Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer
Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer
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DOI：
10.1056/nejmoa1813904
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发表时间：
2019-05-16
影响因子：
158.5
通讯作者：
Juric, Dejan
中科院分区：
文献类型：
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作者：
Andre, Fabrice;Ciruelos, Eva;Juric, Dejan
大约 40% 的激素受体阳性乳腺癌患者发生 PIK3CA 突变。 PI3K 抑制剂 alpelisib 与氟维司群联用可实现 11 个月的中位无进展生存期，而安慰剂加氟维司群的中位无进展生存期为 5.7 个月。使用 alpelisib 时，高血糖、皮疹和腹泻更为常见。 背景 约 40% 的激素受体 (HR) 阳性、人表皮生长因子受体 2 (HER2) 阴性乳腺癌患者发生 PIK3CA 突变。 PI3K α 特异性抑制剂 alpelisib 在早期研究中已显示出抗肿瘤活性。方法 在一项随机 3 期试验中，我们在既往接受过内分泌治疗的 HR 阳性、HER2 阴性晚期乳腺癌患者中比较了 alpelisib（剂量为每天 300 mg）加氟维司群（剂量为每 28 天 500 mg，第 15 天一次）与安慰剂加氟维司群。根据肿瘤组织 PIK3CA 突变状态将患者纳入两个队列。主要终点是研究者评估的 PIK3CA 突变癌症队列中的无进展生存期；还对无 PIK3CA 突变癌症的队列中的无进展生存期进行了分析。次要终点包括总体反应和安全性。结果 共有 572 名患者接受了随机分组，其中 341 名患者确诊为肿瘤组织 PIK3CA 突变。在 PIK3CA 突变癌症患者队列中，阿培利西-氟维司群组中位随访 20 个月的无进展生存期为 11.0 个月（95% 置信区间 [CI]，7.5 至 14.5），而安慰剂-氟维司群组为 5.7 个月（95% CI，3.7 至 7.4）（进展或死亡风险比， 0.65；95% CI，0.50 至 0.85；
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