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对于激素受体阳性HER2阴性晚期乳腺癌患者，首选内分泌治疗，但是起效较慢，如果症状严重、病变进展快速、内脏衰竭需要快速控制病变或者早期内分泌治疗耐药，联合化疗仍然被指南推荐为一线治疗方案，例如多西他赛＋卡培他滨、紫杉醇＋吉西他滨、卡培他滨＋长春瑞滨，起效速度和有效率都优于单药化疗，但是不良事件发生率较高。而且，激素受体阳性乳腺癌与激素受体阴性乳腺癌相比，化疗效果通常较差。因此，对于此类患者，需要正确选择起效快速、疗效持久、同时避免联合化疗相关毒性的一线治疗方案。 MONALEESA-7研究已经证实，对于激素受体阳性HER2阴性晚期乳腺癌绝经前女性患者，细胞周期蛋白依赖性激酶CDK4/6抑制剂瑞波西利联合内分泌与单用内分泌一线治疗相比，有效率显著较高，无进展生存和总生存显著获益，目前已经成为一线治疗标准方案。不过，肿瘤较大较多、内脏转移症状广泛或者内脏功能衰竭患者被排除在这些研究之外。对于激素受体阳性HER2阴性晚期乳腺癌，也从未头对头比较过CDK4/6抑制剂＋内分泌治疗与联合化疗的有效性和安全性。 2024年5月21日，美国临床肿瘤学会官方期刊《临床肿瘤学杂志》在线发表中国台湾大学医院、台南成功大学医院、马来西亚吉隆坡医院、砂拉越中心医院、苏丹依斯迈医院、埃及开罗大学国家癌症研究院、土耳其阿西巴登大学医院、埃格大学医学院、安卡拉医科大学、新加坡国立癌症中心、韩国首尔大学医学院、越南国立癌症医院、印度居里肿瘤中心基德瓦伊纪念肿瘤研究院、俄罗斯圣彼得堡欧洲医疗中心、瑞士诺华、美国诺华、黎巴嫩贝鲁特美国大学医学中心的正确选择（RIGHT Choice）研究最终结果报告全文，首次对瑞波西利＋内分泌治疗与联合化疗一线治疗激素受体阳性HER2阴性晚期乳腺癌绝经前或围绝经女性临床高危患者的有效性和安全性进行头对头比较。该研究中位随访24.1个月初步结果已于2022年12月第45届圣安东尼奥乳腺癌大会公布，引起广泛关注。此次2024年5月15日《临床肿瘤学杂志》收稿，时隔6天就在线发表抢先预览版，也相当罕见。 RIGHT Choice (NCT03839823): Study to Compare the Combination of Ribociclib Plus Goserelin Acetate With Hormonal Therapy Versus Combination Chemotherapy in Premenopausal or Perimenopausal Patients With Advanced or Metastatic Breast Cancer (Official Title: A Phase II Randomized Study of the Combination of Ribociclib Plus Goserelin Acetate With Hormonal Therapy Versus Physician Choice Chemotherapy in Premenopausal or Perimenopausal Patients With Hormone Receptor-positive/ HER2-negative Inoperable Locally Advanced or Metastatic Breast Cancer) 该国际多中心非盲随机对照二期临床研究于2019年3月4日至2021年11月16日从全球13个国家或地区入组激素受体阳性HER2阴性晚期乳腺癌绝经前或围绝经女性临床高危患者222例，其中150例（67.6%）患者出现有症状的内脏转移，41例（18.5%）患者根据研究者判断出现快速病变进展，31例（14.0%）患者出现有症状的非内脏转移。总体而言，106例（47.7%）患者存在研究者评定的内脏危象。将患者按1∶1随机分为两组接受两种一线治疗方案：其中112例给予瑞波西利（每天600毫克，用药3周，停药1周）＋来曲唑或阿那曲唑＋戈舍瑞林，其余110例给予研究者选择的联合化疗方案（多西他赛＋卡培他滨、紫杉醇＋吉西他滨、卡培他滨＋长春瑞滨）。主要研究终点为无进展生存。 
结果，中位随访37.0个月，数据截止时，31.3%（瑞波西利组）和15.5%（联合化疗组）的患者已经完成研究治疗并且转为研究后治疗。 瑞波西利＋内分泌治疗与联合化疗相比： 中位无进展生存：21.8个月比12.8个月（95%置信区间：17.4～26.7、10.1～18.4个月） 进展或死亡风险：降低39%（风险比：0.61，95%置信区间：0.43～0.87，P=0.003） 总有效率：66.1%比61.8% 中位起效时间：4.9个月比3.2个月（风险比：0.76，95%置信区间：0.55～1.06） 有症状不良事件发生率：较低
因此，该研究结果表明，对于激素受体阳性HER2阴性晚期乳腺癌临床高危患者，瑞波西利＋内分泌治疗与联合化疗相比，无进展生存获益显著、有效率和起效时间相似、有症状不良事件发生率较低、耐受性较好，有望取代联合化疗成为一线治疗正确选择，故有必要进一步开展大样本随机对照研究进行验证。 相关链接 J Clin Oncol. 2024 May 21. IF: 45.3Final results of RIGHT Choice: Ribociclib plus endocrine therapy vs combination chemotherapy in premenopausal women with clinically aggressive HR+/HER2- advanced breast cancer.Lu YS, Bin Mohd Mahidin EI, Azim H, Eralp Y, Yap YS, Im SA, Rihani J, Gokmen E, El Bastawisy A, Karadurmus N, Lim YN, Lim CS, Duc LT, Chung WP, Babu KG, Penkov K, Bowles J, Alfaro TD, Wu J, Gao M, Slimane K, El Saghir NS.National Taiwan University Hospital, Taipei, Taiwan, China; National Cheng Kung University, Tainan, Taiwan, China; Hospital Kuala Lumpur, Kuala Lumpur, Malaysia; Sarawak General Hospital, Kuching, Sarawak, Malaysia; Hospital Sultan Ismail, Johor Bharu, Johor Darul Ta'zim, Malaysia; Cairo University, Cairo, Egypt; National Cancer Institute, Cairo University, Egypt; Acibadem University, Istanbul, Turkey; Ege University Faculty of Medicine, Izmir, Turkey; University of Health Sciences, Ankara, Turkey; National Cancer Centre Singapore, Singapore; Seoul National University College of Medicine, Seoul, Korea; Independent Patient