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Ribociclib (LEE011) and letrozole in estrogen receptor-positive (ER+), HER2-negative (HER2–) advanced breast cancer (aBC): Phase Ib safety, preliminary efficacy and molecular analysis.
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2016
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Breast OncologyPathologyPharmacotherapyTumor BiologyPre-clinical PharmacologyTranslational PharmacologySystems PharmacologyMolecular PharmacologyMolecular AnalysisClinical TrialsEr+ BcPhase Ib SafetyCancer ResearchMedicineCancer TreatmentLee 600PharmacologyEndocrine-related CancerPhase Ii DoseClinical PharmacologyBreast CancerOncology
568 Background: Ribociclib (cyclin dependent kinase 4/6 inhibitor; LEE) acts synergistically with letrozole (LET) in preclinical models of ER+ BC. LEE + LET in patients (pts) with ER+ aBC is being investigated in Arm 1 of a 3-arm, phase Ib study (NCT01872260). The Arm 1 recommended phase II dose (RP2D) was reported as LEE 600 mg QD (3 weeks [wks] on/1 wk off) + LET 2.5 mg QD (Juric et al.SABCS 2014;PD-19-24). Methods: Postmenopausal women with ER+, HER2− aBC received oral LEE + LET at the RP2D. Primary objective of expansion: safety and tolerability. Other objectives include efficacy, pharmacokinetics (PK), and biomarkers. Results: As of Aug 21, 2015, 47 pts received LEE + LET in Arm 1: 95% of 19 pts from the initial enrollment were previously treated for aBC (PT group) and 96% of 28 pts in expansion were treatment-naïve for aBC (TN group). Treatment was discontinued in 18 (95%) PT pts (progressive disease [PD], n = 16; adverse events [AEs], n = 1; physician decision, n = 1) and 10 (36%) TN pts (PD, n = 10). Median duration of exposure was 16 and 35 wks in PT and TN groups, respectively. Grade 3/4 AEs suspected to be drug-related included neutropenia (43%), lymphopenia (4%), and leukopenia (2%). Of the 47 evaluable pts, one complete response (CR; TN) was observed. Overall response rate (ORR; CR+partial response [PR]) was 5% (95%CI: 0–26%) for PT and 39% (95%CI: 22–59%) for TN groups. Clinical benefit rate (CBR; CR+PR+stable disease [SD] ≥ 24 wks) was 32% (95%CI: 13–57%) for 19 evaluable PT pts and 73% (95%CI: 50–89%) for 22 evaluable TN pts. PK data for LEE + LET in combination were consistent with historical single-agent data. PR was observed in tumors with PIK3CA alterations (3 PR) or CCND1 amplification (1 PR), which were present in tumor samples from 5 and 2 of 9 PT pts, and 6 and 1 of 10 TN pts, respectively. Conclusions: Based on these preliminary data, LEE + LET has an acceptable safety profile in pts with ER+, HER2– aBC and demonstrated clinical activity, particularly in the TN group (39% ORR; 73% CBR). LEE + LET may also provide benefit to pts with PIK3CA alterations or CCND1 amplification. A phase III study of LEE + LET in 1st line postmenopausal aBC has completed enrollment. Clinical trial information: NCT01872260.