Abstract P5-21-06: Alpelisib plus letrozole in estrogen receptor-Positive (ER+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (aBC): Safety and preliminary efficacy analysis from a phase 1b trial
Authors: D Juric, A Gonçalves, E Hamilton, V Boni, IA Mayer, S Turri, Y Wang, FD Vogl, D Sellami, M Campone
Journal: Cancer Research (2018)

Abstract Background Endocrine therapy is the standard first-line treatment for postmenopausal patients (pts) with ER+, HER2– aBC. However, resistance eventually develops, often through dysregulation of PI3K/AKT/mTOR pathway, specifically mutations in PIK3CA, the gene encoding the p110α subunit of PI3K. The oral, selective PI3K inhibitor alpelisib and letrozole synergistically inhibits tumor growth in preclinical models of ER+ breast cancer. Alpelisib plus letrozole in pts with ER+ aBC is being investigated in arm 2 of a multi-arm, phase 1b study (NCT01872260). Methods Postmenopausal women with ER+, HER2− aBC received alpelisib (300 mg QD; continuous, 28 days cycle) plus letrozole (2.5 mg QD; continuous). Primary endpoints were to confirm MTD/RP2D of alpelisib plus letrozole in the escalation phase and to further characterize safety and tolerability in the expansion phase. Secondary and exploratory endpoints included efficacy, pharmacokinetics, and biomarkers. Results As of August 19, 2016, 56 pts had received alpelisib plus letrozole: 19 pts were enrolled in the escalation phase (designated here as previously treated group), of which, 95% of pts were previously treated for aBC and 37 pts were enrolled in the expansion phase (designated here as first-line group), of which, 81% of pts were treatment-naïve for aBC. 16 previously treated pts and 11 first-line pts (48% of all pts) have discontinued treatment. Most common reasons for treatment discontinuation in the full population were disease progression (23.2%) and adverse events (AEs) (8.9%). Median duration of exposure of combination (alpelisib plus letrozole) was 23 weeks and 12.7 weeks in previously treated and first-line groups, respectively. Most frequently reported any grade treatment-related AEs (≥20% incidence) in all pts were hyperglycemia (48.2%), diarrhea (48.2%), nausea (33.9%), and decreased appetite (28.6%). Most common, grade 3 or 4 AEs (≥3% incidence) suspected to be treatment-related in all pts included hyperglycemia (17.9%), rash (5.4%), and diarrhea (3.6%). Median progression-free survival was 5.7 months in the previously treated group and was not reached in the first-line group. A summary of best overall response, overall response rate and clinical benefit rate in evaluable pts is shown in the table. Alpelisib+Letrozole (Previously Treated group) [N=19]Alpelisib+Letrozole (First-line group) [N=27]All subjects (N=46)Best overall response, n (%)Confirmed CR000Confirmed PR04 (14.8)4 (8.7)NCRNPD6 (31.6)9 (33.3)15 (32.6)SD8 (42.1)9 (33.3)17 (37.0)PD2 (10.5)1 (3.7)3 (6.5)Unknown3 (15.8)3 (11.1)6 (13.0)ORR (CR+PR), % (95% CI)0 (0.0-17.6)14.8 (4.2-33.7)8.7 (2.4-20.8)CBR [CR+PR+(SD/NCRNPD)], % (95% CI)36.8 (16.3-61.6)70.8 (48.9-87.4)55.8 (39.90-70.9)CBR; clinical benefit rate; CI, confidence interval; CR, complete response; NCRNPD; Non-CR/Non-PD; ORR; overall response rate; PD; progressive disease; SD, stable disease. Conclusions Based on these preliminary data, the combination of alpelisib plus letrozole had manageable safety profile in pts with ER+, HER2– aBC and demonstrated encouraging clinical activity, particularly in the first-line patient population. Citation Format: Juric D, Gonçalves A, Hamilton E, Boni V, Mayer IA, Turri S, Wang Y, Vogl FD, Sellami D, Campone M. Alpelisib plus letrozole in estrogen receptor-Positive (ER+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (aBC): Safety and preliminary efficacy analysis from a phase 1b trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-06.