The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor-Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy-MONARCH 2 A Randomized Clinical Trial
The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor-Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy-MONARCH 2 A Randomized Clinical Trial
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DOI：
10.1001/jamaoncol.2019.4782
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发表时间：
2020-01-01
期刊：
影响因子：
28.4
通讯作者：
Llombart-Cussac, Antonio
中科院分区：
文献类型：
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作者：
Sledge, George W.;Toi, Masakazu;Llombart-Cussac, Antonio
在激素受体(HR)阳性、ERBB2(以前称为HER2)阴性的晚期乳腺癌(ABC)患者中，CDK4和CDK6抑制剂与富维斯特联合使用对总体存活率(OS)有显著的统计学意义的好处，而不考虑先前的内分泌治疗(ET)后的绝经状态。目的比较阿贝西利联合福维斯特与安慰剂加福维斯特治疗前ET进展的HR阳性、ERBB2阴性的晚期乳腺癌患者在MANARCH2(338个事件)预定间期对OS的影响。设计、设置和参与者：MONARCH 2是一项全球性、随机、安慰剂对照、双盲的3期试验，阿贝西利加福维斯特与安慰剂加福维斯特治疗在ET期间进展的绝经前或围绝经期妇女(卵巢抑制)和患有HR阳性、ERBB2阴性ABC的绝经后妇女。患者是在2014年8月7日至2015年12月29日之间登记的。本报告的分析是在2019年6月20日数据库锁定时进行的。干预措施患者随机接受阿贝西利或安慰剂150 mg，每12小时一次的连续治疗方案，加用氟维司他500 mg，每个标签。根据转移部位(内脏、骨骼或其他)和对先前ET的抵抗力(原发与继发)进行随机分组。主要结果和测量主要终点是研究人员评估的无进展存活率。总体存活率是一个关键的次要终点。中期分析的边界P值为0.02。结果在入选的669名女性中，446名(中位年龄59[32-91]岁)被随机分为阿贝西利加富维司坦组，223名(中位年龄62[32-87]岁)被随机分配到安慰剂+富维司坦组。在预先指定的过渡期，意向治疗人群中观察到338例死亡(最终分析为计划441例的77%)，阿贝西利加富维司坦组的中位OS为46.7月，安慰剂组为37.3月(风险比[HR]，0.757；95%CI，0.606-0.945；P=.01)。操作系统的改进在所有分层因素中都是一致的。在分层因素中，内脏疾病(HR，0.675；95%CI，0.511-0.891)和对先前ET的初次抵抗(HR，0.686；95%CI，0.451-1.043)的影响更为明显。阿贝西利组与安慰剂组相比，第二次疾病进展时间(中位数，23.1个月对20.6个月)、化疗时间(中位数，50.2个月对22.1个月)和无化疗生存期(中位数，25.5个月对18.2个月)也有显著改善。阿贝西利未观察到新的安全信号。结论和阿贝西利联合福维斯特的相关治疗使HR阳性、ERBB2阴性的ABC患者的中位OS改善9.4个月，具有统计学意义和临床意义，这些患者在既往ET后进展，无论绝经状态如何。这项随机临床试验比较了激素受体阳性、ERBB2阴性的晚期乳腺癌患者在激素受体阳性、ERBB2阴性的晚期乳腺癌患者中接受内分泌治疗期间的总生存期。问题：激素受体(HR)阳性、ERBB2(以前称为HER2)阴性的晚期乳腺癌患者在接受内分泌治疗期间，阿贝西利联合弗维斯特朗的治疗是否延长了患者的总生存期？在对669名HR阳性、ERBB2阴性的晚期乳腺癌患者进行的随机、安慰剂对照的MONARCH 2试验中，阿贝西利加福维斯特显著改善了中位OS至46.7个月，而服用安慰剂加福维斯特的患者为37.3个月。这意味着，对于HR阳性、ERBB2阴性、内分泌治疗取得进展的晚期乳腺癌患者，在fulvestrant的基础上加用阿贝西利可使患者的OS延长9.4个月，具有临床意义。
Importance Statistically significant overall survival (OS) benefits of CDK4 and CDK6 inhibitors in combination with fulvestrant for hormone receptor (HR)-positive, ERBB2 (formerly HER2)-negative advanced breast cancer (ABC) in patients regardless of menopausal status after prior endocrine therapy (ET) has not yet been demonstrated. Objective To compare the effect of abemaciclib plus fulvestrant vs placebo plus fulvestrant on OS at the prespecified interim of MONARCH 2 (338 events) in patients with HR-positive, ERBB2-negative advanced breast cancer that progressed during prior ET. Design, Setting, and Participants MONARCH 2 was a global, randomized, placebo-controlled, double-blind phase 3 trial of abemaciclib plus fulvestrant vs placebo plus fulvestrant for treatment of premenopausal or perimenopausal women (with ovarian suppression) and postmenopausal women with HR-positive, ERBB2-negative ABC that progressed during ET. Patients were enrolled between August 7, 2014, and December 29, 2015. Analyses for this report were conducted at the time of database