The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Seoul National University Hospital, Cancer Research Institute, and Seoul National University College of Medicine, Seoul, South Korea.
Lancet Oncol. 2018 Jul;19(7):904-915. doi: 10.1016/S1470-2045(18)30292-4. Epub 2018 May 24.
In MONALEESA-2, ribociclib plus letrozole showed improved progression-free survival compared with letrozole alone as first-line treatment for postmenopausal patients with hormone receptor (HR)-positive, HER2-negative, advanced breast cancer. MONALEESA-7 aimed to assess the efficacy and safety of ribociclib plus endocrine therapy in premenopausal women with advanced, HR-positive breast cancer.
This phase 3, randomised, double-blind, placebo-controlled trial was done at 188 centres in 30 countries. Eligible patients were premenopausal women aged 18-59 years who had histologically or cytologically confirmed HR-positive, HER2-negative, advanced breast cancer; an Eastern Cooperative Oncology Group performance status of 0 or 1; measurable disease as per Response Evaluation Criteria in Solid Tumors version 1.1 criteria, or at least one predominantly lytic bone lesion; and had not received previous treatment with cyclin-dependent kinases 4 and 6 inhibitors. Endocrine therapy and chemotherapy in the adjuvant or neoadjuvant setting was permitted, as was up to one line of chemotherapy for advanced disease. Patients were randomly assigned (1:1) via interactive response technology to receive oral ribociclib (600 mg/day on a 3-weeks-on, 1-week-off schedule) or matching placebo with either oral tamoxifen (20 mg daily) or a non-steroidal aromatase inhibitor (letrozole 2·5 mg or anastrozole 1 mg, both oral, daily), all with goserelin (3·6 mg administered subcutaneously on day 1 of every 28-day cycle). Patients and investigators were masked to treatment assignment. Efficacy analyses were by intention to treat, and safety was assessed in all patients who received at least one dose of any study treatment. The primary endpoint was investigator-assessed progression-free survival. MONALEESA-7 is registered with ClinicalTrials.gov, NCT02278120 and is ongoing, but no longer enrolling patients.
Between Dec 17, 2014, and Aug 1, 2016, 672 patients were randomly assigned: 335 to the ribociclib group and 337 to the placebo group. Per investigator's assessment, median progression-free survival was 23·8 months (95% CI 19·2-not reached) in the ribociclib group compared with 13·0 months (11·0-16·4) in the placebo group (hazard ratio 0·55, 95% CI 0·44-0·69; p<0·0001). Grade 3 or 4 adverse events reported in more than 10% of patients in either group were neutropenia (203 [61%] of 335 patients in the ribociclib group and 12 [4%] of 337 in the placebo group) and leucopenia (48 [14%] and four [1%]). Serious adverse events occurred in 60 (18%) of 335 patients in the ribociclib group and 39 (12%) of 337 in the placebo group, of which 15 (4%) and six (2%), respectively, were attributed to the study regimen. 12 (4%) of 335 patients in the ribociclib group and ten (3%) of 337 in the placebo group discontinued treatment because of adverse events. No treatment-related deaths occurred. 11 deaths occurred (five [1%] in the ribociclib group and six [2%] in the placebo group) during or within 30 days after treatment, most of which were due to progression of the underlying breast cancer (three [1%] and six [2%]). The remaining two deaths in the ribociclib group were due to an intracranial haemorrhage in an anticoagulated patient, and a pre-existing wound haemorrhage in another patient.
Ribociclib plus endocrine therapy improved progression-free survival compared with placebo plus endocrine therapy, and had a manageable safety profile in patients with premenopausal, HR-positive, HER2-negative, advanced breast cancer. The combination could represent a new first-line treatment option for these patients.
Novartis.
在 MONALEESA-2 中，与单独使用来曲唑相比，接受瑞博西利联合来曲唑治疗的绝经后激素受体（HR）阳性、HER2 阴性、晚期乳腺癌患者的无进展生存期得到了改善。MONALEESA-7 旨在评估瑞博西利联合内分泌治疗在绝经前 HR 阳性、HER2 阴性、晚期乳腺癌患者中的疗效和安全性。
这是一项在 30 个国家的 188 个中心进行的、3 期、随机、双盲、安慰剂对照试验。符合条件的患者为年龄在 18-59 岁之间的绝经前女性，组织学或细胞学确认 HR 阳性、HER2 阴性、晚期乳腺癌；东部肿瘤协作组体能状态为 0 或 1；根据实体瘤反应评价标准 1.1 版标准可测量疾病，或至少有一处主要溶骨性病变；且未接受过细胞周期蛋白依赖性激酶 4 和 6 抑制剂治疗。辅助或新辅助内分泌治疗和化疗是允许的，晚期疾病也可接受最多一线化疗。患者通过交互式反应技术以 1:1 的比例随机分配接受口服瑞博西利（600 mg/天，3 周/1 周停药方案）或匹配安慰剂，联合口服他莫昔芬（20 mg/天）或非甾体芳香化酶抑制剂（来曲唑 2.5 mg 或阿那曲唑 1 mg，均为口服，每天一次），所有患者均接受戈舍瑞林（每 28 天周期第 1 天皮下注射 3.6 mg）。患者和研究者对治疗分配均设盲。疗效分析采用意向治疗，对至少接受过任何研究治疗剂量的所有患者进行安全性评估。主要终点为研究者评估的无进展生存期。MONALEESA-7 在 ClinicalTrials.gov 注册，NCT02278120 号，正在进行中，但不再入组患者。
2014 年 12 月 17 日至 2016 年 8 月 1 日期间，共纳入 672 例患者，随机分为瑞博西利组 335 例和安慰剂组 337 例。根据研究者评估，瑞博西利组中位无进展生存期为 23.8 个月（95%CI 19.2-未达到），安慰剂组为 13.0 个月（11.0-16.4）（风险比 0.55，95%CI 0.44-0.69；p<0.0001）。两组中报告的不良事件发生率超过 10%的不良事件包括中性粒细胞减少症（瑞博西利组 335 例中有 203 例[61%]，安慰剂组 337 例中有 12 例[4%]）和白细胞减少症（瑞博西利组 335 例中有 48 例[14%]，安慰剂组 337 例中有 4 例[1%]）。瑞博西利组 335 例患者中有 60 例（18%）和安慰剂组 337 例患者中有 39 例（12%）发生严重不良事件，其中分别有 15 例（4%）和 6 例（2%）归因于研究方案。瑞博西利组 335 例患者中有 12 例（4%）和安慰剂组 337 例患者中有 10 例（3%）因不良事件停止治疗。无治疗相关死亡。治疗期间或治疗后 30 天内发生 11 例死亡（瑞博西利组 5 例[1%]，安慰剂组 6 例[2%]），其中大多数与基础乳腺癌进展有关（瑞博西利组 3 例[1%]，安慰剂组 6 例[2%]）。瑞博西利组剩余的两例死亡归因于抗凝患者的颅内出血和另一例患者的伤口出血。
与安慰剂联合内分泌治疗相比，瑞博西利联合内分泌治疗改善了无进展生存期，在 HR 阳性、HER2 阴性、晚期乳腺癌的绝经前患者中具有可管理的安全性。该联合治疗方案可能为这些患者提供一种新的一线治疗选择。
诺华公司。
