Giredestrant联合Everolimus治疗晚期乳腺癌。
完整摘要 · 中文译文
背景：吉瑞斯特兰（giredestrant）和依维莫司（everolimus）分别靶向雌激素受体（ER）通路和磷脂酰肌醇3-激酶（PI3K）-蛋白激酶B（AKT）-哺乳动物雷帕霉素靶蛋白（mTOR）通路，这些通路与内分泌治疗耐药相关。 方法：在这项3期、开放标签、随机试验中，我们纳入了雌激素受体（ER）阳性、人表皮生长因子受体2（HER2）阴性的局部晚期或转移性乳腺癌患者，这些患者在接受细胞周期蛋白依赖性激酶4和6（CDK4/6）抑制剂联合内分泌治疗后出现疾病进展或复发。患者按1:1的比例被分配接受吉瑞斯特兰联合依维莫司（均口服）或标准内分泌治疗（即依西美坦、氟维司群或他莫昔芬）联合依维莫司。主要终点为研究者评估的无进展生存期，首先在ESR1突变肿瘤患者中评估，然后在总试验人群中进行评估。 结果：总体而言，373例患者接受了随机分组，其中183例被分配到giredestrant-everolimus组，190例分配到标准疗法-everolimus组。在207例ESR1突变肿瘤患者中，giredestrant-everolimus组的中位无进展生存期为10.0个月，标准疗法-everolimus组为5.5个月（疾病进展或死亡的风险比为0.38；95%置信区间[CI]，0.27至0.54；P<0.001）。在总体人群中，giredestrant-everolimus组的中位无进展生存期为8.8个月，标准疗法-everolimus组为5.5个月（风险比为0.56；95% CI，0.44至0.71；P<0.001）。接受giredestrant-everolimus的患者中有98.9%发生不良事件，接受标准疗法-everolimus的患者中有96.8%发生不良事件。最常见的不良事件是口腔炎（giredestrant-everolimus接受者中占47.3%，标准疗法-everolimus接受者中占48.9%）、腹泻（分别占26.9%和22.6%）和贫血（分别占23.6%和21.0%）。 结论：在既往接受过CDK4/6抑制剂治疗的ER阳性、HER2阴性晚期乳腺癌患者中，与标准内分泌疗法-everolimus相比，全口服的giredestrant-everolimus方案显著延长了无进展生存期，主要见于ESR1突变肿瘤患者。两组的不良事件发生率相似。（由Genentech资助；evERA Breast Cancer临床试验注册号，NCT05306340。）
完整摘要 · 英文原文
BACKGROUND: Giredestrant and everolimus target the estrogen receptor (ER) pathway and the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT)-mammalian target of rapamycin (mTOR) pathway, respectively, which are implicated in endocrine-therapy resistance. METHODS: In this phase 3, open-label, randomized trial, we enrolled patients with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer who had disease progression or recurrence after receipt of a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor plus endocrine therapy. Patients were assigned, in a 1:1 ratio, to receive giredestrant plus everolimus (each given orally) or standard endocrine therapy (i.e., exemestane, fulvestrant, or tamoxifen) plus everolimus. The primary end point was investigator-assessed progression-free survival, evaluated first among patients with ESR1-mutated tumors and then in the overall trial population. RESULTS: Overall, 373 patients underwent randomization, with 183 assigned to the giredestrant-everolimus group and 190 to the standard therapy-everolimus group. Among 207 patients with ESR1-mutated tumors, the median progression-free survival was 10.0 months with giredestrant-everolimus and 5.5 months with standard therapy-everolimus (hazard ratio for disease progression or death, 0.38; 95% confidence interval [CI], 0.27 to 0.54; P<0.001). In the overall population, the median progression-free survival was 8.8 months with giredestrant-everolimus and 5.5 months with standard therapy-everolimus (hazard ratio, 0.56; 95% CI, 0.44 to 0.71; P<0.001). Adverse events occurred in 98.9% of patients who received giredestrant-everolimus and in 96.8% of those who received standard therapy-everolimus. The most common adverse events were stomatitis (in 47.3% of giredestrant-everolimus recipients and 48.9% of standard therapy-everolimus recipients), diarrhea (in 26.9% and 22.6%, respectively), and anemia (in 23.6% and 21.0%). CONCLUSIONS: An all-oral giredestrant-everolimus regimen led to significantly longer progression-free survival than standard endocrine therapy-everolimus among patients with ER-positive, HER2-negative advanced breast cancer who had received a CDK4/6 inhibitor previously, mainly in patients with ESR1-mutated tumors. The incidence of adverse events was similar in the two groups. (Funded by Genentech; evERA Breast Cancer ClinicalTrials.gov number, NCT05306340.).