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.
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.
复制标题
DOI：
10.1016/s1470-2045(17)30376-5
复制
发表时间：
2017-07
期刊：
影响因子：
--
通讯作者：
Campone M
中科院分区：
文献类型：
--
作者：
Baselga J;Im SA;Iwata H;Cortés J;De Laurentiis M;Jiang Z;Arteaga CL;Jonat W;Clemons M;Ito Y;Awada A;Chia S;Jagiełło-Gruszfeld A;Pistilli B;Tseng LM;Hurvitz S;Masuda N;Takahashi M;Vuylsteke P;Hachemi S;Dharan B;Di Tomaso E;Urban P;Massacesi C;Campone M
磷脂酰肌醇3-激酶(PI3K)通路激活是内分泌治疗耐药、激素受体阳性乳腺癌的标志。这项3期研究评估了PAN-PI3K抑制剂Buparlisib和Fulvestrant在晚期乳腺癌患者中的疗效，包括评估PI3K通路的激活状态作为临床受益的生物标记物。Belle-2试验是一项随机、双盲、安慰剂对照的多中心研究。包括18岁或以上、组织学确诊、激素受体阳性、人类表皮生长因子(HER2)阴性、局部无法手术的晚期或转移性乳腺癌的绝经后妇女，这些妇女的疾病在芳香酶抑制剂治疗期间或之后有所进展，并曾接受过多达一种晚期疾病的化疗。符合条件的患者在第1周期的第15天采用交互式语音应答技术(区块大小为6)随机分配(1：1)，从第1周期的第15天开始，口服丁帕利西(100 mg/天)或匹配的安慰剂，第1周期的第1天和第15天，以及随后28天周期的第1天，加用富维斯特(500 Mg)肌肉注射。通过一种有效的互动反应技术，患者被分配了随机数字；这些数字与不同的治疗组相关联，而不同的治疗组又与治疗数字相关联。肿瘤组织中的PI3K状态通过中心实验室在14天的磨合阶段进行测定。根据PI3K通路激活状态(激活与非激活与未知)和内脏疾病状态(存在与不存在)进行随机分层。患者、研究人员、当地放射科医生、研究小组和任何参与研究的人都被掩盖了治疗的身份，直到不失明。主要终点是在全人群中、已知(激活或非激活)PI3K通路状态的患者以及PI3K通路激活的患者中，根据本地研究人员根据反应评估标准进行的无进展生存率(1.1版)。在意向治疗人群中进行了疗效分析。对所有接受了至少一剂研究药物并根据他们所接受的治疗至少进行了一次基线后安全性评估的患者进行了安全性分析。这项试验在ClinicalTrials.gov注册，编号NCT01610284，目前正在进行中，但没有招募参与者。在2012年9月7日至2014年9月10日期间，来自29个国家的267个中心的1147名患者被随机分配到接受丁帕利西布(n=576)或安慰剂加富维斯特朗(n=571)。在全部患者中，丁帕利西布组的中位无进展生存期为6.9个月(95%可信区间为6·8~7·8)，而安慰剂组为5.0个月(4·0~5.2)(风险比[HR]0·78[95%可信区间0·67~0·89]；单侧P=0·00021)。在已知PI3K状态的患者(n=851)中，丁帕利西布组的中位无进展生存期为6.8个月(95%CI为5·0~7·0)，而安慰剂组为4·5个月(3·3~5·0)(HR为0·80[95%CI为0·68~0·94]；单侧P=0·0033)。在PI3K途径激活的患者(n=372)中，丁帕利西布组的中位无进展生存期为6.8个月(95%CI为4·9~7·1)，安慰剂组为4·0个月(3·1~5·2)(HR为0·76[0·60-0·97]，单侧P=0·014)。与安慰剂组相比，丁立西布组最常见的3-4级不良事件是丙氨酸转氨酶升高(573名患者中146名[25%]比570名患者中6名[1%])、天冬氨酸转氨酶升高(103名[18%]比16名[3%])、高血糖(88名[15%]比1名[1%])和皮疹(45名[8%]比无)。最常见的严重不良事件(影响≥的2%)是丙氨酸氨基转移酶升高(17例[3%]比1/570例)和天冬氨酸氨基转移酶升高(14[2%]比1[1%])。没有发生与治疗相关的死亡。这项研究的结果表明，PI3K抑制结合内分泌治疗对内分泌抵抗、激素受体阳性和HER2阴性的绝经后妇女晚期乳腺癌是有效的。在这种情况下，有必要使用更具选择性的PI3K抑制剂，如α特异性PI3K抑制剂，以进一步提高安全性和益处。由于这种组合的毒性，目前没有进行进一步的研究。
Phosphatidylinositol 3-kinase (PI3K) pathway activation is a hallmark of endocrine therapy-resistant, hormone receptor-positive breast cancer. This phase 3 study assessed the efficacy of the pan-PI3K inhibitor buparlisib plus fulvestrant in patients with advanced breast cancer, including an evaluation of the PI3K pathway activation status as a biomarker for clinical benefit. The BELLE-2 trial was a randomised, double-blind, placebo-controlled, multicentre study. Postmenopausal women aged 18 years or older with histologically confirmed, hormone receptor-positive and human epidermal growth factor (HER2)-negative inoperable locally advanced or metastatic breast cancer whose disease had progressed on or after aromatase inhibitor treatment and had received up to one previous line of chemotherapy for advanced disease were included. Eligible patients were randomly assigned (1:1) using interactive voice response technology (block size of 6) on day 15 of cycle 1 to receive oral buparlisib (100 mg/day) or matching placebo, starting on day 15 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1, and on day 1 of subsequent 