The Netherlands Cancer Institute, PO Box 90203, 1006 BE, Amsterdam, The Netherlands.
Amsterdam UMC, location VUmc, PO Box 7057, 1007 MB, Amsterdam, The Netherlands.
BMC Cancer. 2018 Nov 20;18(1):1146. doi: 10.1186/s12885-018-4978-1.
Combining cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors with endocrine therapy is an effective strategy to improve progression-free survival in hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. There is a lack of comparative data to help clinicians decide if CDK4/6 inhibitors can best be added to first- or second-line endocrine therapy. Improvement in median progression-free survival in first-line studies is larger than in second-line studies, but CDK4/6 inhibitors have not consistently shown to improve overall survival or quality of life. They do come with added toxicity and costs, and many patients have lasting disease remission on endocrine therapy alone. No subgroup has been identified to select patients who are most likely to benefit from the addition of CDK4/6 inhibition in any line of treatment. Altogether, these factors make that the optimal strategy for using CDK4/6 inhibitors in clinical practice is unknown.
The SONIA study is an investigator-initiated, multicenter, randomized phase III study in patients with HR+/HER2-negative advanced breast cancer. Patients are randomly assigned to receive either strategy A (first-line treatment with a non-steroidal aromatase inhibitor combined with CDK4/6 inhibition, followed on progression by fulvestrant) or strategy B (first-line treatment with a non-steroidal aromatase inhibitor, followed on progression by fulvestrant combined with CDK4/6 inhibition). The primary objective is to test whether strategy A is more effective than strategy B. The primary endpoint is time from randomization to second objective progression (PFS2). Secondary endpoints include overall survival, safety, quality of life, and cost-effectiveness. Five-hundred seventy-four events yield 89% power to show that strategy A has statistically significant, clinically meaningful superior PFS2 (according to ESMO-MCBS) in a log-rank test at the two-sided 95% confidence level. Given an accrual period of 42 months and an additional 18 months follow-up, inclusion of 1050 evaluable patients is required.
This study design represents daily clinical practice, and the results will aid clinicians in deciding when adding CDK4/6 inhibitors to endocrine therapy will benefit their patients most. Additional biomarker analyses may help to optimize patient selection.
http://clinicaltrials.gov: NCT03425838 (8 February 2018). EudraCT-number: 2017-002334-23 (29 September 2017).
联合细胞周期蛋白依赖性激酶 4 和 6（CDK4/6）抑制剂与内分泌治疗是改善激素受体阳性（HR+）、人表皮生长因子受体 2（HER2）阴性晚期乳腺癌无进展生存期的有效策略。缺乏比较数据来帮助临床医生确定 CDK4/6 抑制剂是否最好添加到一线或二线内分泌治疗中。一线研究中中位无进展生存期的改善大于二线研究，但 CDK4/6 抑制剂并未一致显示改善总生存期或生活质量。它们确实带来了额外的毒性和成本，许多患者单独接受内分泌治疗就可以持久缓解疾病。没有确定亚组来选择最有可能从任何一线治疗中添加 CDK4/6 抑制中获益的患者。总而言之，这些因素使得 CDK4/6 抑制剂在临床实践中的最佳策略尚不清楚。
SONIA 研究是一项由研究者发起的、多中心、随机 III 期研究，入组 HR+/HER2-阴性晚期乳腺癌患者。患者随机分配接受方案 A（一线治疗采用非甾体类芳香化酶抑制剂联合 CDK4/6 抑制剂，进展后改用氟维司群）或方案 B（一线治疗采用非甾体类芳香化酶抑制剂，进展后改用氟维司群联合 CDK4/6 抑制剂）。主要目的是检验方案 A 是否比方案 B 更有效。主要终点是从随机分组到第二次客观进展的时间（PFS2）。次要终点包括总生存期、安全性、生活质量和成本效益。需要 574 例事件，才能以双侧 95%置信区间的对数秩检验显示方案 A 在 ESMO-MCBS 中有统计学意义的、临床上有意义的 PFS2 显著改善（根据 ESMO-MCBS），把握度为 89%。考虑到入组期为 42 个月，外加 18 个月随访期，需要纳入 1050 例可评估患者。
这种研究设计代表了日常临床实践，研究结果将有助于临床医生决定何时将 CDK4/6 抑制剂添加到内分泌治疗中最能使患者受益。额外的生物标志物分析可能有助于优化患者选择。
http://clinicaltrials.gov：NCT03425838（2018 年 8 月 8 日）。EudraCT 编号：2017-002334-23（2017 年 9 月 29 日）。
