Juric D, et al. - In patients with ER+ advanced breast cancer (ABC), researchers evaluated the maximum tolerated dose (MTD), safety, and activity of alpelisib, an oral, PI3Kα-specific inhibitor, plus fulvestrant. A manageable safety profile of alpelisib plus fulvestrant is seen in patients with ER+ ABC, and findings suggested the probability of this combination with to have greater clinical activity in PIK3CA-altered vs wild-type tumors.

• Authors conducted an open-label, single-arm, phase 1b study of alpelisib plus fulvestrant at 10 centers in 5 countries.
• The participants included in this trial were 87 postmenopausal women with PIK3CA-altered or PIK3CA-wild-type ER+ ABC, whose cancer progressed during or after antiestrogen therapy.
• They started enrolling patients October 5, 2010, and the data cutoff was March 22, 2017.
• They administered escalating doses of alpelisib once daily, starting at 300 mg, plus fixed-dose fulvestrant, 500 mg, in the dose-escalation phase; alpelisib at the recommended phase 2 dose plus fulvestrant in the dose-expansion phase.
• Determination of the MTD of once-daily alpelisib plus fulvestrant was the primary end point.
• Safety and preliminary activity were included in secondary end points.

• Findings suggested that, 87 women (median age: 58 years [range, 37-79 years]; median of 5 prior lines of antineoplastic therapy) received escalating once-daily doses of alpelisib (300 mg, n = 9; 350 mg, n = 8; 400 mg, n = 70) plus fixed-dose fulvestrant (500 mg) from October 5, 2010, to March 22, 2017.
• During dose escalation, they reported dose-limiting toxic effects in 1 patient (alpelisib, 400 mg): diarrhea (grade 2), vomiting, fatigue, and decreased appetite (all grade 3).
• When combined with fulvestrant, the MTD of alpelisib was 400 mg once daily, and the recommended phase 2 dose was 300 mg once daily.
• Results demonstrated that overall, the most frequent grade 3/4 adverse events with alpelisib, 400 mg, once daily (≥10% of patients), regardless of causality, were hyperglycemia (19 [22%]) and maculopapular rash (11 [13%]); 9 patients permanently discontinued therapy owing to adverse events.
• They noted 5.4 months (95% CI, 4.6-9.0 months) to be median progression-free survival at the MTD.
• As per data, median progression-free survival with alpelisib, 300 to 400 mg, once daily plus fulvestrant was longer in patients with PIK3CA-altered tumors (9.1 months; 95% CI, 6.6-14.6 months) vs wild-type tumors (4.7 months; 95% CI, 1.9-5.6 months).
• Overall response rate in the PIK3CA-altered group was 29% (95% CI, 17%-43%), with no objective tumor responses in the wild-type group.