evaluated over a median follow-up of 10.4 months. The median duration of exposure to RIB was 8.1 months. Treatment-related AEs were reported in 3043 (93.7%) patients, and led to dose modification in 2092 (64.4%) patients and treatment discontinuation in 370 (11.4%) patients. Dose modification occurred most often in patients with grade ≥3 neutropenia (dose interruption, 1572 [48.4%] patients; dose reduction, 349 [10.8%] patients), whereas treatment discontinuation occurred most frequently in patients with increased alanine aminotransferase (ALT, grade ≥3; n = 110 [3.4%]) or aspartate aminotransferase (AST, grade ≥3; n = 73 [2.2%]). Overall, increased ALT was reported in 476 (14.7%) patients and increased AST in 412 (12.7%) patients. Grade &lt;3 events occurred in, respectively, 239 and 241 of these patients. Grade ≥3 neutropenia (based on laboratory neutrophil counts) occurred in 1740/2329 (74.7%) patients with neutropenia, with a median time to first occurrence of 4.14 weeks. Of 201 patients with QT prolongation, 174 (86.6%) were grade &lt;3. AESIs resolved in most patients, including 303/476 (63.7%) with increased ALT, 271/412 (65.8%) with increased AST, 2133/2329 (91.6%) with neutropenia, and 171/201 (85.1%) with QT prolongation (Table 1). Collectively, these findings were consistent with the safety profile for RIB in the MONALEESA-2 and MONALEESA-7 clinical trials.
Conclusions: AEs associated with RIB + LET combination therapy were manageable and often reversible. This interim safety analysis is consistent with previous phase 3 trials of RIB + LET and further supports its use for first-line treatment of HR+, HER2- ABC in both men and women of any menopausal status in real-world settings.
Table 1. Incidence and clinical impact of adverse events of special interest in CompLEEment-1aPatients with ≥1 event, nIncreased ALTIncreased ASTNeutropeniabQT ProlongationPatients with outcome, n (%)c4764122329201Dose reductionDose interruption39(8.2)23(5.6)441(18.9)17(8.5)Drug withdrawn225(47.3)191(46.4)1611(69.2)35(17.4)Treatment with medication192(40.3)126(30.6)11(0.5)5(2.5)Hospitalization51(10.7)46(11.2)108(4.6)7(3.5)Resolution8(1.7)6(1.5)5(0.2)0303(63.7)271(65.8)2133(91.6)171(85.1)aAs of data cutoff (August 8, 2018).bNeutropenia includes “neutropenia” and “neutrophil count decreased.”cPercentages are relative to the number of patients with events. Values do not sum to 100% across columns because patients could have more than one type of event.Patients with multiple severity grades for an AE were only counted once under the maximum grade.MedDRA version 21.1, CTCAE version 4.03.CTCAE, Common Terminology Criteria for Adverse Events; MedDRA, Medical Dictionary for Regulatory Activities.
Citation Format: Janice Lu, Paul Cottu, Miguel Martin, Claudio Zamagni, Katie Zhou, Jiwen Wu, Nii Ankrah, Michelino De Laurentiis. Ribociclib + letrozole in patients with HR+, HER2− advanced breast cancer: Safety analysis of the phase 3b CompLEEment-1 trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-21.