Abstract P5-19-24: Phase Ib/II study of LEE011 and BYL719 and letrozole in ER+, HER2– breast cancer: Safety, preliminary efficacy and molecular analysis
Authors: Juric Dejan , Hamilton Erika , Garcia Estévez Laura , De Boer Richard H , Mayer Ingrid , Campone Mario , Asano Shizuka , Bhansali Suraj , Zhang Vickie , Hewes Becker , Munster Pamela 
Published: May 2015

Abstract
Background: Activation of the PI3K/AKT/mTOR and cyclin D–CDK4/6–INK4–Rb pathways, including through alteration of PIK3CA and CCND1, has been implicated in resistance to aromatase inhibitors. BYL719 (BYL), an α-isoform selective PI3K inhibitor, demonstrated clinical activity as a single agent and in combination with hormone therapy in pts with advanced HR+ breast cancer (BC), while the CDK4/6 inhibitor LEE011 (LEE) showed evidence of clinical activity as a single agent in pts with advanced solid tumors and in combination with letrozole (LET) in pts with heavily pretreated advanced ER+ BC. In ER+ BC models, the triple combination of LEE, BYL, and LET had enhanced activity vs each agent alone. A Ph Ib/II, 3-arm study is currently investigating the combination of LEE, BYL, and LET in pts with ER+ BC. Here we report on safety, preliminary efficacy, and molecular analysis from Arm (A)1 (LEE + LET) and A2 (BYL + LET) of the Ph Ib part of the study.
Methods: Postmenopausal pts with advanced ER+, HER2– BC receive daily oral LEE (3-wks-on/1-wk-off; A1) or BYL (continuous; A2), plus fixed, daily LET (2.5 mg, continuous) in 28-day cycles. Primary objective: determine the MTD and/or RP2D of each combination. A Bayesian Logistic Regression Model using the escalation with overdose control principle and real-time PK guide dose escalation. Secondary objectives: safety, PK, and preliminary efficacy. Potential biomarkers that are predictive of response are also being assessed by next-generation sequencing of tumor samples.
Results: As of March 28, 2014, 10 pts received 600 mg LEE plus LET (A1), and 7 pts 300 mg BYL plus LET (A2). At study entry, all pts had stage IV disease; number of prior endocrine regimens for advanced disease was: 0–1 (47%); 2–3 (35%); 4–5 (18%); 35% of pts had previously received PI3K/AKT/mTOR pathway inhibitors for advanced disease. Of the 15 pts evaluable for dose determination (10 in A1 and 5 in A2), 1 dose-limiting toxicity was observed (A1: Grade [G]4 neutropenia; data cut-off: May 15). Most common (all grade &gt;30%) study drug-related AEs (all grade/G3–4) were: A1: neutropenia (90%/50%) and nausea (40%/0%); A2: hyperglycemia (57%/14%), decreased appetite, diarrhea, and nausea (43%/0% each). PK of LEE and BYL on Days 1 and 21, and LET on Day 1, are comparable with historic single-agent data. PK of LET at steady state is being evaluated. In A1, of 6 pts with known response, 1 pt had a PR, 2 pts had SD, 1 pt without measurable disease had NCRNPD, and 2 pts had PD. In A2, of 5 pts with known response, 2 pts had SD, and 3 pts had NCRNPD. Biomarker analysis showed that 2 pts in A2 with SD who are still on study (1 with 25% tumor shrinkage) had PIK3CA mutations.
Conclusion: LET plus LEE or BYL had an acceptable safety profile and preliminary clinical activity in pts with ER+/HER2– advanced BC. Dose escalation continues, and upon determination of the MTD/RP2D in A1 and A2, enrollment into A3 (LEE + BYL + LET) will begin to determine the MTD/RP2D. Genetic alterations in PIK3CA were observed in A2. Analysis of baseline aberrations in the cyclin D–CDK4/6–INK4–Rb pathway in A1 and A3 are ongoing and will be updated. The Ph II part of the trial will compare LET plus LEE or BYL with the triple combination.
Citation Format: Dejan Juric, Erika Hamilton, Laura Garcia Estévez, Richard H De Boer, Ingrid Mayer, Mario Campone, Shizuka Asano, Suraj Bhansali, Vickie Zhang, Becker Hewes, Pamela Munster. Phase Ib/II study of LEE011 and BYL719 and letrozole in ER+, HER2– breast cancer: Safety, preliminary efficacy and molecular analysis [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-24.