Abstract P1-19-37: Pharmacokinetic assessment of ribociclib, an oral CDK4/6 inhibitor, and the interaction with endocrine therapy partners in patients with advanced breast cancer
Authors: Ji Yan , Samant Tanay , Quinlan Michelle , Chakraborty Abhijit 
Published: March 2020

Abstract
Background: Ribociclib (RIB) is an oral CDK4/6 inhibitor used in combination with endocrine therapy (ET) to treat women with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative locally advanced breast cancer (ABC). ET partners are aromatase inhibitors (AI), eg letrozole or anastrozole, in pre-/perimenopausal women, and AI or fulvestrant in postmenopausal women. Here we characterize the pharmacokinetics (PK) of RIB as a single agent in patients with advanced cancer, assess the potential for drug-drug interactions (DDIs) between RIB and these ET partners in patients with HR+ ABC, and estimate the in vivo potency of RIB on CDK4.
Methods: The PK of RIB as a single agent was characterized in patients with advanced cancer in study CLEE011X2101 (X2101; NCT01237236). The potential for DDIs was assessed by comparing the steady-state exposures (AUC, Cmax and Ctrough) of RIB when used alone in study X2101 with those of RIB when used in combination with ET in patients with HR+ ABC (studies CLEE011X2107 [X2107; NCT01872260], MONALEESA-2 [ML-2; NCT01958021], MONALEESA-7 [ML-7; NCT02278120], and MONALEESA-3 [ML-3; NCT02422615]). The effect of RIB on the PK of ET was also assessed in these studies. The CDK4 inhibition of RIB in patients was estimated based on its steady-state exposure and in vitro potency.
Results: In study X2101, RIB showed rapid absorption (median Tmax 1-4 h), mean effective half-life (t1/2,acc) of 12.0-33.1 h, and slightly over-proportional increases in exposure (Cmax and AUC) over the dose range of 50-1200 mg QD. Steady state was generally achieved by Day 8, with a geo-mean accumulation ratio of 2.51 at the dose of 600 mg. The PK of RIB in combination with letrozole in studies X2107, ML-2 and ML-7 was consistent with that of RIB in study X2101 (Table 1). Additionally, in study ML-7, exposure parameters for letrozole were similar between the letrozole + RIB 600 mg and letrozole alone arms: Ctrough geo-mean (geo-CV%) 92.7 ng/mL (50.2%) vs 96.8 ng/mL (55.9%). In study ML-7, the steady-state exposure (Ctrough) of RIB in combination with anastrozole was consistent with that in study X2101 (Table 1). Furthermore, in the same study, anastrozole Ctrough geo-mean (geo-CV%) values were broadly similar in the anastrozole + RIB 600 mg and anastrozole alone arms considering variability: 38.5 ng/mL (59.5%) and 28.4 ng/mL (70.4%). Mean plasma Ctrough of RIB in combination with fulvestrant observed in study ML-3 was consistent with the results in study X2101 (Table 1). Although PK of fulvestrant was not evaluated, it is unlikely to have a DDI with RIB because induction or inhibition of CYP3A4 have been shown to have no impact on the PK of fulvestrant. Population PK analysis suggests that concomitant use of letrozole, anastrozole, or fulvestrant has no statistically significant or clinically relevant impact on RIB exposure. Based on steady-state RIB exposure in patients, and its in vitro potency measured by inhibition of Rb phosphorylation in CDK4-dependent breast cancer cell lines, RIB is predicted to attain approximately 90% inhibition of CDK4 inhibition at steady state.
Conclusion: RIB demonstrated rapid absorption and a mean t1/2,acc of 32.0 h after oral administration of 600 mg QD in patients with cancer. Concomitant use of ET partners letrozole, anastrozole, and fulvestrant appears to have no clinically relevant PK interaction with RIB in patients with ABC.
Steady-state PK Parameters of RIB Across Clinical Studies Where RIB Was Administered at 600 mg QDStudy Dose given on Cycle (C), Day (D)Study designPatient populationET combination partnerCmax (ng/mL),geo-mean (geo-CV%)Tmax (h), geo-mean (min, max)AUC0-24h or AUC06ha (hr•ng/mL), geo-mean (geo-CV%)Ctrough (ng/mL), geo-mean (geo-CV%)X2101bn = 57n = 57n = 54n = 58C1, D18/21Phase 1, open-label, dose-escalation studyAdult patients with advanced solid tumors or lymphomasNone1820 (62.4)2.40 (0.68-7.82)23,800 (66.0)483 (92.7)X2107n = 28n = 28n = 23n = 25C1, D21Phase 1b/2, open-label, dose-escalation studyAdult patients with advanced HR+ breast cancerLetrozole 2.5 mg oral QD1720 (44.6)2.11 (1.057.67)23,290 (52.2)578 (67.1)ML-2n = 44C1, D15Phase 3, randomized, double-blind, placebo-controlled, efficacy and safety studyPostmenopausal women with HR+, HER2- ABCLetrozole 2.5 mg oral QD---687 (69.8)ML-7n = 45n = 45n = 43n = 76C3, D15Phase 3, randomized, double-blind, placebo-controlled, efficacy and safety studyPre-/perimenopausal women with HR+, HER2- ABCLetrozole 2.5 mg oral QD1680 (30.6)3.62 (1.676.35)7590 (34.4)457 (67.3)n = 3n = 3n = 3n = 15Anastrozole 1 mg oral QD2570 (51.5)3.92 (3.854.17)12,600 (48.1)372 (109.7)ml-3Fulvestrant 500 mgC1, D15: n = 253627 (67.6)C2, D15: n = 177C1, D15 c2, d15Phase 3, randomized, double-blind, placebo-controlled, efficacy and safety studyPostmenopausal women with HR+, HER2- ABC5 mL im BID---553 (80.7)aRIB AUC0-6h was measured when letrozole and anastrozole were given as combination partners in study ML-7. b Pooled data from patients with cancer receiving intermittent schedule (50, 70, 140, 260, 280, 350, 400, 600, 750, 900, 1200 mg QD, 3-weeks on 1-week off) and patients with cancer with continuous dosing (300, 400, 600 mg QD for 28 days).ABC, advanced breast cancer; AUC, area under the curve; BID, twice daily; Cmax, maximum plasma concentration following drug administration; Ctrough, trough plasma concentration; ET, endocrine therapy; HER2-, human epidermal growth receptor-2-negative; HR+, hormone receptor-positive; im, intramuscular; QD, daily; Tmax, time to reach the maximum plasma concentration after drug administration
Citation Format: Yan Ji, Tanay Samant, Michelle Quinlan, Abhijit Chakraborty. Pharmacokinetic assessment of ribociclib, an oral CDK4/6 inhibitor, and the interaction with endocrine therapy partners in patients with advanced breast cancer [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 P1-19-37.