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

被引：88

作者：

Loibl, Sibylle ^{[1
,2
]}

de la Pena, Lorena ^{[3
]}

Nekljudova, Valentina ^{[1
]}

Zardavas, Dimitrios ^{[4
]}

Michiels, Stefan ^{[5
,6
]}

Denkert, Carsten ^{[7
]}

Rezai, Mahdi ^{[8
]}

Bermejo, Begona ^{[9
]}

Untch, Michael ^{[10
]}

Lee, Soo Chin ^{[11
]}

Turri, Sabine ^{[12
]}

Urban, Patrick ^{[13
]}

Kuemmel, Sherko ^{[14
]}

Steger, Guenther ^{[15
,16
]}

Gombos, Andrea ^{[17
]}

Lux, Michael ^{[18
]}

Piccart, Martine J. ^{[4
,17
]}

Von Minckwitz, Gunter ^{[1
]}

Baselga, Jose ^{[3
,19
]}

Loi, Sherene ^{[20
,21
]}

机构：

[1] German Breast Grp, Neu Isenburg, Germany

[2] Sana Klinikum Offenbach, Offenbach, Germany

[3] SOLTI Breast Canc Res Grp, Barcelona, Spain

[4] Breast Int Grp, Brussels, Belgium

[5] Gustave Roussy, Serv Biostat & Epidemiol, Villejuif, France

[6] Univ Paris Saclay, Univ Paris Sud, Inserm U1018, CESP, Villejuif, France

[7] Charite, Inst Pathol, Berlin, Germany

[8] Luisenkrankenhaus Dusseldorf, Dusseldorf, Germany

[9] Hosp Clin Univ Valencia, Valencia, Spain

[10] Helios Klinikum Berlin Buch, Dept Obstet & Gynaecol, Berlin, Germany

[11] Natl Univ Canc Inst, Dept Haematol Oncol, Singapore, Singapore

[12] Novartis Pharma SAS, Rueil Malmaison, France

[13] Novartis Pharma AG, Basel, Switzerland

[14] Kliniken Essen Mitte, Essen, Germany

[15] Med Univ Vienna, Div Oncol, Dept Internal Med 1, Vienna, Austria

[16] Comprehens Canc Ctr Vienna, Vienna, Austria

[17] Univ Libre Bruxelles, Inst Jules Rue Heger Bordet 1, Med Oncol Clin, Brussels, Belgium

[18] Univ Hosp Erlangen, CCC Erlangen EMN, OBGYN Dept, Univ Breast Ctr Franconia, Erlangen, Germany

[19] Mem Sloan Kettering Canc Ctr, New York, NY USA

[20] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia

[21] ANZBCTG, Newcastle, NSW, Australia

来源：

EUROPEAN JOURNAL OF CANCER | 2017年 / 85卷

关键词：

NeoPHOEBE; Buparlisib; pCR; HER2; Primary breast cancer; Neoadjuvant; PATHOLOGICAL COMPLETE RESPONSE; SURGICAL ADJUVANT BREAST; OPEN-LABEL; PREOPERATIVE CHEMOTHERAPY; PIK3CA MUTATIONS; LAPATINIB; COMBINATION; MULTICENTER; RESISTANCE; PERTUZUMAB;

D O I：

10.1016/j.ejca.2017.08.020

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 Z 25; placebo n Z 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 Z 0.811). A trend towards higher ORR (68.8% versus 33.3%; P Z 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-interaction = 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. (C) 2017 Elsevier Ltd. All rights reserved.

引用

页码：133 / 145

页数：13

共 45 条

[1] Phase I dose- escalation study of buparlisib ( BKM120), an oral pan- class I PI3K inhibitor, in Japanese patients with advanced solid tumors [J].

Ando, Yuichi ;

Inada-Inoue, Megumi ;

Mitsuma, Ayako ;

Yoshino, Takayuki ;

Ohtsu, Atsushi ;

Suenaga, Naoko ;

Sato, Masahiko ;

Kakizume, Tomoyuki ;

Robson, Matthew ;

Quadt, Cornelia ;

Doi, Toshihiko .

CANCER SCIENCE, 2014, 105 (03) :347-353

[2] Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial [J].

Andre, Fabrice ;

O'Regan, Ruth ;

Ozguroglu, Mustafa ;

Toi, Masakazu ;

Xu, Binghe ;

Jerusalem, Guy ;

Masuda, Norikazu ;

Wilks, Sharon ;

Arena, Francis ;

Isaacs, Claudine ;

Yap, Yoon-Sim ;

Papai, Zsuzsanna ;

Lang, Istvan ;

Armstrong, Anne ;

Lerzo, Guillermo ;

White, Michelle ;

Shen, Kunwei ;

Litton, Jennifer ;

Chen, David ;

Zhang, Yufen ;

Ali, Shyanne ;

Taran, Tetiana ;

Gianni, Luca .

