布帕利昔（布帕利塞、布帕利司）属于磷脂酰肌醇-3-羟激酶（PI3K）广泛抑制剂，BELLE-2研究初步结果已经证实布帕利昔可以显著改善氟维司群治疗激素受体阳性HER2阴性晚期乳腺癌患者的无进展生存。
2018年11月，欧洲癌症治疗研究组织、欧洲癌症组织、欧洲乳腺癌专科学会《欧洲癌症杂志》正式发表法国诺华、西部肿瘤学研究所、韩国首尔大学、日本爱知癌症中心、日本癌症研究基金会癌症研究所医院、国立大阪医院、加拿大渥太华医院研究所、不列颠哥伦比亚癌症中心、比利时布鲁塞尔自由大学朱尔博尔代研究所、波兰居里夫人纪念癌症中心、意大利马切拉塔医院、中国台北荣民总医院、台北阳明大学、美国诺华、洛杉矶加利福尼亚大学、范德比大学、纽约纪念医院斯隆凯特林癌症中心、西班牙马德里大学拉蒙卡哈尔医院、巴塞罗那大学沃尔德希布伦肿瘤研究所、意大利帕斯卡基金会国家肿瘤研究所、德国基尔大学石勒苏益格荷尔斯泰因医院、解放军总医院第五医学中心（军事医学研究院附属医院、解放军第三〇七医院）江泽飞等学者的BELLE-2研究总生存结果报告。
该III期安慰剂随机对照研究于2012年9月7日～2014年9月10日入组激素受体阳性HER2阴性晚期乳腺癌患者2025例，按1∶1随机分组接受布帕利昔（每天100毫克，每周期连续28天）或安慰剂＋氟维司群（500mg，第1周期第15天、随后每周期第1天）。对全体患者和已知PI3K通路状态患者（二者均无进展生存都显著改善）进行总生存终点评定，并且根据循环肿瘤DNA（ctDNA）PIK3CA基因是否突变，对总生存终点进行探索分析。
结果，导入期间接受氟维司群（500mg）患者1178例，其中31例患者停药，其余1147例患者（中位年龄62岁）东部肿瘤协作组（ECOG）体力状态评分≤1占98%，内脏病变占59%。随机分组至数据截止（2016年12月23日）中位随访37.6个月。
布帕利昔组与安慰剂组相比，中位总生存时间略长，但是统计学意义不大：
总体人群1147例：33.2比30.4个月（单侧P=0.045）
已知PI3K通路状态患者851例：30.9比28.9个月（单侧P=0.144）
ctDNA有PIK3CA突变患者200例：26.0比24.8个月（单侧P=0.127）
布帕利昔组与安慰剂组发生率相差≥10%的III/IV级不良事件：
谷丙转氨酶升高（26%比1%）
谷草转氨酶升高（18%比3%）
高血糖（15%比<1%）
因此，该研究总生存结果表明，对于激素受体阳性HER2阴性晚期乳腺癌患者，布帕利昔＋氟维司群优于安慰剂＋氟维司群，但是缺乏统计学意义，而且III/IV级不良事件报告较多。选择性更高的PI3K抑制剂可能提供最大临床获益和可耐受安全性，故有必要进一步评估PIK3CA突变ctDNA的预测作用。
相关阅读
Eur J Cancer. 2018 Nov;103:147-154.
Buparlisib plus fulvestrant versus placebo plus fulvestrant for postmenopausal, hormone receptor-positive, human epidermal growth factor receptor 2-negative, advanced breast cancer: Overall survival results from BELLE-2.
Campone M, Im SA, Iwata H, Clemons M, Ito Y, Awada A, Chia S, Jagiello-Gruszfeld A, Pistilli B, Tseng LM, Hurvitz S, Masuda N, Cortés J, De Laurentiis M, Arteaga CL, Jiang Z, Jonat W, Le Mouhaer S, Sankaran B, Bourdeau L, El-Hashimy M, Sellami D, Baselga J.
