Abstract CT232: SU2C Phase Ib study of the PI3K-alpha inhibitor BYL719 (alpelisib) with letrozole in ER+/HER2-metastatic breast cancer
Authors: Mayer Ingrid A. , Abramson Vandana , Balko Justin , Sanders Melinda , Juric Dejan , Solit David , Li Yisheng , Cantley Lewis , Winer Eric , Arteaga Carlos 
Published: August 2015

Abstract
Background: Mutations in PIK3CA, the gene encoding the p110α subunit of PI3K, have been associated with antiestrogen resistance in ER+ BC. In general, antiestrogen-resistant cancers retain ER and responsiveness to estradiol. This suggests that treatment of ER+ BC with PI3K inhibitors should also include antiestrogens.
Methods: We conducted a phase Ib 3+3 dose escalation trial of letrozole (2.5 mg/day) with the PI3Kα inhibitor BYL719 in post-menopausal patients (pts) with ER+/HER2- metastatic breast cancer (MBC) refractory to previous endocrine therapy. BYL719 doses ranged from 300-400 mg/daily. Treatment continued until unacceptable toxicity or disease progression. Disease was assessed every 2 months. PIK3CA mutation status was determined by SNaPshot or targeted next generation sequencing (NGS) in all patients’ tumors.
Results: Twenty-six pts were accrued; all patients were refractory to endocrine therapies in the metastatic setting, 18 had prior aromatase inhibitor (AI) therapy in their first or second-line MBC treatment. Median age was 53 years (31-72); 76% of pts had bone and 61% had visceral metastases; 50% of pts had a somatic PIK3CA hotspot mutation. Toxicities are summarized in Table 1. Rash was the dose limiting toxicity* at 350 mg/day. Of the 5 pts with a partial response, 3 (60%) had a PI3KCA mutation, 6/9 pts (67%) that were on treatment for ≥6 months; 3/6 pts (50%) that were on treatment for ≥12 months and 4/6 pts (67%) that are still on study (range 11 - 19 months) had a PI3KCA mutation.
Discussion: The combination of letrozole/ BYL719 is safe and tolerable in pts with AI-refractory ER+/HER2-negative MBC. The MTD and recommended dose for phase II trials of BYL719 in combination with letrozole was 300 mg/day. Rash and hyperglycemia were observed at this dose, suggesting drug-induced inhibition of PI3K. Pts with PIK3CA-mutant tumors appeared to derive better clinical benefit, although activity of the combination was also seen in patients with PIK3CA-wild type cancers. Additional NGS of &gt;300 cancer genes and their correlation with clinical response will be updated at the meeting. Clinical trial information: NCT01791478.
Adverse Events (% by Grade)Toxicity300 mg (N = 20)300 mg (N = 20)350 mg (N = 6)350 mg (N = 6)% by Grade% by Grade% Total% by Grade% by Grade% Total2323Hyperglycemia181256202070Diarrhea12128110050Fatigue2504330080Rash180431020*40Nausea0062101060Vomiting00250030Anorexia602510040Dysgeusia00180050
Citation Format: Ingrid A. Mayer, Vandana Abramson, Justin Balko, Melinda Sanders, Dejan Juric, David Solit, Yisheng Li, Lewis Cantley, Eric Winer, Carlos Arteaga. SU2C Phase Ib study of the PI3K-alpha inhibitor BYL719 (alpelisib) with letrozole in ER+/HER2-metastatic breast cancer. [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 CT232. doi:10.1158/1538-7445.AM2015-CT232