Abstract P4-22-12: Ribociclib + fulvestrant in postmenopausal women with HR+, HER2– advanced breast cancer (ABC)
Authors: Tolaney SM , Forero-Torres A , Boni V , Bachelot T , Lu Y-S , Maur M , Fasolo A , Motta M , Pan C , Dobson J , Hewes B , Chin Lee S 
Published: March 2017

Abstract
Background: Endocrine therapy (ET) is the treatment backbone for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) ABC, but efficacy is limited by ET resistance. The cyclin-dependent kinase (CDK) 4/6–cyclin D (CCND1)–retinoblastoma (Rb) and phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathways have been implicated in ET resistance. CDK4/6 and PI3K/mTOR inhibitors act synergistically with ET in preclinical and clinical studies of HR+ breast cancer. Ribociclib (LEE011; CDK4/6 inhibitor) + fulvestrant ± alpelisib (BYL719) or buparlisib (BKM120) in HR+, HER2– ABC is being investigated in a Phase Ib/II study (NCT02088684). Here, we present results from the ribociclib + fulvestrant combination, with intermittent and continuous ribociclib dosing.
Methods: Postmenopausal patients (pts) with HR+, HER2– ABC refractory to aromatase inhibitors received ribociclib intermittently (600 mg/day, 3-weeks-on/1-week-off; Arm A) or continuously (400 mg/day; Arm B; following Arm A safety evaluation) + fulvestrant (500 mg; Cycle 1 Day 1 and 15; subsequent cycles Day 1). Primary objective: dose-limiting toxicities (DLTs) to confirm the recommended Phase II dose of ribociclib + fulvestrant. Secondary objectives: safety, pharmacokinetics, and preliminary antitumor activity (RECIST v1.1); biomarkers that may correlate with response were also assessed.
Results: As of March 10, 2016, 24 pts received ribociclib + fulvestrant (Arm A, n=13; Arm B, n=11); 4 pts in Arm B were ongoing; median duration of exposure was 7.4 (Arm A) and 4.5 (Arm B) months. Median number of prior regimens: 4 (Arm A) and 3 (Arm B). Treatment discontinuation (n; Arm A, Arm B) was due to disease progression (11, 4), physician decision (1, 2), and adverse events (AEs; 1, 1). DLTs in Cycle 1 (n; Arm A, Arm B) were Grade [G] 3 pulmonary embolism (1, 0) and G3 aspartate aminotransferase elevation (0, 1). The most common G3/4 drug-related AE (Arm A, Arm B) was neutropenia (62%, 36%); 5 pts had QTcF prolongation &gt;60 ms (n; 4, 1).
Common all-Grade drug-related AEs (&gt;35% pts) n (%)Arm A (n=13)Arm B (n=11)Neutropenia10 (77)7 (64)Fatigue9 (69)3 (27)Nausea6 (46)5 (46)Anemia6 (46)0 (0)Reduced appetite5 (39)1 (9)
Best overall responses (BORs; n; Arm A, Arm B): partial response (PR; 3, 1), stable disease (SD; 9, 6), and neither complete response nor progressive disease (NCRNPD; non-measurable disease; 1, 4). Overall response rate: 23% (Arm A) and 9% (Arm B); disease control rate (BOR of complete response, PR, SD, or NCRNPD): 100% in both arms. Next-generation sequencing data (n; Arm A, Arm B) were available for 16 pts (7, 9): 5 pts had CCND1 alterations (PR [1, 0], SD [2, 1], and NCRNPD [0, 1]); 11 pts had PIK3CA alterations (PR [1, 0], SD [3, 4], and NCRNPD [1, 2]); 2 of these pts had both CCND1 and PIK3CA alterations (SD [1, 0] and NCRNPD [0, 1]).
Conclusions: Ribociclib + fulvestrant has a manageable safety profile and shows preliminary clinical activity in pretreated pts with HR+, HER2– ABC. Both ribociclib intermittent and continuous dosing schedules were well tolerated. Clinical responses were observed in tumors with and without CDK4/6–cyclin D–Rb and PI3K/mTOR pathway alterations.
Citation Format: Tolaney SM, Forero-Torres A, Boni V, Bachelot T, Lu Y-S, Maur M, Fasolo A, Motta M, Pan C, Dobson J, Hewes B, Chin Lee S. Ribociclib + fulvestrant in postmenopausal women with HR+, HER2– advanced breast cancer (ABC) [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 P4-22-12.