Institut de Cancérologie de L'Ouest, Saint Herblain, France; Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; Aichi Cancer Center, Nagoya, Japan; Ottawa Hospital Research Institute, Ottawa, Canada; Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan; Institut Jules Bordet, Brussels, Belgium; BC Cancer Agency, Vancouver, Canada; Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology (MCMCC), Warsaw, Poland; Macerata Hospital, Macerata, Italy; Taipei-Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan; UCLA Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, USA; National Hospital Organization Osaka National Hospital, Osaka, Japan; Ramón y Cajal University Hospital, Madrid, Spain; Vall D'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Istituto Nazionale Tumori Fondazione G. Pascale, Naples, Italy; Vanderbilt University, Nashville, USA; Beijing 307 Hospital of PLA, Beijing, China; University Hospital Schleswig-Holstein, Kiel, Germany; Novartis Pharma S.A.S., Paris, France; Novartis Institutes for BioMedical Research, Cambridge, USA; Novartis Pharmaceuticals Corporation, East Hanover, USA; Memorial Sloan Kettering Cancer Center, New York, USA.
HIGHLIGHTS
In this phase III study, median overall survival trended in favour of buparlisib plus fulvestrant versus placebo plus fulvestrant.
In the overall population (1147 patients), median OS was 33.2 versus 30.4 months; 1-sided P = 0.045.
In patients with known PI3K pathway status (851 patients), median OS was 30.9 versus 28.9 months; 1-sided P = 0.144.
Both outcomes were not statistically significant and more frequent grade III/IV adverse events were reported.
Investigation of selective PI3K inhibitors is warranted.
BACKGROUND: Buparlisib, a pan-phosphatidylinositol 3-kinase (PI3K) inhibitor, plus fulvestrant in the BELLE-2 study significantly improved progression-free survival (PFS) in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer.
PATIENTS AND METHODS: In this phase III study, patients were randomised 1:1 to buparlisib (100 mg/day; continuously in 28-day cycles) or placebo, plus fulvestrant (500 mg on cycle 1 day 15, and day 1 of subsequent cycles). Overall survival (OS) was assessed in the overall population and patients with known PI3K pathway status (both had shown significant PFS improvements). OS by PIK3CA status in circulating tumour DNA (ctDNA) was an exploratory end-point.
RESULTS: A total of 2025 patients were screened for eligibility between 7th September 2012 and 10th September 2014, and 1178 received fulvestrant (500 mg) during a run-in phase; 31 discontinued. Of 1147 patients (median age 62 years), 98% had the Eastern Cooperative Oncology Group performance status ≤1, and 59% had visceral disease. Median follow-up from randomisation to data cut-off (23rd December 2016) was 37.6 months. Median OS trended in favour of the buparlisib arm in the overall population (33.2 versus 30.4 months; P = 0.045) and among patients with known PI3K pathway status (30.9 versus 28.9 months; P = 0.144); neither outcome was statistically significant. Median OS also trended in favour of buparlisib among patients with PIK3CA-mutant ctDNA (26.0 versus 24.8 months). Grade III/IV adverse events with ≥10% difference between the buparlisib versus placebo arms were elevated alanine aminotransferase (26% versus 1%), elevated aspartate aminotransferase (18% versus 3%) and hyperglycemia (15% versus <1%).
CONCLUSIONS: OS results were in favour of buparlisib plus fulvestrant versus placebo plus fulvestrant; however, there is no statistical significance and more frequent grade III/IV adverse events were reported. Use of more selective PI3K inhibitors might provide the greatest clinical benefit and tolerable safety profile in this setting. Further evaluation of the predictive benefit of PIK3CA-mutant ctDNA is warranted.
TRIAL REGISTRATION NUMBER: NCT01610284.
KEYWORDS: Buparlisib; Fulvestrant; Hormone receptor-positive breast cancer; Overall survival; PIK3CA; ctDNA
PMID: 30241001
DOI: 10.1016/j.ejca.2018.08.002
联系客服