LANCET ONCOLOGY, 2014, 15 (06) :580-591

[3]

[Anonymous], SAN ANT BREAST CANC

[4] 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 [J].

Baselga, Jose ;

Cortes, Javier ;

Im, Seock-Ah ;

Clark, Emma ;

Ross, Graham ;

Kiermaier, Astrid ;

Swain, Sandra M. .

JOURNAL OF CLINICAL ONCOLOGY, 2014, 32 (33) :3753-+

[5] Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial [J].

Baselga, Jose ;

Bradbury, Ian ;

Eidtmann, Holger ;

Di Cosimo, Serena ;

de Azambuja, Evandro ;

Aura, Claudia ;

Gomez, Henry ;

Dinh, Phuong ;

Fauria, Karine ;

Van Dooren, Veerle ;

Aktan, Gursel ;

Goldhirsch, Aron ;

Chang, Tsai-Wang ;

Horvath, Zsolt ;

Coccia-Portugal, Maria ;

Domont, Julien ;

Tseng, Ling-Min ;

Kunz, Georg ;

Sohn, Joo Hyuk ;

Semiglazov, Vladimir ;

Lerzo, Guillermo ;

Palacova, Marketa ;

Probachai, Volodymyr ;

Pusztai, Lajos ;

Untch, Michael ;

Gelber, Richard D. ;

Piccart-Gebhart, Martine .

LANCET, 2012, 379 (9816) :633-640

[6] 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 [J].

Carey, Lisa A. ;

Berry, Donald A. ;

Cirrincione, Constance T. ;

Barry, William T. ;

Pitcher, Brandelyn N. ;

Harris, Lyndsay N. ;

Ollila, David W. ;

Krop, Ian E. ;

Henry, Norah Lynn ;

Weckstein, Douglas J. ;

Anders, Carey K. ;

Singh, Baljit ;

Hoadley, Katherine A. ;

Iglesia, Michael ;

Cheang, Maggie Chon U. ;

Perou, Charles M. ;

Winer, Eric P. ;

Hudis, Clifford A. .

JOURNAL OF CLINICAL ONCOLOGY, 2016, 34 (06) :542-+

[7] 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 [J].

Denkert, Carsten ;

von Minckwitz, Gunter ;

Brase, Jan C. ;

Sinn, Bruno V. ;

Gade, Stephan ;

Kronenwett, Ralf ;

Pfitzner, Berit M. ;

Salat, Christoph ;

Loi, Sherene ;

Schmitt, Wolfgang D. ;

Schem, Christian ;

Fisch, Karin ;

Darb-Esfahani, Silvia ;

Mehta, Keyur ;

Sotiriou, Christos ;

Wienert, Stephan ;

Klare, Peter ;

Andre, Fabrice ;

Klauschen, Frederick ;

Blohmer, Jens-Uwe ;

Krappmann, Kristin ;

Schmidt, Marcus ;

Tesch, Hans ;

Kuemmel, Sherko ;

Sinn, Peter ;

Jackisch, Christian ;

Dietel, Manfred ;

Reimer, Toralf ;

Untch, Michael ;

Loibl, Sibylle .

JOURNAL OF CLINICAL ONCOLOGY, 2015, 33 (09) :983-991

[8] Phosphatidylinositol 3-Kinase Hyperactivation Results in Lapatinib Resistance that Is Reversed by the mTOR/Phosphatidylinositol 3-Kinase Inhibitor NVP-BEZ235 [J].

Eichhorn, Pieter J. A. ;

Gili, Magui ;

Scaltriti, Maurizio ;

Serra, Violeta ;

Guzman, Marta ;

Nijkamp, Wouter ;

Beijersbergen, Roderick L. ;

Valero, Vanesa ;

Seoane, Joan ;

Bernards, Rene ;

Baselga, Jose .

CANCER RESEARCH, 2008, 68 (22) :9221-9230

[9] 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 [J].

Fisher, B ;

Brown, A ;

Mamounas, E ;

Wieand, S ;

Robidoux, A ;

Margolese, RG ;

Cruz, AB ;

Fisher, ER ;

Wickerham, DL ;

Wolmark, N ;

DeCillis, A ;

Hoehn, JL ;

Lees, AW ;

Dimitrov, NV .

JOURNAL OF CLINICAL ONCOLOGY, 1997, 15 (07) :2483-2493

[10] Pathobiology of preoperative chemotherapy - Findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-18 [J].

Fisher, ER ;

Wang, JP ;

Bryant, J ;

Fisher, B ;

Mamounas, E ;

Wolmark, N .

CANCER, 2002, 95 (04) :681-695

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