Alpelisib Monotherapy for PI3K-Altered Pretreated Advanced Breast Cancer A Phase II Study

There is limited knowledge on the benefi t of the alpha-subunit-specifi c PI3K inhibitor alpe-lisib in later lines of therapy for advanced estrogen receptor-positive (ER +) HER2- and triple-negative breast cancer (TNBC). We conducted a phase II multicohort study of alpelisib monotherapy in patients with advanced PI3K pathway mutant ER +HER2- and TNBC. In the intention-to-treat ER +cohort, the overall response rate was 30% and the clinical benefi t rate was 36%. A decline in PI3K pathway mutant circulating tumor DNA (ctDNA) levels from baseline to week 8 while on therapy was signifi cantly associated with a partial response, clinical benefi t, and improved progression-free-survival [HR 0.24; 95% confi dence interval (CI), 0.083-0.67, P= 0.0065]. Detection of ESR1 mutations at baseline in plasma was also associ-ated with clinical benefi t and improved progression-free survival (HR 0.22; 95% CI, 0.078-0.60, P= 0.003). SIGNIFICANCE: Alpelisib monotherapy displayed effi cacy in heavily pretreated ER + breast cancer with PIK3CA mutations. PIK3CA mutation dynamics in plasma during treatment and ESR1 mutations detected in plasma at baseline were candidate biomarkers predictive of benefi t from alpelisib, high-lighting the utility of ctDNA assays in this setting.