28-day cycles. Patients were assigned randomisation numbers with a validated interactive response technology; these numbers were linked to different treatment groups which in turn were linked to treatment numbers. PI3K status in tumour tissue was determined via central laboratory during a 14-day run-in phase. Randomisation was stratified by PI3K pathway activation status (activated vs non-activated vs and unknown) and visceral disease status (present vs absent). Patients, investigators, local radiologists, study team, and anyone involved in the study were masked to the identity of the treatment until unblinding. The primary endpoints were progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 1.1) in the total population, in patients with known (activated or non-activated) PI3K pathway status, and in PI3K pathway-activated patients. Efficacy analyses were done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment according to the treatment they received. This trial is registered with ClinicalTrials.gov, number NCT01610284, and is currently ongoing but not recruiting participants. Between Sept 7, 2012, and Sept 10, 2014, 1147 patients from 267 centres in 29 countries were randomly assigned to receive buparlisib (n=576) or placebo plus fulvestrant (n=571). In the total patient population (n=1147), median progression-free survival was 6·9 months (95% CI 6·8–7·8) in the buparlisib group versus 5·0 months (4·0–5·2) in the placebo group (hazard ratio [HR] 0·78 [95% CI 0·67–0·89]; one-sided p=0·00021). In patients with known PI3K status (n=851), median progression-free survival was 6·8 months (95% CI 5·0–7·0) in the buparlisib group vs 4·5 months (3·3–5·0) in the placebo group (HR 0·80 [95% CI 0·68–0·94]; one-sided p=0·0033). In PI3K pathway-activated patients (n=372), median progression-free survival was 6·8 months (95% CI 4·9–7·1) in the buparlisib group versus 4·0 months (3·1–5·2) in the placebo group (HR 0·76 [0·60–0·97], one-sided p=0·014). The most common grade 3–4 adverse events in the buparlisib group versus the placebo group were increased alanine aminotransferase (146 [25%] of 573 patients vs six [1%] of 570), increased aspartate aminotransferase (103 [18%] vs 16 [3%]), hyperglycaemia (88 [15%] vs one [<1%]), and rash (45 [8%] vs none). Serious adverse events were reported in 134 (23%) of 573 patients in the buparlisib group compared with 90 [16%] of 570 patients in the placebo group; the most common serious adverse events (affecting ≥2% of patients) were increased alanine aminotransferase (17 [3%] of 573 vs one [<1%] of 570) and increased aspartate aminotransferase (14 [2%] vs one [<1%]). No treatment-related deaths occurred. The results from this study show that PI3K inhibition combined with endocrine therapy is effective in postmenopausal women with endocrine-resistant, hormone receptor-positive and HER2-negative advanced breast cancer. Use of more selective PI3K inhibitors, such as α-specific PI3K inhibitor, is warranted to further improve safety and benefit in this setting. No further studies are being pursued because of the toxicity associated with this combination.