Advocate, Amman, Jordan; National Cancer Hospital, Hanoi, Vietnam; HCG Curie Centre of Oncology and Kidwai Memorial Institute of Oncology, Bangalore, India; Private Medical Institution Euromedservice, St Petersburg, Russian; Novartis Pharma AG, Basel, Switzerland; Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; American University of Beirut Medical Center, Beirut, Lebanon.PURPOSE: A head-to-head comparison of efficacy between a cyclin-dependent kinase 4/6 inhibitor plus endocrine therapy (ET) versus combination chemotherapy (CT) has never been reported in patients with clinically aggressive hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC).PATIENTS AND METHODS: In this open-label, multi-center, randomized phase 2 trial, pre/perimenopausal women with clinically aggressive HR+/HER2- ABC were randomized 1:1 to first-line ribociclib (600 mg daily; 3-weeks-on, 1-week-off) plus letrozole/anastrozole and goserelin or investigator's choice of combination CT (docetaxel plus capecitabine, paclitaxel plus gemcitabine, or capecitabine plus vinorelbine). The primary endpoint was progression-free survival (PFS).RESULTS: Among 222 patients randomized to ribociclib plus ET (n=112) or combination CT (n=110), 150 (67.6%) had symptomatic visceral metastases, 41 (18.5%) had rapid disease progression per investigator's judgment, and 31 (14.0%) had symptomatic non-visceral disease. Overall, 106 (47.7%) patients had investigator-assessed visceral crisis. Median follow-up time was 37.0 months. At data cutoff, 31.3% (ribociclib arm) and 15.5% (CT arm) of patients had completed study treatment and transitioned to post-trial access. The median PFS was 21.8 months (ribociclib plus ET; 95% CI, 17.4-26.7 months) and 12.8 months (combination CT; 95% CI, 10.1-18.4 months); hazard ratio [HR], 0.61; 95% CI, 0.43-0.87; P=.003. The overall response rates and the median time to response in the ribociclib versus CT arms, respectively, were 66.1% and 61.8% and 4.9 months and 3.2 months (HR, 0.76; 95% CI, 0.55-1.06). Lower rates of symptomatic adverse events were observed in the ribociclib versus CT arm.CONCLUSIONS: First-line ribociclib plus ET showed a significant PFS benefit, similar response rates, and better tolerability over combination CT in patients with clinically aggressive HR+/HER2- ABC.KEY OBJECTIVE: Can a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET) be used instead of combination chemotherapy (CT) for treating patients with clinically aggressive hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC), in which combination CT is typically used to achieve a rapid response?KNOWLEDGE GENERATED: This first ever prospective head-to-head comparison between a CDK4/6i (ribociclib) plus ET, and combination CT showed improved progression-free survival, similar response rates, and lower symptomatic adverse event rates with ribociclib plus ET versus combination CT in patients with clinically aggressive HR+/HER2- ABC.RELEVANCE: The 'conventional wisdom' that patients with visceral disease need chemotherapy even if ER+ should be retired.KEYWORDS: advanced breast cancer; combination chemotherapy; cyclin-dependent kinases 4 and 6 inhibitors; endocrine therapy; ribociclibDOI: 10.1200/JCO.24.00144
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