Abstract CT330: Phase I study of PI3Kα inhibitor BYL719 + aromatase inhibitor (AI) in patients (pts) with hormone receptor-positive (HR+) metastatic breast cancer (MBC)
Authors: Shah Payal D. , Moynahan Mary E. , Modi Shanu , Hamilton Nicola , Caravella Betty Ann , Zamora Stephen , Dang Chau , Gilewski Theresa , Traina Tiffany , Comen Elizabeth , Sugarman Steven M. , D'Andrea Gabriella , Lake Diana , Goldfarb Shari , Patil Sujata , Covey Anne , Berger Michael , Lacouture Mario , Norton Larry , Hudis Clifford A. , Baselga Jose , Chandarlapaty Sarat , Dickler Maura 
Published: August 2015

Abstract
Background: Phosphatidylinositol 3-kinase (PI3K) hyperactivation contributes to endocrine therapy resistance. An α-selective PI3K inhibitor (BYL719) added to hormonal therapy may overcome this resistance. We conducted a phase I study to evaluate the safety and determine preliminary efficacy of BYL719 and an AI in pts with HR+ MBC.
Methods: This 3+3 dose-escalation trial added oral BYL719 to letrozole (L) or exemestane (E) at standard doses using daily (Arm A: L; Arm B: E) and then intermittent dosing (Arm C: L + BYL719 every other week; Arm D: E + BYL719 on 5 of 7 days weekly). Pts with HR+ MBC, any or no PIK3CA mutation, and already on L/E were eligible. Endpoints were dose-limiting toxicity (DLT), tolerability (CTCAE 4.0), and efficacy. Paired tumor biopsies and serial plasma collection facilitated genomic, proteomic, and cell-free (cfDNA) correlatives.
Results: 32 patients (Arm A/B: n = 7/7; Arm C/D: n = 9/9) received a mean of 99 days (range: 6-473d) of BYL719 + L or E. All were evaluable for toxicity; 25 (Arm A/B: 5/5; Arm C/D: 7/8) were evaluable for response. Median (M) age was 58.5 (30-83). M number of prior MBC therapies was 3 (1-12). PIK3CA status was mutant(MT)/wild-type(WT)/unknown in 8/5/1 pts on Arms A+B and 17/1/0 on Arms C+D. During dose escalation on Arms A+B, 14 pts received BYL719 doses up to 300mg/d, where 4 pts had 5 distinct DLTs: maculopapular rash (N = 3), hyperglycemia (N = 1), abdominal pain (N = 1). 8 week (w) best response on continuous dosing arms (n = 10 evaluable pts) was 1 PR (pt heavily pre-treated, including prior L, MBC to liver, Arm A, completed 10C); 7 SD (included -29.9%, -19%, -12%), and 2 POD. Due to toxicity, enrollment to these arms was halted prior to MTD determination. The protocol was amended to include 2 intermittent dosing arms. 3 DLTs were seen: Arm C, grade (G)3 rash, G1 fever and hypotension with &gt;7d therapy hold; Arm D, G3 rash. Toxicities (Arms C+D, all cohorts, n = 18) included G≥4: hyperglycemia (n = 1, while pt on corticosteroids); G3: rash (n = 4); G1/2: mucositis (n = 9), hyperglycemia (n = 8), and anorexia (n = 5). MTD determinations are pending with evaluation of 350mg BYL719 5d on, 2d off ongoing on Arm D. On Arm C, of 7 evaluable pts, best response was SD in 3 pts (28w, 12w, 8+w in 1 pt each) and POD in 4 pts. On Arm D, of 8 evaluable pts, best response is SD in 6 pts (28+w, 16+w in 1 pt each; 20w, 8+w in 2 pts each), and POD in 2 pts. Using serial cfDNA analysis, PIK3CA mutant allele fraction declined with SD and PR and increased in pts with POD. Correlative studies including genomics and proteomics are ongoing.
Conclusions: BYL719 with L or E is an active combination. Skin toxicity warranted evaluation of alternate schedules. A 5d on, 2d off schedule of BYL719 + exemestane appears tolerable and may allow for higher doses than daily administration, with MTD determination pending. Further safety, efficacy, and correlative data will be presented.
Citation Format: Payal D. Shah, Mary E. Moynahan, Shanu Modi, Nicola Hamilton, Betty Ann Caravella, Stephen Zamora, Chau Dang, Theresa Gilewski, Tiffany Traina, Elizabeth Comen, Steven M. Sugarman, Gabriella D'Andrea, Diana Lake, Shari Goldfarb, Sujata Patil, Anne Covey, Michael Berger, Mario Lacouture, Larry Norton, Clifford A. Hudis, Jose Baselga, Sarat Chandarlapaty, Maura Dickler. Phase I study of PI3Kα inhibitor BYL719 + aromatase inhibitor (AI) in patients (pts) with hormone receptor-positive (HR+) metastatic breast cancer (MBC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT330. doi:10.1158/1538-7445.AM2015-CT330