Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer

被引:1802
作者
Andre, Fabrice [1 ]
Ciruelos, Eva [4 ]
Rubovszky, Gabor [5 ]
Campone, Mario [2 ]
Loibl, Sibylle [7 ,8 ]
Rugo, Hope S. [9 ]
Iwata, Hiroji [10 ]
Conte, Pierfranco [14 ,15 ,16 ,17 ]
Mayer, Ingrid A. [18 ]
Kaufman, Bella [19 ]
Yamashita, Toshinari [11 ]
Lu, Yen-Shen [20 ]
Inoue, Kenichi [12 ]
Takahashi, Masato [13 ]
Papai, Zsuzsanna [6 ]
Longin, Anne-Sophie [3 ]
Mills, David [21 ]
Wilke, Celine [21 ]
Hirawat, Samit [22 ]
Juric, Dejan [23 ]
机构
[1] Univ Paris Sud, Inst Gustave Roussy, INSERM, U981, Villejuif, France
[2] Inst Cancarol Ouest, St Herblain, France
[3] Novartis Pharmaceut, Paris, France
[4] Hosp Univ 12 Octubre, Madrid, Spain
[5] Natl Inst Oncol, Budapest, Hungary
[6] Duna Med Ctr, Budapest, Hungary
[7] German Breast Grp, Neu Isenburg, Germany
[8] Ctr Hematol & Oncol Bethanien, Frankfurt, Germany
[9] UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA
[10] Aichi Canc Ctr, Nagoya, Aichi, Japan
[11] Kanagawa Canc Ctr, Yokohama, Kanagawa, Japan
[12] Saitama Canc Ctr, Saitama, Japan
[13] Natl Hosp Org Hokkaido Canc Ctr, Sapporo, Hokkaido, Japan
[14] Ist Oncol Veneto, Padua, Italy
[15] Univ Padua, Dept Surg, Padua, Italy
[16] Univ Padua, Dept Oncol, Padua, Italy
[17] Univ Padua, Dept Gastroenterol, Padua, Italy
[18] Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA
[19] Chaim Sheba Med Ctr, Tel Hashomer, Israel
[20] Natl Taiwan Univ Hosp, Taipei, Taiwan
[21] Novartis Pharmaceut, Basel, Switzerland
[22] Novartis Pharmaceut, E Hanover, NJ USA
[23] Massachusetts Gen Hosp, Ctr Canc, 55 Fruit St, Boston, MA 02114 USA
关键词
ESTROGEN;
D O I
10.1056/NEJMoa1813904
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
PIK3CA mutations occur in approximately 40% of patients with hormone receptor-positive breast cancer. A PI3K inhibitor, alpelisib, combined with fulvestrant led to a median progression-free survival of 11 months, as compared with 5.7 months with placebo plus fulvestrant. Hyperglycemia, rash, and diarrhea were more common with alpelisib. Background PIK3CA mutations occur in approximately 40% of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. The PI3K alpha-specific inhibitor alpelisib has shown antitumor activity in early studies. Methods In a randomized, phase 3 trial, we compared alpelisib (at a dose of 300 mg per day) plus fulvestrant (at a dose of 500 mg every 28 days and once on day 15) with placebo plus fulvestrant in patients with HR-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously. Patients were enrolled into two cohorts on the basis of tumor-tissue PIK3CA mutation status. The primary end point was progression-free survival, as assessed by the investigator, in the cohort with PIK3CA-mutated cancer; progression-free survival was also analyzed in the cohort without PIK3CA-mutated cancer. Secondary end points included overall response and safety. Results A total of 572 patients underwent randomization, including 341 patients with confirmed tumor-tissue PIK3CA mutations. In the cohort of patients with PIK3CA-mutated cancer, progression-free survival at a median follow-up of 20 months was 11.0 months (95% confidence interval [CI], 7.5 to 14.5) in the alpelisib-fulvestrant group, as compared with 5.7 months (95% CI, 3.7 to 7.4) in the placebo-fulvestrant group (hazard ratio for progression or death, 0.65; 95% CI, 0.50 to 0.85; P<0.001); in the cohort without PIK3CA-mutated cancer, the hazard ratio was 0.85 (95% CI, 0.58 to 1.25; posterior probability of hazard ratio <1.00, 79.4%). Overall response among all the patients in the cohort without PIK3CA-mutated cancer was greater with alpelisib-fulvestrant than with placebo-fulvestrant (26.6% vs. 12.8%); among patients with measurable disease in this cohort, the percentages were 35.7% and 16.2%, respectively. In the overall population, the most frequent adverse events of grade 3 or 4 were hyperglycemia (36.6% in the alpelisib-fulvestrant group vs. 0.7% in the placebo-fulvestrant group) and rash (9.9% vs. 0.3%). Diarrhea of grade 3 occurred in 6.7% of patients in the alpelisib-fulvestrant group, as compared with 0.3% of those in the placebo-fulvestrant group; no diarrhea of grade 4 was reported. The percentages of patients who discontinued alpelisib and placebo owing to adverse events were 25.0% and 4.2%, respectively. Conclusions Treatment with alpelisib-fulvestrant prolonged progression-free survival among patients with PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously.
