蒙娜利莎Ⅱ乳腺癌研究结果更新

　　编者按：2016年10月，欧洲肿瘤内科学会（ESMO）年会和美国《新英格兰医学杂志》发表的III期研究（MONALEESA-2：Mammary ONcology Assessment of LEE011's Efficacy and SAfety）第一次中期分析表明，利泊昔布（LEE011）联合来曲唑与安慰剂联合来曲唑相比，用于一线治疗显著延长了激素受体阳性、HER2阴性晚期乳腺癌患者的无进展生存，进展和死亡风险减少44%（风险比：0.56，95%置信区间：0.43～0.72，P=3.29×10-6）。

　　2018年4月27日，ESMO和牛津大学出版社旗下《肿瘤学年鉴》在线发表美国诺华、德克萨斯大学MD安德森癌症中心、莎拉坎农研究所、杜克大学医学中心、达纳法伯癌症研究所、范德比大学英格拉姆癌症中心、以色列特拉维夫大学拉宾医学中心、希巴医学中心、新加坡国立癌症中心、荷兰癌症研究所、法国西部癌症研究所、捷克马萨里克纪念癌症研究所、德国乌尔姆大学、加拿大汤姆贝克癌症中心、意大利帕多瓦大学威尼托肿瘤研究所、英国爱丁堡大学癌症研究中心的研究报告，更新了MONALEESA-2的有效性和安全性数据以及生物标志探索分析结果。

　　该研究共入组激素受体阳性HER2阴性复发转移性乳腺癌绝经后女性668例，根据有无肝和/或肺转移进行分层、按1∶1随机分配接受利泊昔布（每天600mg，连用21天、连休7天，每28天重复）联合来曲唑（每天2.5mg，连用）或安慰剂联合来曲唑。主要终点为当地评定的无进展生存，关键次要终点为总生存，其他次要终点包括总缓解率和安全性，探索终点为生物标志分析。

　　第二次中期分析的中位随访时间为26.4个月（第一次为15.3个月，相距11.1个月）。

　　利泊昔布＋来曲唑与安慰剂＋来曲唑相比，中位无进展生存分别为25.3、16.0（95%置信区间：23.0～30.3、13.4～18.2）个月，进展和死亡风险减少43.2%（风险比：0.568，95%置信区间：0.457～0.704，对数秩P=9.63×10-8）。

　　无论PIK3CA或TP53突变状态、Rb或Ki67或p16蛋白质总表达、CDKN2A或CCND1或ESR1的mRNA水平如何，利泊昔布均治疗获益相似。

　　受体酪氨酸激酶基因野生型与变异型的患者相比，利泊昔布获益更为明显。

　　患者死亡116例（尚未达到中位总生存分析所需半数），其中利泊昔布组50例、安慰剂组66例（风险比：0.746，95%置信区间：0.517～1.078）。

　　利泊昔布＋来曲唑与安慰剂＋来曲唑相比，总缓解率分别为：

• 所有接受治疗患者：42.5%比28.7%

• 病灶可以测量患者：54.5%比38.8%

　　第二次与第一次中期分析相比，安全性结果相似，未见新的或意外毒性反应，并且无累积毒性反应证据。

　　因此，与来曲唑单药相比，利泊昔布联合来曲唑一线治疗的效果提高、耐受性可管控，经过更长随访时间仍然保持。

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Ann Oncol. 2018 Apr 27. [Epub ahead of print]

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.

G N Hortobagyi, S M Stemmer, H A Burris, Y S Yap, G S Sonke, S Paluch-Shimon, M Campone, K Petrakova, K L Blackwell, E P Winer, W Janni, S Verma, P Conte, C L Arteaga, D A Cameron, S Mondal, F Su, M Miller, M Elmeliegy, C Germa, J O'Shaughnessy.

The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Davidoff Center, Rabin Medical Center, Tel Aviv University, Tel Aviv, Israel; Sarah Cannon Research Institute, Nashville, TN, USA; National Cancer Centre Singapore, Singapore; Netherlands Cancer Institute and BOOG Study Center, Amsterdam, the Netherlands; Sheba Medical Center, Ramat Gan, Israel; Institut de Cancérologie de l'Ouest/René Gauducheau, Saint-Herblain, France; Masaryk Memorial Cancer Institute, Brno, Czech Republic; Duke University Medical Center, Durham, NC, USA; Dana-Farber Cancer Institute, Boston, MA, USA; University of Ulm, Ulm, Germany; Tom Baker Cancer Centre, Calgary, Canada; University of Padua and Istituto Oncologico Veneto, IRCCS, Padua, Italy; Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, UK; Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.

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 (600mg/day; 3-weeks-on/1-week-off; 28-day treatment cycles) plus letrozole (2.5mg/day; continuous) or placebo plus letrozole. The primary endpoint was locally assessed PFS. The key secondary endpoint was overall survival (OS). Other secondary endpoints included overall response rate (ORR) and safety. Biomarker analysis was an exploratory endpoint.

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=9.63×10-8). 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.

CLINICAL TRIALS NUMBER: NCT01958021

KEYWORDS: ribociclib, CDK4/6 inhibitor, advanced breast cancer

DOI: 10.1093/annonc/mdy155

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