Rugo Hope S, Lerebours Florence, Ciruelos Eva, Drullinsky Pamela, Ruiz-Borrego Manuel, Neven Patrick, Park Yeon Hee, Prat Aleix, Bachelot Thomas, Juric Dejan, Turner Nicholas, Sophos Nickolas, Zarate Juan Pablo, Arce Christina, Shen Yu-Ming, Turner Stuart, Kanakamedala Hemanth, Hsu Wei-Chun, Chia Stephen
University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
Institut Curie, Saint-Cloud, France.
Lancet Oncol. 2024 Dec;25(12):e629-e638. doi: 10.1016/S1470-2045(24)00673-9.
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.
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.
Between Aug 14, 2017, and Jul 29, 2022 (data cutoff), 127 patients with at least 18 months' follow-up were enrolled into cohort A. 119 patients had a centrally confirmed PIK3CA mutation. At data cutoff, median follow-up was 21·8 months (IQR 10·8-37·6). 64 (53·8%; 95% CI 44·4-63·0) of 119 patients were alive without disease progression at 6 months. The most frequent grade 3 or worse adverse events were hyperglycaemia (37 [29%] of 127 patients), rash (13 [10%]), and rash maculopapular (11 [9%]). Serious adverse events occurred in 37 (29%) of 127 patients. No treatment-related deaths were reported.
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.
Novartis Pharmaceuticals.
Alpelisib是一种PI3Kα选择性抑制剂和降解剂，与氟维司群联合应用在SOLAR-1研究中显示出对激素受体阳性、人表皮生长因子受体2（HER2）阴性、PIK3CA突变的晚期乳腺癌有效；在细胞周期蛋白依赖性激酶4/6（CDK4/6）抑制剂治疗后的相关数据有限。BYLieve旨在评估Alpelisib联合内分泌治疗在根据既往直接治疗定义的三个队列中的疗效；在此，我们报告队列A的结果。
这项正在进行的2期多中心、开放标签、非对照研究，纳入了来自全球18个国家114个研究地点（癌症中心、医学中心、大学医院和医院）的激素受体阳性、HER2阴性、晚期乳腺癌且肿瘤存在PIK3CA突变的患者，这些患者在包括CDK4/6抑制剂在内的既往治疗期间或之后病情进展。年龄18岁及以上、东部肿瘤协作组体能状态为2或更低、既往抗癌治疗不超过两种且既往化疗方案不超过一种的参与者被纳入三个队列。在队列A中，患者必须在CDK4/6抑制剂加芳香化酶抑制剂作为既往直接治疗期间或之后病情进展。患者在每28天周期的第1天以及第1周期的第15天接受口服Alpelisib 300mg/天（持续服用）加氟维司群500mg肌肉注射。主要终点是根据实体瘤疗效评价标准1.1版，在经中心确认存在PIK3CA突变的患者中，经当地评估6个月时无疾病进展存活的患者比例。本试验已在ClinicalTrials.gov注册，注册号为NCT03056755。
在2017年8月14日至2022年7月29日（数据截止）期间，127例至少随访18个月的患者被纳入队列A。119例患者经中心确认存在PIK3CA突变。在数据截止时，中位随访时间为21.8个月（四分位间距10.8 - 37.6）。119例患者中有64例（53.8%；95%置信区间44.4 - 63.0）在6个月时无疾病进展存活。最常见的3级或更严重不良事件为高血糖（127例患者中的37例[29%]）、皮疹（13例[10%]）和斑丘疹（11例[9%]）。127例患者中有37例（29%）发生严重不良事件。未报告与治疗相关的死亡。
BYLieve研究显示，在CDK4/6抑制剂加芳香化酶抑制剂治疗后病情进展的PIK3CA突变型、激素受体阳性、HER2阴性晚期乳腺癌患者中，Alpelisib联合氟维司群具有活性且毒性可控。
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