Abstract PD5-5: Phase I study of the PI3Kα inhibitor BYL719 plus fulvestrant in patients with PIK3CA-altered and wild type ER+/HER2- locally advanced or metastatic breast cancer

Background: BYL719 selectively inhibits the α-isoform of Class I PI3K. PI3Kα is encoded by PIK3CA, a frequently altered gene in human cancers. Preclinical data indicate BYL719 may be more effective in patients (pts) with PIK3CA-altered tumors; however there are data to suggest that PIK3CA-wild-type (wt) tumors may also be sensitive to BYL719. Here, we present updated data from the Phase I study of BYL719 + fulvestrant in pts with PIK3CA-altered or -wt ER+/HER2– locally advanced/metastatic breast cancer (BC) (NCT01219699). Methods: Adult women with PIK3CA-altered (mutation or amplification) ER+/HER2– BC received continuous oral BYL719 (300–400 mg/day; 28-day cycles) + fixed-dose fulvestrant (500 mg every 4 weeks, plus an additional dose 2 weeks after first dose) during dose escalation and expansion. Pts with PIK3CA-wt ER+/HER2– BC were enrolled into the dose expansion to receive BYL719 400 mg/day + fulvestrant. A Bayesian logistic regression model with overdose control guided dose escalation. Primary objective: to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of BYL719 in combination with fulvestrant, which was declared previously as 400 mg/day. An expansion cohort at the MTD assessed safety (CTCAE v4.0), tolerability, pharmacokinetics (PK), and preliminary efficacy (RECIST v1.0). Results: As of May 2, 2014, 64 pts (PIK3CA-altered n=41; PIK3CA-wt n=16; PIK3CA status unknown/pending n=7) received BYL719 300–400 mg/day + fulvestrant. Median number of prior antineoplastic therapies: 5 (range: 1–12) for pts with PIK3CA-altered tumors and 5 (range: 4–16) for pts with PIK3CA-wt tumors. Prior fulvestrant treatment: 19 (46%) and 7 (44%) pts with PIK3CA-altered and -wt tumors, respectively. Overall, the most common (≥25%) adverse events (AEs; all grades/all doses) suspected to be study drug-related were hyperglycemia (41%), diarrhea (34%), nausea (30%), and vomiting (25%). The most common (>10%) study drug-related Grade 3/4 AEs (all doses) were maculopapular rash (14%) and hyperglycemia (13%). Preliminary antitumor activity was observed in this trial. At data cut-off, partial responses (PRs) were observed in 2 patients with PIK3CA-altered tumors evaluable for response (2/33, 6%), but no PRs were observed in the 15 evaluable patients with PIK3CA-wt tumors. Duration of exposure was >16 weeks in 24 (59%) patients with PIK3CA-altered tumors and in 5 (31%) patients with PIK3CA-wt tumors. PK and exposure of BYL719 + fulvestrant was similar to that observed with single-agent BYL719 at the same dose levels. At data cut-off, treatment was ongoing in 20 (49%) and 2 (13%) pts with PIK3CA-altered and -wt tumors, respectively. Conclusions: BYL719 + fulvestrant demonstrated a favorable safety profile in pts with PIK3CA-altered and -wt ER+/HER2– BC, with mostly on-target effects (i.e. hyperglycemia, rash). Preliminary clinical activity was seen in pts with PIK3CA-altered and -wt tumors, but confirmed PRs were only observed in pts with PIK3CA-altered tumors. The low number of pts with PIK3CA-wt tumors limits further conclusion. Citation Format: Filip Janku, Dejan Juric, Javier Cortes, Hope Rugo, Howard A Burris, Martin Schuler, Barbara Deschler-Baier, Mark R Middleton, Marta Gil-Martin, Jordan Berlin, Eric Winer, Douglas Bootle, Lars Blumenstein, David Demanse, Christina Coughlin, Cornelia Quadt, José Baselga. Phase I study of the PI3Kα inhibitor BYL719 plus fulvestrant in patients with PIK3CA-altered and wild type ER+/HER2- locally advanced or metastatic breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PD5-5.