阿培利司联合氟维司群治疗 CDK4/6 抑制剂治疗后 PI3KCA 突变、激素受体阳性的晚期乳腺癌（BYLieve）：一项多中心、开放标签、非对照、2 期研究的一个队列。
Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): one cohort of a phase 2, multicentre, open-label, non-comparative study.
机构信息
University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
Institut Curie, Saint-Cloud, France.
出版信息
Lancet Oncol. 2021 Apr;22(4):489-498. doi: 10.1016/S1470-2045(21)00034-6.
BACKGROUND
Alpelisib, a PI3Kα-selective inhibitor and degrader, plus fulvestrant showed efficacy in hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer in SOLAR-1; limited data are available in the post-cyclin-dependent kinase 4/6 inhibitor setting. BYLieve aimed to assess alpelisib plus endocrine therapy in this setting in three cohorts defined by immediate previous treatment; here, we report results from cohort A.
METHODS
This ongoing, phase 2, multicentre, open-label, non-comparative study enrolled patients with hormone receptor-positive, HER2-negative, advanced breast cancer with tumour PIK3CA mutation, following progression on or after previous therapy, including CDK4/6 inhibitors, from 114 study locations (cancer centres, medical centres, university hospitals, and hospitals) in 18 countries worldwide. Participants aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 2 or less, with no more than two previous anticancer treatments and no more than one previous chemotherapy regimen, were enrolled in three cohorts. In cohort A, patients must have had progression on or after a CDK4/6 inhibitor plus an aromatase inhibitor as the immediate previous treatment. Patients received oral alpelisib 300 mg/day (continuously) plus fulvestrant 500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1. The primary endpoint was the proportion of patients alive without disease progression at 6 months per local assessment using Response Evaluation Criteria in Solid Tumors, version 1.1, in patients with a centrally confirmed PIK3CA mutation. This trial is registered with ClinicalTrials.gov, NCT03056755.
FINDINGS
Between Aug 14, 2017, and Dec 17, 2019 (data cutoff), 127 patients with at least 6 months' follow-up were enrolled into cohort A. 121 patients had a centrally confirmed PIK3CA mutation. At data cutoff, median follow-up was 11·7 months (IQR 8·5-15·9). 61 (50·4%; 95% CI 41·2-59·6) of 121 patients were alive without disease progression at 6 months. The most frequent grade 3 or worse adverse events were hyperglycaemia (36 [28%] of 127 patients), rash (12 [9%]), and rash maculopapular (12 [9%]). Serious adverse events occurred in 33 (26%) of 127 patients. No treatment-related deaths were reported.
INTERPRETATION
BYLieve showed activity of alpelisib plus fulvestrant with manageable toxicity in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer, after progression on a CDK4/6 inhibitor plus an aromatase inhibitor.
FUNDING
Novartis Pharmaceuticals.
背景
Alpelisib 是一种 PI3Kα 选择性抑制剂和降解剂，与氟维司群联合治疗激素受体阳性、HER2 阴性、PIK3CA 突变的晚期乳腺癌在 SOLAR-1 研究中显示出疗效；在细胞周期蛋白依赖性激酶 4/6 抑制剂之后的背景下，该药物的数据有限。BYLieve 旨在评估 Alpelisib 联合内分泌治疗在这一背景下的疗效，该研究分为三个队列，队列 A 纳入了符合以下条件的患者：在之前的治疗中进展或进展后，接受过 CDK4/6 抑制剂治疗，包括在 18 个国家/地区的 114 个研究地点（癌症中心、医疗中心、大学医院和医院）入组了接受过 CDK4/6 抑制剂加芳香化酶抑制剂治疗的激素受体阳性、HER2 阴性、晚期乳腺癌患者，这些患者肿瘤存在 PIK3CA 突变，并且在之前的治疗中进展或进展后。
方法
这是一项正在进行的、多中心、开放标签、非对照的 2 期研究，共纳入了来自全球 18 个国家/地区的 114 个研究地点（癌症中心、医疗中心、大学医院和医院）的 127 名患者，这些患者在之前的治疗中进展或进展后，接受过 CDK4/6 抑制剂加芳香化酶抑制剂治疗，存在激素受体阳性、HER2 阴性、晚期乳腺癌，肿瘤存在 PIK3CA 突变，并且 ECOG 体能状态为 2 或以下，在之前的治疗中接受过不超过两种抗癌治疗，在之前的化疗方案中接受过不超过一种化疗方案。在队列 A 中，患者必须在 CDK4/6 抑制剂加芳香化酶抑制剂治疗后进展。患者接受口服 Alpelisib 300 mg/天（连续）加氟维司群 500 mg，每 28 天周期的第 1 天和第 1 周期的第 15 天肌内注射。主要终点是在有中心确认的 PIK3CA 突变的患者中，根据实体瘤反应评估标准 1.1（Response Evaluation Criteria in Solid Tumors, version 1.1），在经过 6 个月的局部评估后，无疾病进展的患者比例。该试验在 ClinicalTrials.gov 上注册，NCT03056755。
结果
从 2017 年 8 月 14 日至 2019 年 12 月 17 日（数据截止），共有 127 名至少有 6 个月随访的患者入组队列 A。其中 121 名患者有中心确认的 PIK3CA 突变。数据截止时，中位随访时间为 11.7 个月（IQR 8.5-15.9）。在 121 名患者中，有 61 名（50.4%；95%CI 41.2-59.6）在 6 个月时无疾病进展。最常见的 3 级或更高级别的不良事件是高血糖（36 名患者，占 28%）、皮疹（12 名患者，占 9%）和皮疹斑丘疹（12 名患者，占 9%）。33 名患者（26%）发生严重不良事件。没有与治疗相关的死亡报告。
解释
BYLieve 显示，在接受 CDK4/6 抑制剂加芳香化酶抑制剂治疗后进展的 PIK3CA 突变、激素受体阳性、HER2 阴性晚期乳腺癌患者中，Alpelisib 联合氟维司群具有可管理的毒性和疗效。
资助
诺华制药公司。
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