Sibylle Loibl1, Lorena de la Pena2, Valentina Nekljudova3, Dimitrios Zardavas4, Stefan Michiels5, Carsten Denkert6, Mahdi Rezai7, Begoña Bermejo8, Michael Untch9, Soo Chin Lee10, Sabine Turri11, Patrick Urban12, Sherko Kümmel13, Guenther Steger14, Andrea Gombos15, Michael Lux16, Martine J Piccart17, Gunter Von Minckwitz3, José Baselga18, Sherene Loi19. 1. German Breast Group, Neu-Isenburg, Germany; Sana-Klinikum Offenbach, Germany. Electronic address: Sibylle.Loibl@gbg.de. 2. SOLTI Breast Cancer Research Group, Barcelona, Spain. 3. German Breast Group, Neu-Isenburg, Germany. 4. Breast International Group, Brussels, Belgium. 5. Gustave Roussy, Service de Biostatistique et d'Epidémiologie, Villejuif, France; CESP, Inserm U1018, Univ. Paris Sud, Univ. Paris-Saclay, Villejuif, France. 6. Institute of Pathology, Charité University Hospital, Berlin, Germany. 7. Luisenkrankenhaus Düsseldorf, Germany. 8. Hospital Clinico Universitario de Valencia, Spain. 9. Helios Klinikum Berlin-Buch, Department of Obstetrics and Gynaecology, Berlin, Germany. 10. Department of Haematology-Oncology, National University Cancer Institute, Singapore. 11. Novartis Pharma SAS, Rueil Malmaison, France. 12. Novartis Pharma AG, Basel, Switzerland. 13. Kliniken Essen-Mitte, Essen, Germany. 14. Department of Internal Medicine I, Division of Oncology, Medical University of Vienna, Austria; Comprehensive Cancer Center Vienna, Austria. 15. Université Libre de Bruxelles, Institut Jules Rue Héger-Bordet 1, Medical Oncology Clinic, Belgium. 16. University Breast Centre of Franconia, OBGYN Department, University Hospital Erlangen, CCC Erlangen-EMN, Germany. 17. Breast International Group, Brussels, Belgium; Université Libre de Bruxelles, Institut Jules Rue Héger-Bordet 1, Medical Oncology Clinic, Belgium. 18. SOLTI Breast Cancer Research Group, Barcelona, Spain; Memorial Sloan-Kettering Cancer Center, New York, USA. 19. Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Australian New Zealand Breast Cancer Trials Group (ANZBCTG), Newcastle, Australia. Electronic address: sherene.loi@petermac.org.
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 (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.
RCT Entities:
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.
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