Abstract P6-10-07: Phase I study of BYL719, an alpha-specific PI3K inhibitor, in patients with <i>PIK3CA</i> mutant advanced solid tumors: preliminary efficacy and safety in patients with <i>PIK3CA</i> mutant ER-positive (ER+) metastatic breast cancer (MBC) (2012)

Abstract Background: Deregulation of the PI3K pathway occurs in &gt;50% of breast cancers. Mutations in PIK3CA, the gene encoding the p110alpha subunit of PI3K contributes to resistance to endocrine and anti-HER2 therapies. BYL719 is a potent, specific oral inhibitor of the alpha subunit of PI3K, which inhibits wild-type p110alpha and its most common somatic mutations (IC50=5 nM) much more potently than other PI3K isoforms. Methodology: BYL719 has been investigated in a phase I study in patients with PIK3CA mutant advanced solid tumors. BYL719 has a favorable safety and PK profile; the MTD was established at 400 mg once daily (Juric et al., AACR 2012). As of 5 September 2012, 79 patients have been enrolled in this phase I study, among them 20 patients with PIK3CA mutant ER+ MBC. 5 of these patients had ER+/HER2 positive (HER2+) MBC. Presence of PIK3CA mutations was determined by either local or central assessment. Results: 20 patients with ER+ PIK3CA mutant MBC were treated once daily with BYL719 at doses of 30 mg (n = 1), 180 mg (n = 1), 270 mg (n = 1), 400 mg (n = 14) and 450 mg (n = 3). Median age was 55 years (range 40–78). 15/20 patients with ER+ PIK3CA mutant MBC had HER2 negative and 5/20 had HER2+ MBC. Patients had received a median of 5 previous treatment regimens (range 1–11). Most patients had received multiple prior lines of endocrine therapy including tamoxifen and aromatase inhibitors; 9 patients also received fulvestrant and 16 patients received prior chemotherapy. HER2+ patients have been previously treated with trastuzumab and/or lapatinib. Based on a recent analysis of 19 patients (data cut-off 5 July 2012), the safety of BYL719 in patients with ER+ MBC was comparable to the overall study population. Most frequent adverse events (AEs; ≥10%) suspected to be related to BYL719 were hyperglycemia, diarrhea, nausea, fatigue, decreased appetite, vomiting, rash and erythematous rash, dysgeusia, dry mouth, and stomatitis. The majority of AEs were CTCAE grade 1/2 and were clinically well manageable. Most frequent CTCAE grade 3/4 events were hyperglycemia and erythematous rash. 18/20 PIK3CA mutant ER+ MBC patients were treated at potentially effective doses of ≥270 mg/day. 6/18 patients (33%) achieved tumor shrinkage &gt; 20%, among them 2 patients achieved partial responses (PR) by RECIST. Median progression free survival (PFS) analyzed in 17 patients treated at ≥270 mg/day in the ER+ BC patients was 7.3 months (CI [4.6,9.5]), compared to 3.7 months (CI [1.8,5.5]) in 38 patients with other PIK3CA mutant solid tumors (data cut-off 5 July 2012) Conclusion: BYL719 has a favorable safety profile with manageable side effects, which were mainly related to its mechanism of action. BYL719 shows promising preliminary clinical activity as single agent in patients with PIK3CA mutant ER+ MBC, warranting further clinical development. The investigation of BYL719 continues in patients with ER+ MBC as single agent, and in combination with endocrine therapy. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-10-07.