buparlisib and Chemical-and-Drug-Induced-Liver-Injury

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.. 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.. 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.. NCT01816594.

Topics: Adult; Aged; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Australia; Biomarkers, Tumor; Biopsy; Breast Neoplasms; Chemical and Drug Induced Liver Injury; Chemotherapy, Adjuvant; Class I Phosphatidylinositol 3-Kinases; Double-Blind Method; Early Termination of Clinical Trials; Europe; Female; Humans; Ki-67 Antigen; Lymphocytes, Tumor-Infiltrating; Middle Aged; Morpholines; Mutation; Neoadjuvant Therapy; Paclitaxel; Protein Kinase Inhibitors; Receptor, ErbB-2; Time Factors; Trastuzumab; Treatment Outcome