Tolaney Sara M, Im Young-Hyuck, Calvo Emiliano, Lu Yen-Shen, Hamilton Erika, Forero-Torres Andres, Bachelot Thomas, Maur Michela, Fasolo Angelica, Tiedt Ralph, Nardi Lisa, Stammberger Uz, Abdelhady Ahmed M, Ruan Shiling, Lee Soo Chin
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Department of Medicine, Sungkyunkwan University, Seoul, South Korea.
Clin Cancer Res. 2021 Jan 15;27(2):418-428. doi: 10.1158/1078-0432.CCR-20-0645. Epub 2020 Sep 4.
Resistance to treatment with endocrine therapy in patients with HR, HER2 advanced breast cancer (ABC) is common and dual inhibition of CDK4/6 and PI3K pathways may delay the development of resistance. This phase Ib trial evaluates the safety and tolerability of triple and double regimens containing the CDK4/6 inhibitor ribociclib.
In this open-label, multicenter, phase Ib study, 70 postmenopausal women with HR, HER2 ABC were enrolled into one of four treatment combinations: ribociclib (once daily, 3 weeks on, 1 week off) plus fulvestrant; ribociclib (continuous dosing) plus fulvestrant; ribociclib plus alpelisib plus fulvestrant; or ribociclib plus buparlisib plus fulvestrant.
The recommended phase II dose (RP2D) of ribociclib was confirmed to be 600 mg (3 weeks on, 1 week off) and 400 mg (continuous dosing) plus fulvestrant 500 mg. For the triple combination with buparlisib, the RP2D was ribociclib 400 mg plus buparlisib 30 mg plus fulvestrant 500 mg. Enrollment for the triple combinations was stopped due to unexpected toxicity. No RP2D was determined for the alpelisib combination. The safety profiles of the ribociclib plus fulvestrant combinations were consistent with those in previous studies. There was no marked difference in ribociclib exposure in the presence of triple-combination partners. The highest overall response rate was seen in the buparlisib triple combination (25.0%; 95% confidence interval, 9.8-46.7).
Ribociclib plus fulvestrant demonstrated safety in the treatment of patients with HR, HER2 ABC. Triple combinations with alpelisib or buparlisib plus fulvestrant are not recommended for phase II investigation..
激素受体（HR）、人表皮生长因子受体2（HER2）阴性晚期乳腺癌（ABC）患者对内分泌治疗产生耐药很常见，对细胞周期蛋白依赖性激酶4/6（CDK4/6）和磷脂酰肌醇-3-激酶（PI3K）通路的双重抑制可能会延缓耐药的发展。这项Ib期试验评估了含CDK4/6抑制剂瑞博西尼的三联和双联方案的安全性和耐受性。
在这项开放标签、多中心的Ib期研究中，70名绝经后HR、HER2阴性ABC女性被纳入四种治疗组合之一：瑞博西尼（每日一次，服用3周，停药1周）加氟维司群；瑞博西尼（持续给药）加氟维司群；瑞博西尼加阿培利司加氟维司群；或瑞博西尼加布帕利昔加氟维司群。
瑞博西尼的推荐II期剂量（RP2D）确定为600mg（服用3周，停药1周）和400mg（持续给药）加500mg氟维司群。对于与布帕利昔的三联组合，RP2D为瑞博西尼400mg加布帕利昔30mg加氟维司群500mg。由于意外毒性，三联组合的入组停止。阿培利司组合未确定RP2D。瑞博西尼加氟维司群组合的安全性与既往研究一致。在三联组合伙伴存在的情况下，瑞博西尼的暴露量无明显差异。布帕利昔三联组合的总体缓解率最高（25.0%；95%置信区间，9.8-46.7）。
瑞博西尼加氟维司群在治疗HR、HER2阴性ABC患者中显示出安全性。不推荐阿培利司或布帕利昔加氟维司群的三联组合用于II期研究。
