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

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 (Pinteraction = 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.

[1]  E. Perez,et al.  Improved Survival of HER2+ Breast Cancer Patients Treated with Trastuzumab and Chemotherapy Is Associated with Host Antibody Immunity against the HER2 Intracellular Domain. , 2016, Cancer research.

[2]  D. Wickerham,et al.  Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  J. Baselga,et al.  Trastuzumab emtansine for HER2-positive advanced breast cancer. , 2012, The New England journal of medicine.

[4]  W. Sellers,et al.  Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor , 2011, Molecular Cancer Therapeutics.

[5]  A. Rademaker,et al.  Phase I study of alpelisib (BYL-719) and T-DM1 in HER2-positive metastatic breast cancer after trastuzumab and taxane therapy. , 2017 .

[6]  P. Fasching,et al.  Pathologic complete response after neoadjuvant chemotherapy plus trastuzumab predicts favorable survival in human epidermal growth factor receptor 2-overexpressing breast cancer: results from the TECHNO trial of the AGO and GBG study groups. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  J. Baselga,et al.  Biomarker analyses in CLEOPATRA: a phase III, placebo-controlled study of pertuzumab in human epidermal growth factor receptor 2-positive, first-line metastatic breast cancer. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  J. R. Reeves,et al.  Expression of the HER1–4 family of receptor tyrosine kinases in breast cancer , 2003, The Journal of pathology.

[9]  C. Isaacs,et al.  Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial. , 2014, The Lancet. Oncology.

[10]  Guy Jerusalem,et al.  Phase Ib Study of Buparlisib plus Trastuzumab in Patients with HER2-Positive Advanced or Metastatic Breast Cancer That Has Progressed on Trastuzumab-Based Therapy , 2014, Clinical Cancer Research.

[11]  Carsten Denkert,et al.  Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  A. Musolino,et al.  Preoperative chemotherapy plus trastuzumab, lapatinib, or both in human epidermal growth factor receptor 2-positive operable breast cancer: results of the randomized phase II CHER-LOB study. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  M. Kaufmann,et al.  Histologische Regression des Mammakarzinoms nach primärer (neoadjuvanter) Chemotherapie , 1994 .

[14]  P. Fasching,et al.  Integrated Analysis of PTEN and p4EBP1 Protein Expression as Predictors for pCR in HER2-Positive Breast Cancer , 2016, Clinical Cancer Research.

[15]  T. Nielsen,et al.  The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. , 2015, Annals of oncology : official journal of the European Society for Medical Oncology.

[16]  Sung-Bae Kim,et al.  Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. , 2014, The Lancet. Oncology.

[17]  Carsten Denkert,et al.  Standardized Ki67 Diagnostics Using Automated Scoring—Clinical Validation in the GeparTrio Breast Cancer Study , 2014, Clinical Cancer Research.

[18]  C. Arteaga,et al.  Direct inhibition of PI3K in combination with dual HER2 inhibitors is required for optimal antitumor activity in HER2+ breast cancer cells , 2014, Breast Cancer Research.

[19]  R. Gelber,et al.  Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial , 2012, The Lancet.

[20]  M. Robson,et al.  Phase I dose-escalation study of buparlisib (BKM120), an oral pan-class I PI3K inhibitor, in Japanese patients with advanced solid tumors , 2014, Cancer science.

[21]  T. Mukohara,et al.  PI3K mutations in breast cancer: prognostic and therapeutic implications , 2015, Breast cancer.

[22]  M. Duffy,et al.  Activated Phosphoinositide 3-Kinase/AKT Signaling Confers Resistance to Trastuzumab but not Lapatinib , 2010, Molecular Cancer Therapeutics.

[23]  S. Paik,et al.  Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial. , 2013, The Lancet. Oncology.

[24]  Carsten Denkert,et al.  PIK3CA mutations are associated with lower rates of pathologic complete response to anti-human epidermal growth factor receptor 2 (her2) therapy in primary HER2-overexpressing breast cancer. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[25]  Marc Buyse,et al.  Adjuvant trastuzumab in HER2-positive breast cancer. , 2011, The New England journal of medicine.

[26]  D. Berry,et al.  Molecular Heterogeneity and Response to Neoadjuvant Human Epidermal Growth Factor Receptor 2 Targeting in CALGB 40601, a Randomized Phase III Trial of Paclitaxel Plus Trastuzumab With or Without Lapatinib. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  Giulia Bianchi,et al.  Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. , 2012, The Lancet. Oncology.

[28]  M. Rezai,et al.  Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. , 2012, The Lancet. Oncology.

[29]  S. Bicciato,et al.  Prospective Biomarker Analysis of the Randomized CHER-LOB Study Evaluating the Dual Anti-HER2 Treatment With Trastuzumab and Lapatinib Plus Chemotherapy as Neoadjuvant Therapy for HER2-Positive Breast Cancer. , 2015, The oncologist.

[30]  J. Bryant,et al.  Pathobiology of preoperative chemotherapy , 2002 .

[31]  R. Bernards,et al.  PIK3CA mutations are associated with decreased benefit to neoadjuvant human epidermal growth factor receptor 2-targeted therapies in breast cancer. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[32]  Terry L. Smith,et al.  Weekly paclitaxel improves pathologic complete remission in operable breast cancer when compared with paclitaxel once every 3 weeks. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[33]  T. Mukohara,et al.  Association between gain-of-function mutations in PIK3CA and resistance to HER2-targeted agents in HER2-amplified breast cancer cell lines. , 2010, Annals of oncology : official journal of the European Society for Medical Oncology.

[34]  A. D. Van den Abbeele,et al.  Stand up to cancer phase Ib study of pan-phosphoinositide-3-kinase inhibitor buparlisib with letrozole in estrogen receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  Obi L. Griffith,et al.  A Phase I Trial of BKM120 (Buparlisib) in Combination with Fulvestrant in Postmenopausal Women with Estrogen Receptor–Positive Metastatic Breast Cancer , 2015, Clinical Cancer Research.

[36]  A. Schneeweiss,et al.  Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). , 2013, Annals of oncology : official journal of the European Society for Medical Oncology.

[37]  E. Winer,et al.  Abstract PD5-2: Ph1b study of the PI3K inhibitor taselisib (GDC-0032) in combination with letrozole in patients with hormone receptor-positive advanced breast cancer , 2015 .

[38]  M. Campone,et al.  A randomized adaptive phase II/III study of buparlisib, a pan-class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2– advanced breast cancer (BELLE-4) , 2016, Annals of oncology : official journal of the European Society for Medical Oncology.

[39]  Qingyuan Zhang,et al.  Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): a phase 3, randomised, double-blind, multicentre trial. , 2015, The Lancet. Oncology.

[40]  A. Reuben.  Hy's law , 2004, Hepatology.

[41]  Violeta Serra,et al.  Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. , 2008, Cancer research.