Abstract CT061: A phase Ib study of alpelisib (BYL719) + everolimus ± exemestane in patients with advanced solid tumors or HR+/HER2-breast cancer
Authors: Baselga Jose , Curigliano Giuseppe , Martín Miguel , André Fabrice , Beck J. Thaddeus , Tortora Giampaolo , Wilke Celine , Charbonnier Laure , Blumenstein Lars , Donnet Valerie , Fazio Nicola 
Published: July 2016

Abstract
Background: PIK3CA (encoding phosphatidylinositol 3-kinase [PI3K] p110α) is frequently altered in cancer, resulting in PI3K/mammalian target of rapamycin (mTOR) pathway activation, and contributing to targeted therapy resistance and disease progression. Here, we report results from the dose-escalation phase of an ongoing Phase Ib study (NCT02077933) of the p110α-selective inhibitor alpelisib combined with the mTOR inhibitor (mTORi) everolimus (EVE) ± the aromatase inhibitor exemestane (EXE).
Methods: Adult patients (pts) with advanced solid tumors (doublet arm: alpelisib + EVE) and postmenopausal women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2—) advanced breast cancer (ABC; triplet arm: alpelisib + EVE + EXE) were enrolled. The primary objective was to determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE) of the doublet and triplet regimens, based on dose-limiting toxicities (DLTs) reported during the first 35 days of treatment. Starting doses were alpelisib 300 mg once daily (QD) and EVE 2.5 mg QD. Dose de-escalation was guided by a Bayesian logistic regression model with overdose control. In the triplet arm, EXE was fixed at 25 mg QD. Safety (adverse events [AEs] per CTCAE v4.03) and pharmacokinetics (PK) were secondary endpoints. Efficacy (per RECIST v1.1) was an exploratory endpoint.
Results: In the doublet arm (as of Feb 5, 2015), 13 pts received alpelisib 300 mg (n = 6), 250 mg (n = 6), or 200 mg (n = 1; dose error) with EVE 2.5 mg. In the alpelisib 300 mg group, 2/3 evaluable pts had DLTs of Grade (Gr) 3 diarrhea or Gr2 hyperglycemia lasting &gt; 14 days (n = 1 each); 2/6 pts at 250 mg had DLTs of Gr2 hyperglycemia or Gr4 hypocalcemia (n = 1 each); and 1/1 pt at 200 mg had DLTs of Gr3 diarrhea and Gr3 stomatitis. The doublet MTD/RDE was declared as alpelisib 250 mg + EVE 2.5 mg. The most common (? 10% of pts) Gr3/4 AEs were hyperglycemia (6 [46%] pts: 3 at 300 mg, 3 at 250 mg), diarrhea (4 [31%] pts: 3 at 300 mg, 1 at 200 mg), and lipase elevation (2 [15%] pts: 1 at 300 mg, 1 at 250 mg). Four pts at the MTD/RDE had stable disease as best overall response. PK parameters for alpelisib and EVE were not significantly altered by co-administration. In the triplet arm (as of Nov 24, 2015), 7 pts received alpelisib 200 mg with EVE 2.5 mg and EXE 25 mg. Of 7 evaluable pts, 1 had a DLT of Gr3 acute kidney injury. The triplet MTD/RDE was declared as alpelisib 200 mg + EVE 2.5 mg + EXE 25 mg. The most frequent (? 10% of pts) Gr3/4 AEs were fatigue (2 [29%] pts) and elevated γ­-glutamyltransferase (1 [14%] pt).
Conclusions: Alpelisib demonstrated a manageable safety profile in combination with EVE ± EXE. A dose-expansion phase is ongoing in pts with mTORi-naïve renal cell carcinoma and pancreatic neuroendocrine tumors, and mTORi-pretreated solid tumors (doublet regimen), and in postmenopausal women with PIK3CA mutant and non-mutant HR+/HER2— ABC (triplet regimen).
Citation Format: Jose Baselga, Giuseppe Curigliano, Miguel Martín, Fabrice André, J. Thaddeus Beck, Giampaolo Tortora, Celine Wilke, Laure Charbonnier, Lars Blumenstein, Valerie Donnet, Nicola Fazio. A phase Ib study of alpelisib (BYL719) + everolimus ± exemestane in patients with advanced solid tumors or HR+/HER2-breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT061.