Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer
Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer
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DOI：
10.1093/annonc/mdy155
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发表时间：
2018-07-01
影响因子：
50.5
通讯作者：
O'Shaughnessy, J.
中科院分区：
文献类型：
--
作者：
Hortobagyi, G. N.;Stemmer, S. M.;O'Shaughnessy, J.
背景资料：III期MONALEESA-2研究表明，在激素受体阳性（HR+）、人表皮生长因子受体2阴性（HER 2-）晚期乳腺癌患者中，与安慰剂+来曲唑相比，一线治疗ribociclib+来曲唑可显著延长无进展生存期（PFS），且毒性特征可控。在这里，我们报告了MONALEESA-2研究的最新疗效和安全性数据，以及探索性生物标志物分析。（1：1;根据是否存在肝和/或肺转移分层）与ribociclib（600 mg/天; 3周给药/1周停药; 28天治疗周期）加来曲唑（2.5 mg/天;连续）或安慰剂加来曲唑。主要终点是当地评估的PFS。关键的次要终点是总生存期（OS）。其他次要终点包括总缓解率（ORR）和安全性。生物标志物分析是一个探索性的endpoint.Results：在第二次中期分析时，随访的中位持续时间为26.4个月。ribociclib+来曲唑的中位PFS为25.3个月[95%置信区间（CI）23.0-30.3]，安慰剂+来曲唑为16.0个月（95% CI 13.4-18.2）（风险比0.568; 95% CI 0.457-0.704;对数秩P = 9.63 x 10（-8））。无论PIK 3CA或TP 53突变状态、总Rb、Ki 67或p16蛋白表达以及CDKN 2A、CCND 1或ESR 1 mRNA水平如何，Ribociclib治疗获益均得以维持。Ribociclib的获益在野生型与受体酪氨酸激酶基因改变的患者中更为明显。OS数据仍不成熟，观察到116例死亡; ribociclib组50例，安慰剂组66例（风险比0.746; 95% CI 0.517-1.078）。所有接受ribociclib+来曲唑治疗的患者与安慰剂+来曲唑治疗的患者的ORR分别为42.5%和28.7%，可测量疾病患者的ORR分别为54.5%和38.8%。安全性结果，经过进一步的11.1个月的后续行动，是可比的，在第一次分析报告，没有新的或意外的毒性观察，并没有证据的累积toxicity.Conclusions：改善疗效的结果和可控的耐受性观察与一线ribociclib加来曲唑保持较长的后续行动，相对于来曲唑单药治疗。
Background: The phase III MONALEESA-2 study demonstrated significantly prolonged progression-free survival (PFS) and a manageable toxicity profile for first-line ribociclib plus letrozole versus placebo plus letrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. Here, we report updated efficacy and safety data, together with exploratory biomarker analyses, from the MONALEESA-2 study.Patients and methods: A total of 668 postmenopausal women with HR+, HER2-recurrent/metastatic breast cancer were randomized (1 : 1; stratified by presence/absence of liver and/or lung metastases) to ribociclib (600 mg/day; 3-weeks-on/1-week-off; 28-day treatment cycles) plus letrozole (2.5 mg/day; continuous) or placebo plus letrozole. The primary end point was locally assessed PFS. The key secondary end point was overall survival (OS). Other secondary end points included overall response rate (ORR) and safety. Biomarker analysis was an exploratory end point.Results: At the time of the second interim analysis, the median duration of follow-up was 26.4 months. Median PFS was 25.3 months [95% confidence interval (CI) 23.0-30.3] for ribociclib plus letrozole and 16.0 months (95% CI 13.4-18.2) for placebo plus letrozole (hazard ratio 0.568; 95% CI 0.457-0.704; log-rank P = 9.63 x 10(-8)). Ribociclib treatment benefit was maintained irrespective of PIK3CA or TP53 mutation status, total Rb, Ki67, or p16 protein expression, and CDKN2A, CCND1, or ESR1 mRNA levels. Ribociclib benefit was more pronounced in patients with wild-type versus altered receptor tyrosine kinase genes. OS data remain immature, with 116 deaths observed; 50 in the ribociclib arm and 66 in the placebo arm (hazard ratio 0.746; 95% CI 0.517-1.078). The ORR was 42.5% versus 28.7% for all patients treated with ribociclib plus letrozole versus placebo plus letrozole, respectively, and 54.5% versus 38.8%, respectively, for patients with measurable disease. Safety results, after a further 11.1 months of follow-up, were comparable with those reported at the first analysis, with no new or unexpected toxicities observed, and no evidence of cumulative toxicity.Conclusions: The improved efficacy outcomes and manageable tolerability observed with first-line ribociclib plus letrozole are maintained with longer follow-up, relative to letrozole monotherapy.