Abstract P2-16-14: Preliminary safety, pharmacokinetics and anti-tumor activity of BYL719, an alpha-specific PI3K inhibitor in combination with fulvestrant: Results from a phase I study

Background: Phosphatidylinositol-3-kinase (PI3K) pathway activation has been associated with resistance to anti-estrogen receptor (ER) therapy and PIK3CA mutated ER+ breast cancer (BC) cells are sensitive to inhibition of PI3K under estrogen deprivation. In an in vitro study, the combination of BYL719 and fulvestrant was synergistic in PIK3CA mutated BC cell lines. In the BYL719 single agent part of this study out of 21 ER+ BC patients (pts), 3 partial responses were observed and 5 pts remained on the study with stable disease for over 26 weeks. Median PFS in pts with ER+ PIK3CA mutated BC was 5.5 months (Gonzalez-Angulo, 2013). Methods: This phase I study was amended to determine the Maximum Tolerated Dose (MTD) of BYL719 in combination with the ER antagonist fulvestrant in PIK3CA mutated ER+ breast cancer pts. Dose escalation of BYL719 in combination with fixed dose fulvestrant used an adaptive Bayesian logistic regression model with overdose control. The starting dose of BYL719 was 300 mg once daily, 25% below the MTD of single agent BYL719. All pts received the standard dose of 500 mg fulvestrant every 4 weeks. No dose escalation of fulvestrant was permitted. Following the MTD declaration, a dose expansion cohort will open. Results: At the data cut-off (27 March 2013), 4 pts were enrolled in the initial cohort of 300 mg/q.d. BYL719 plus 500 mg/qmonth (with an additional dose at week 2) fulvestrant, followed by 8 pts into the subsequent 400 mg/q.d. BYL719 plus fulvestrant dose combination. No pts experienced dose limiting toxicity (DLT) in the 300 mg cohort, and 1 pt experienced a DLT of CTCAE grade 3 diarrhea, vomiting, fatigue, anorexia and bloating in the 400 mg cohort. The MTD of BYL719 in combination with fulvestrant has been declared as 400 mg/q.d. The most frequent BYL719 related toxicities (>15% pts), regardless of grade and treatment group, are diarrhea (42%), hyperglycemia (33%), decreased appetite (25%), nausea (25%), and fatigue (17%). Systemic drug exposure of oral BYL719 when given in combination with fulvestrant was found to be similar to the single agent data. The patients were typically pre-treated with numerous chemotherapy, hormonal or targeted therapies. One pt in the 300 mg/q.d. cohort had a confirmed partial response, and 2 pts in the 400 mg/q.d. cohort had a partial response (one confirmed and one only occurring after the data cut-off). From the 12 breast cancer pts treated, 2 (17%) discontinued treatment due to progressive disease, and the median exposure of all pts at the time of data cut-off was 9 weeks. Conclusions: This combination displays a favorable safety and PK profile, both comparable to the single agent BYL719 experience. BYL719 in combination with fulvestrant shows encouraging preliminary anti-tumor activity, which supports further investigation of this combination. Recruitment within the dose expansion is continuing to obtain a sample size of 20 patients carrying the PIK3CA mutation. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-14.