Abstract P3-14-01: Phase Ib/II study of ribociclib and alpelisib and letrozole in ER+, HER2– breast cancer: Safety, preliminary efficacy and molecular analysis
Authors: Juric D , Ismail-Khan R , Campone M , García-Estévez L , Becerra C , De Boer R , Hamilton E , Mayer IA , Hui R , Lathrop KI , Pagani O , Asano S , Bhansali SG , Zhang V , Hewes B , Munster P 
Published: May 2016

Abstract
Background: The interaction between the PI3K/AKT/mTOR and cyclin D–CDK4/6–INK4–Rb pathways has been reported to play a critical role in ER-driven breast cancer (BC). Furthermore, in preclinical ER+ BC models, the combination of ribociclib (LEE011; LEE), alpelisib (BYL719; BYL), and letrozole (LET) has recently shown enhanced activity vs each agent alone. A Phase Ib/II, 3-arm study is investigating the combination of LEE, BYL, and LET in pts with ER+ advanced (a)BC (CLEE011X2107; NCT01872260). Here, we report on safety, preliminary efficacy, and molecular analysis focusing on Arm (A)3 (LEE + BYL + LET) of Phase Ib.
Methods: Postmenopausal women with ER+, HER2– aBC received a fixed dose of 2.5 mg LET QD (continuous) with escalating doses of either oral LEE QD (3-wks-on/1-wk-off) or BYL QD (continuous), or both, in 28-day cycles. The primary objective is to determine the MTD and/or RP2D of each combination by assessing DLTs in Cycle 1 using an adaptive Bayesian Logistic Regression Model with overdose control principle. Secondary objectives include safety, PK, and preliminary efficacy assessments. Potential biomarkers predictive of response were assessed by next-generation sequencing in all patients, and immunohistochemistry in available tumor samples.
Results: As of Mar 2, 2015, 41 pts received LEE + LET (A1), 21 pts received BYL + LET (A2), and 36 pts received LEE (300–500 mg) + BYL (200–250 mg) + LET (A3). Here, we present results from A3. The number of prior endocrine regimens for advanced disease was: 0 (14 pts); 1–2 (14 pts); 3–4 (7 pts); ≥5 (1 pt); 33% of pts had previously received PI3K/AKT/mTOR inhibitors for aBC. Fifteen pts discontinued treatment: 7 (19%) due to PD and 8 (22%) due to AEs. The most frequent study drug-related AEs (all grade &gt;35%) were: nausea (all grade, 44%; G3/4, 6%), hyperglycemia (44%; 17%), neutropenia (42%; 22%), and fatigue (36%; 11%). The median duration of exposure was 8 weeks; 9 (25%) pts received treatment for ≥4 cycles. Of 27 evaluable pts, 2 (7%) pts had PR, 4 (15%) pts had unconfirmed PR, 6 (22%) pts had SD, 6 (22%) pts had non-CR non-PD (NCRNPD), and 5 (19%) pts had PD as best overall response. One pt with PR was treated for 9 cycles, had 5 lines of prior therapy including a PI3K/AKT/mTOR inhibitor, and had alterations in PIK3R1 and CDK4. The other pt with PR was treated for &gt;9 cycles, had 3 lines of prior therapy, and had alterations in PIK3CA and CCND1. In A1, an increase from baseline to C1D15 in pAKT and pS6(235) was observed in 5 and 3 pts, respectively; importantly, there was a more consistent reduction in Ki67 in A3 vs A1 or A2.
Conclusions: LET + LEE + BYL (A3) has an acceptable safety profile and demonstrates preliminary clinical activity in heavily pretreated pts with ER+, HER2– aBC. Preliminary data suggest CDK4/6 pathway activation is associated with improved response to triplet therapy. Importantly, the pathway analysis reported is supportive of a mechanistic combination effect whereby inhibition of the three pathways provides a sustained downregulation of Ki67, potentially preventing a feedback mechanism and hence delaying progression through therapy. Future randomized studies will compare LET + LEE or BYL with LET + LEE + BYL.
Citation Format: Juric D, Ismail-Khan R, Campone M, García-Estévez L, Becerra C, De Boer R, Hamilton E, Mayer IA, Hui R, Lathrop KI, Pagani O, Asano S, Bhansali SG, Zhang V, Hewes B, Munster P. Phase Ib/II study of ribociclib and alpelisib and letrozole in ER+, HER2– breast cancer: Safety, preliminary efficacy and molecular analysis. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-14-01.