lock on June 20, 2019. Interventions Patients were randomized 2:1 to receive abemaciclib or placebo, 150 mg, every 12 hours on a continuous schedule plus fulvestrant, 500 mg, per label. Randomization was stratified based on site of metastasis (visceral, bone only, or other) and resistance to prior ET (primary vs secondary). Main Outcomes and Measures The primary end point was investigator-assessed progression-free survival. Overall survival was a gated key secondary end point. The boundary P value for the interim analysis was .02. Results Of 669 women enrolled, 446 (median [range] age, 59 [32-91] years) were randomized to the abemaciclib plus fulvestrant arm and 223 (median [range] age, 62 [32-87] years) were randomized to the placebo plus fulvestrant arm. At the prespecified interim, 338 deaths (77% of the planned 441 at the final analysis) were observed in the intent-to-treat population, with a median OS of 46.7 months for abemaciclib plus fulvestrant and 37.3 months for placebo plus fulvestrant (hazard ratio [HR], 0.757; 95% CI, 0.606-0.945; P = .01). Improvement in OS was consistent across all stratification factors. Among stratification factors, more pronounced effects were observed in patients with visceral disease (HR, 0.675; 95% CI, 0.511-0.891) and primary resistance to prior ET (HR, 0.686; 95% CI, 0.451-1.043). Time to second disease progression (median, 23.1 months vs 20.6 months), time to chemotherapy (median, 50.2 months vs 22.1 months), and chemotherapy-free survival (median, 25.5 months vs 18.2 months) were also statistically significantly improved in the abemaciclib arm vs placebo arm. No new safety signals were observed for abemaciclib. Conclusions and Relevance Treatment with abemaciclib plus fulvestrant resulted in a statistically significant and clinically meaningful median OS improvement of 9.4 months for patients with HR-positive, ERBB2-negative ABC who progressed after prior ET regardless of menopausal status. Abemaciclib substantially delayed the receipt of subsequent chemotherapy.This randomized clinical trial compared the effect of abemaciclib plus fulvestrant vs placebo plus fulvestrant on overall survival in women with hormone receptor-positive, ERBB2-negative advanced breast cancer that progressed during prior endocrine therapy.Question Does treatment with abemaciclib plus fulvestrant prolong the overall survival (OS) of patients with hormone receptor (HR)-positive, ERBB2 (formerly HER2)-negative advanced breast cancer who progressed during prior endocrine therapy? Findings In the randomized, placebo-controlled MONARCH 2 trial of 669 patients with HR-positive, ERBB2-negative advanced breast cancer, abemaciclib plus fulvestrant significantly improved median OS to 46.7 months compared with 37.3 months for patients receiving placebo plus fulvestrant. Meaning The addition of abemaciclib to fulvestrant provided a clinically meaningful median OS benefit of 9.4 months for patients with HR-positive, ERBB2-negative advanced breast cancer that had progressed on endocrine therapy.