Phase Ib Safety, Efficacy, And Molecular Analysis Of Ribociclib (Lee011) Plus Letrozole For The Treatment Of Er+, Her2-Advanced Breast Cancer

Background: Aromatase inhibitors are the standard first-line treatment for patients (pts) with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (aBC). However, resistance via disruption of the cyclin D–cyclin-dependent kinase (CDK)4/6–inhibitor of CDK4–retinoblastoma pathway is common. The oral, selective CDK4/6 inhibitor ribociclib has demonstrated synergistic activity with letrozole in preclinical models of ER+ breast cancer. This Phase Ib study investigated ribociclib plus letrozole in ER+, HER2– aBC (NCT01872260). Methods: Postmenopausal pts with ER+, HER2− aBC received ribociclib (600 mg/day; 3-weeks-on/1-week-off) plus letrozole (2.5 mg; continuous). The primary objective of the expansion phase was to evaluate safety and tolerability. Secondary and exploratory objectives included efficacy, pharmacokinetics (PK), and biomarkers. Results: As of October 30, 2015, 47 pts received ribociclib plus letrozole: 19 pts in the initial enrollment and 28 pts in the expansion phase. In the initial enrollment, 17/19 pts (89%) were previously treated for aBC (PT group); in the expansion phase, 27/28 pts (96%) were treatment-naive for aBC (first-line group). All 19 PT pts and 10 first-line pts (62% of all pts) have discontinued treatment. Common (u003e5% of pts) treatment-related Grade 3/4 adverse events included neutropenia (43%), neutrophil count decreased (11%), and white blood cell count decreased (6%). Complete response (CR) was observed in 1 pt (4%) in the first-line group. In the PT and first-line groups, 1 pt (5%) and 10 pts (36%) had a partial response (PR), 7 pts (37%) and 4 pts (14%) had neither CR nor progressive disease (PD), 7 pts (37%) and 10 pts (36%) had stable disease (SD), and 4 pts (21%) and 3 pts (11%) had PD, respectively. Among pts with measurable disease, overall response rate (ORR; CR + PR) was 9% (95% confidence interval [CI]: 0–41%) for 11 PT pts and 46% (95% CI: 26–67%) for 24 first-line pts, and clinical benefit rate (CBR; CR + PR + SD ≥24 weeks) was 18% (95% CI: 2–52%) for 11 PT pts and 79% (95% CI: 58–93%) for 24 first-line pts. Ribociclib PK data were consistent with single-agent data and indicated no drug–drug interaction with letrozole. Notable genetic alterations detected by next-generation sequencing included PIK3CA mutations (4/10 PT pts [40%]; 14/22 first-line pts [64%]) and ESR1 mutations (2/10 PT pts [20%]). Responses were observed in pts harboring PIK3CA mutations (1 CR [first-line pt], 1 unconfirmed CR [first-line pt], 3 PR [1 PT pt, 2 first-line pts], and 3 unconfirmed PR [first-line pts]). Progression-free survival data for ribociclib plus letrozole, in addition to updated ORR and CBR, will be presented at the symposium. Conclusions: The combination of ribociclib plus letrozole demonstrated encouraging clinical activity, particularly in pts treatment-naive for aBC, with an acceptable safety profile that is in line with CDK4/6 inhibition. These results, which are consistent with the positive results of the MONALEESA-2 study (NCT01958021), provide additional safety and efficacy evidence for the use of ribociclib plus letrozole for the first-line treatment of postmenopausal aBC. Citation Format: Munster P, Ismail-Khan R, Garcia-Estevez L, Mayer IA, Becerra C, Hamilton E, De Boer R, Wardley AM, Im S-A, Teixeira L, Wang Y, Su F, Germa C, Hirawat S, Juric D. Phase Ib safety, efficacy, and molecular analysis of ribociclib (LEE011) plus letrozole for the treatment of ER+, HER2– advanced breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-18.