Pipa: A Phase Ib Study Of Beta-Isoform Sparing Phosphatidylinositol 3-Kinase (Pi3k) Inhibitor Taselisib (T) Plus Palbociclib (P) And Fulvestrant (Ful) In Pik3ca-Mutant (Mt) Er-Positive And Taselisib (T) Plus Palbociclib (P) In Pik3ca-Mutant (Mt) Er-Negative Advanced Breast Cancer.

1051 Background: PI3K and CDK4/6 inhibitors synergise in ER+ve and –ve PIK3CA-mt breast cancer (BC) models. Escalation phase of this study set recommended phase 2 dose (RP2D) at P 125mg on a 3/1 scheme plus T 2mg daily ( Lim, ASCO 2017). Here we present the results of expansion cohorts for PIK3CA-mt BC patients (pts). Methods: The primary objective was to assess the confirmed objective response rate (ORR) of the P + T + FUL triplet in pts with measurable PIK3CA-mt ER+ve HER2-ve advanced BC, with up to two prior lines of chemotherapy for advanced disease. PIK3CA mutation was assessed in tissue or plasma DNA analysis. Exploratory objectives included assessment of efficacy of P + T in a cohort of pts with PIK3CA-mt advanced ER-ve BC. Safety is reported overall for 44 patients including an additional cohort of 7 PIK3CA-unknown ER+ve BC pts treated with P + T + letrozole (LET). For the P + T + FUL triplet a Simon minmax design was used, with 6 responses in 25 patients required to declare efficacy. Results: We recruited 24 assessable patients with PIK3CA-mt ER+ve HER2-ve advanced BC, median age 57 (42-74), median 3 (1-9) prior therapy lines for advance disease, with 24 (100%) receiving prior endocrine therapy and 23 (96%) prior aromatase inhibitor. ORR was 33% (8/24, 95% CI 16-55%), with median progression free survival (PFS) 7.9m (95% CI 5.6-11.8). For the 11 assessable PIK3CA-mt ER-ve pts (8 HER2-ve, 3 HER2+ve) receiving P + T, ORR was 0% (0/11), clinical benefit rate (CBR) 27% (3/11) and median PFS 4.3m (95% CI 1.8-6.1). Most common AEs across all cohorts were neutropenia (80%), fatigue (50%), mucositis (50%) and thrombocytopenia (30%). Most common grade 3/4 AEs were neutropenia (57%) and rash (11%). Translational research is ongoing. Conclusions: The triplet of P + T + FUL has promising efficacy in pre-treated PIK3CA-mt ER+ve advanced BC. A subset of patients with PIK3CA-mt ER-ve advanced BC had clinical benefit from P + T. The combination of P + T +/- FUL/LET was well tolerated with anticipated AEs. Clinical trial information: NCT02389842.