Abstract P1-14-01: Phase II, randomized, parallel-cohort study of neoadjuvant buparlisib (BKM120) in combination with trastuzumab and paclitaxel in women with HER2-positive, PIK3CA mutant and PIK3CA wild-type primary breast cancer – NeoPHOEBE
Authors: Loibl S , de la Pena L , Nekljudova V , Zardavas D , Michiels S , Denkert C , Rezai M , Bermejo B , Lee S-C , Turri S , Urban P , Kümmel S , Lux M , Piccart M , von Minckwitz G , Baselga J , Loi S 
Published: May 2016

Abstract
Background: The PI3K/Akt/mTOR pathway is frequently activated in breast cancer (BC) and is important for the oncogenic function of HER2. Buparlisib is an oral pan-PI3K inhibitor that targets all 4 isoforms of class I PI3K (a, b, g, d). Clinical activity was observed with buparlisib in patients (pts) with advanced BC as a single agent, and in combination with endocrine and anti-HER2 treatment.
Methods: NeoPHOEBE (NCT01816594) is a phase II, randomized, double-blind, parallel-cohort study of neoadjuvant buparlisib/placebo plus trastuzumab and weekly paclitaxel in women with, untreated primary HER2-positive BC. Pts were stratified upfront into 2 independent cohorts according to PIK3CA mutation status. Other eligibility criteria: tumor size &gt;2 cm; unilateral disease; available tumor tissue for central review of estrogen receptor (ER), HER2 status, and PIK3CA genotype; known PIK3CA mutation status; and ECOG PS ≤1. Pts in each cohort (PIK3CA mutant or wild-type [wt]) were randomized (1:1) to receive continuous daily buparlisib (100 mg) or placebo and weekly trastuzumab (4 mg/kg loading dose then 2 mg/kg) for 6 weeks, followed by continuous daily buparlisib (80 mg) or placebo with weekly trastuzumab (2 mg/kg) and weekly paclitaxel (80 mg/m2) for 12 weeks. Study treatment was followed by surgery. Stratification at randomization was based on PIK3CA (mutant vs wt) and ER (positive vs negative) status. The primary endpoint was pathologic complete response (pCR; ypT0) rate at time of surgery. The key secondary endpoint was objective response rate (ORR) at the end of week 6. Other secondary endpoints included pCR by other definitions, ORR prior to surgery, pCR and objective response by ER status, percent of pts with node-negative disease at surgery, rate of breast conserving surgery, and safety, as well as pCR by PTEN expression, Ki67 level, apoptosis rates, percentage of tumor infiltrating lymphocytes (TIL), and by phenotype of 50% TIL at baseline. The sample size is based on a minimax 2-stage randomized phase II design with a prospective control. This design allowed for early stopping if the desired efficacy was not observed after stage 1. Both cohorts were powered (80%) to detect a clinically meaningful increase in pCR of 18% at a one-sided significance level (α=0.15).
Results: Between 9/2013 and 10/2014 50 pts were randomized in 38 sites in 4 countries. Recruitment was suspended due to toxicity in 10/2014. Median age was 50 years, 42 pts had a PIK3CA wt and 8 a PIK3CA mutant tumor, 62% of pts presented with HER2+/ER+, 90% with ductal or ductal-lobular invasive, and 62% with G3 tumors; 86% had Ki67 &gt;20%; 9 pts reported a serious adverse event including 3 pts with hepatotoxicity. Overall 14/50 (28 %) pts developed grade 3-4 liver enzyme elevation, of whom 9 (64%) recovered to at least grade1. Final safety and efficacy data on the primary endpoint (pCR) and biomarker data will be presented at the meeting.
Conclusions: The NeoPHOEBE study investigates for the first time the efficacy of adding a pan-PIK3 inhibitor to a taxane/trastuzumab-based neoadjuvant therapy in pts with primary HER2-positive BC with or without a PIK3CA mutation.
Citation Format: Loibl S, de la Pena L, Nekljudova V, Zardavas D, Michiels S, Denkert C, Rezai M, Bermejo B, Lee S-C, Turri S, Urban P, Kümmel S, Lux M, Piccart M, von Minckwitz G, Baselga J, Loi S. Phase II, randomized, parallel-cohort study of neoadjuvant buparlisib (BKM120) in combination with trastuzumab and paclitaxel in women with HER2-positive, PIK3CA mutant and PIK3CA wild-type primary breast cancer – NeoPHOEBE. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-14-01.