引用
收藏
页码:1929 / 1940
页数:12
相关论文
共 23 条
[1]  
[Anonymous], 2018, NCCN Clinical Practice Guidelines in Oncology
[2]   Phase III study of taselisib (GDC-0032) + fulvestrant (FULV) v FULV in patients (pts) with estrogen receptor (ER)-positive, PIK3CA-mutant (MUT), locally advanced or metastatic breast cancer (MBC): Primary analysis from SANDPIPER. [J].
Baselga, Jose ;
Dent, Susan Faye ;
Cortes, Javier ;
Im, Young-Hyuck ;
Dieras, Veronique ;
Harbeck, Nadia ;
Krop, Ian E. ;
Verma, Sunil ;
Wilson, Timothy R. ;
Jin, Huan ;
Wang, Lijia ;
Schimmoller, Frauke ;
Hsu, Jerry Y. ;
He, Jing ;
DeLaurentiis, Michelino ;
Drullinsky, Pamela ;
Jacot, William .
JOURNAL OF CLINICAL ONCOLOGY, 2018, 36 (18)
[3]   Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial [J].
Baselga, Jose ;
Im, Seock-Ah ;
Iwata, Hiroji ;
Cortes, Javier ;
De laurentiis, Michele ;
Jiang, Zefei ;
Arteaga, Carlos L. ;
Jonat, Walter ;
Clemons, Mark ;
Ito, Yoshinori ;
Awada, Ahmad ;
Chia, Stephen ;
Jagiello-Gruszfeld, Agnieszka ;
Pistilli, Barbara ;
Tseng, Ling-Ming ;
Hurvitz, Sara ;
Masuda, Norikazu ;
Takahashi, Masato ;
Vuylsteke, Peter ;
Hachemi, Soulef ;
Dharan, Bharani ;
Di Tomaso, Emmanuelle ;
Urban, Patrick ;
Massacesi, Cristian ;
Campone, Mario .
LANCET ONCOLOGY, 2017, 18 (07) :904-916
[4]   PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer [J].
Bosch, Ana ;
Li, Zhiqiang ;
Bergamaschi, Anna ;
Ellis, Haley ;
Toska, Eneda ;
Prat, Aleix ;
Tao, Jessica J. ;
Spratt, Daniel E. ;
Viola-Villegas, Nerissa T. ;
Castel, Pau ;
Minuesa, Gerard ;
Morse, Natasha ;
Rodon, Jordi ;
Ibrahim, Yasir ;
Cortes, Javier ;
Perez-Garcia, Jose ;
Galvan, Patricia ;
Grueso, Judit ;
Guzman, Marta ;
Katzenellenbogen, John A. ;
Kharas, Michael ;
Lewis, Jason S. ;
Dickler, Maura ;
Serra, Violeta ;
Rosen, Neal ;
Chandarlapaty, Sarat ;
Scaltriti, Maurizio ;
Baselga, Jose .
