新辅助性布帕利西布联合曲妥珠单抗和紫杉醇治疗HER2阳性原发性乳腺癌女性：一项随机、双盲、安慰剂对照的II期试验（NeoPHOEBE）。

Neoadjuvant buparlisib plus trastuzumab and paclitaxel for women with HER2+ primary breast cancer: A randomised, double-blind, placebo-controlled phase II trial (NeoPHOEBE).

作者信息

Loibl Sibylle, de la Pena Lorena, Nekljudova Valentina, Zardavas Dimitrios, Michiels Stefan, Denkert Carsten, Rezai Mahdi, Bermejo Begoña, Untch Michael, Lee Soo Chin, Turri Sabine, Urban Patrick, Kümmel Sherko, Steger Guenther, Gombos Andrea, Lux Michael, Piccart Martine J, Von Minckwitz Gunter, Baselga José, Loi Sherene

机构信息

German Breast Group, Neu-Isenburg, Germany; Sana-Klinikum Offenbach, Germany.

SOLTI Breast Cancer Research Group, Barcelona, Spain.

出版信息

Eur J Cancer. 2017 Nov;85:133-145. doi: 10.1016/j.ejca.2017.08.020. Epub 2017 Sep 17.

DOI:10.1016/j.ejca.2017.08.020

PMID:28923573

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5640494/

Abstract

AIM

The Neoadjuvant PI3K inhibition in HER2 OverExpressing Breast cancEr (NeoPHOEBE) trial evaluated the efficacy and safety of buparlisib, a pan-phosphatidylinositol 3-kinase (PI3K) inhibitor, plus trastuzumab and paclitaxel as neoadjuvant treatment for human epidermal growth factor receptor-2 positive (HER2+) breast cancer.

METHODS

NeoPHOEBE was a neoadjuvant, phase II, randomised, double-blind study. Women with HER2+ breast cancer were randomised within two independent cohorts by PIK3CA mutation status and, in each cohort stratified by oestrogen receptor (ER) status to receive buparlisib or placebo plus trastuzumab (first 6 weeks) followed by buparlisib or placebo with trastuzumab and paclitaxel. Primary end-point was pathological complete response (pCR) rate; key secondary end-point was objective response rate (ORR) at 6 weeks. Exploratory end-points were evaluation of Ki67 levels and change in tumour infiltrating lymphocytes (TILs) in intermediate biopsies at day 15.

RESULTS

Recruitment was suspended mainly due to liver toxicity after enrolment of 50 of the planned 256 patients. In each arm (buparlisib n = 25; placebo n = 25) 21 patients (84%) had wild type PIK3CA and 4 patients (16%) had mutant PIK3CA. Overall, pCR rate was similar between buparlisib and placebo arms (32.0% versus 40%; one-sided P = 0.811). A trend towards higher ORR (68.8% versus 33.3%; P = 0.053) and a significant decrease in Ki67 (75% versus 26.7%; P = 0.021) was observed in buparlisib versus placebo arm in the ER+ subgroup (P = 0.03).

CONCLUSIONS

Addition of the pan-PI3K inhibitor buparlisib to taxane-trastuzumab-based therapy in HER2+ early breast cancer was not feasible. However, the higher ORR and Ki67 reduction in the ER+, HER2+ subgroup indicates a potential role for PI3K-targeted therapy in this setting and may warrant further investigation with better-tolerated second-generation PI3K inhibitors.

TRIAL REGISTRATION IDENTIFIER

NCT01816594.

摘要

目的

HER2过表达乳腺癌新辅助PI3K抑制（NeoPHOEBE）试验评估了泛磷脂酰肌醇3激酶（PI3K）抑制剂布帕利西布联合曲妥珠单抗和紫杉醇作为人表皮生长因子受体2阳性（HER2+）乳腺癌新辅助治疗的疗效和安全性。

方法

NeoPHOEBE是一项新辅助、II期、随机、双盲研究。HER2+乳腺癌女性患者按PIK3CA突变状态在两个独立队列中随机分组，并在每个队列中按雌激素受体（ER）状态分层，接受布帕利西布或安慰剂联合曲妥珠单抗（前6周），随后接受布帕利西布或安慰剂联合曲妥珠单抗和紫杉醇。主要终点是病理完全缓解（pCR）率；关键次要终点是6周时的客观缓解率（ORR）。探索性终点是评估第15天中间活检时的Ki67水平和肿瘤浸润淋巴细胞（TILs）的变化。

结果

在计划入组的256例患者中入组50例后，主要因肝毒性而暂停招募。在每个治疗组（布帕利西布组n = 25；安慰剂组n = 25）中，21例患者（84%）为PIK3CA野生型，4例患者（16%）为PIK3CA突变型。总体而言，布帕利西布组和安慰剂组的pCR率相似（32.0%对40%；单侧P = 0.811）。在ER+亚组中，布帕利西布组与安慰剂组相比，观察到ORR有升高趋势（68.8%对33.3%；P = 0.053），且Ki67显著降低（75%对26.7%；P = 0.021）（P = 0.03）。