SCIENCE TRANSLATIONAL MEDICINE, 2015, 7 (283)
[5]   4th ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4) [J].
Cardoso, F. ;
Senkus, E. ;
Costa, A. ;
Papadopoulos, E. ;
Aapro, M. ;
Andre, F. ;
Harbeck, N. ;
Aguilar Lopez, B. ;
Barrios, C. H. ;
Bergh, J. ;
Biganzoli, L. ;
Boers-Doers, C. B. ;
Cardoso, M. J. ;
Carey, L. A. ;
Cortes, J. ;
Curigliano, G. ;
Dieras, V. ;
El Saghir, N. S. ;
Eniu, A. ;
Fallowfield, L. ;
Francis, P. A. ;
Gelmon, K. ;
Johnston, S. R. D. ;
Kaufmann, B. ;
Koppikar, S. ;
Krop, I. E. ;
Mayer, M. ;
Nakigudde, G. ;
Offersen, B. V. ;
Ohno, S. ;
Pagani, O. ;
Paluch-Shimon, S. ;
Penault-Llorca, F. ;
Prat, A. ;
Rugo, H. S. ;
Sledge, G. W. ;
Spence, D. ;
Thomssen, C. ;
Vorobiof, D. A. ;
Xu, B. ;
Norton, L. ;
Winer, E. P. .
ANNALS OF ONCOLOGY, 2018, 29 (08) :1634-1657
[6]   Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial [J].
Di Leo, Angelo ;
Johnston, Stephen ;
Lee, Keun Seok ;
Ciruelos, Eva ;
Lonning, Per E. ;
Janni, Wolfgang ;
O'Regan, Ruth ;
Mouret-Reynier, Marie-Ange ;
Kalev, Dimitar ;
Egle, Daniel ;
Csoszi, Tibor ;
Bordonaro, Roberto ;
Decker, Thomas ;
Tjan-Heijnen, Vivianne C. G. ;
Blau, Sibel ;
Schirone, Alessio ;
Weber, Denis ;
El-Hashimy, Mona ;
Dharan, Bharani ;
Sellami, Dalila ;
Bachelot, Thomas .
LANCET ONCOLOGY, 2018, 19 (01) :87-100
[7]   Characterization of the Novel and Specific PI3Kα Inhibitor NVP-BYL719 and Development of the Patient Stratification Strategy for Clinical Trials [J].
Fritsch, Christine ;
Huang, Alan ;
Chatenay-Rivauday, Christian ;
Schnell, Christian ;
Reddy, Anupama ;
Liu, Manway ;
Kauffmann, Audrey ;
Guthy, Daniel ;
Erdmann, Dirk ;
De Pover, Alain ;
Furet, Pascal ;
Gao, Hui ;
Ferretti, Stephane ;
Wang, Youzhen ;
Trappe, Joerg ;
Brachmann, Saskia M. ;
Maira, Sauveur-Michel ;
Wilson, Christopher ;
Boehm, Markus ;
Garcia-Echeverria, Carlos ;
Chene, Patrick ;
Wiesmann, Marion ;
Cozens, Robert ;
Lehar, Joseph ;
Schlegel, Robert ;
Caravatti, Giorgio ;
Hofmann, Francesco ;
Sellers, William R. .
MOLECULAR CANCER THERAPEUTICS, 2014, 13 (05) :1117-1129
[8]   Phosphatidylinositol 3-Kinase, Growth Disorders, and Cancer [J].
Goncalves, Marcus D. ;
Hopkins, Benjamin D. ;
Cantley, Lewis C. .
NEW ENGLAND JOURNAL OF MEDICINE, 2018, 379 (21) :2052-2062
[9]   US Incidence of Breast Cancer Subtypes Defined by Joint Hormone Receptor and HER2 Status [J].
Howlader, Nadia ;
Altekruse, Sean F. ;
Li, Christopher I. ;
Chen, Vivien W. ;
Clarke, Christina A. ;
Ries, Lynn A. G. ;
Cronin, Kathleen A. .
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 2014, 106 (05)
[10]  
Juric D., 2019, JAMA Oncol