Phosphatidylinositol 3-Kinase α-Selective Inhibition With Alpelisib (BYL719) in PIK3CA-Altered Solid Tumors: Results From the First-in-Human Study.
Phosphatidylinositol 3-Kinase α-Selective Inhibition With Alpelisib (BYL719) in PIK3CA-Altered Solid Tumors: Results From the First-in-Human Study.
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DOI：
10.1200/jco.2017.72.7107
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发表时间：
2018-05-01
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影响因子：
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通讯作者：
Baselga J
中科院分区：
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作者：
Juric D;Rodon J;Tabernero J;Janku F;Burris HA;Schellens JHM;Middleton MR;Berlin J;Schuler M;Gil-Martin M;Rugo HS;Seggewiss-Bernhardt R;Huang A;Bootle D;Demanse D;Blumenstein L;Coughlin C;Quadt C;Baselga J
我们报告了据我们所知的首次人体Ia期研究（ClinicalTrials.gov标识符：NCT 01219699），确定了单药alpelisib（BYL 719）的最大耐受剂量并评估了其安全性和初步疗效，这是一种口服磷脂酰肌醇3-激酶α（PI 3 K α）选择性抑制剂。在剂量递增阶段，患有PIK 3CA改变的晚期实体瘤的患者按连续时间表接受每日一次或每日两次口服alpelisib。在剂量扩展阶段，PIK 3CA改变的实体瘤和PIK 3CA野生型、雌激素受体阳性/人表皮生长因子受体2阴性乳腺癌患者接受alpelisib 400 mg每日一次治疗。134名患者接受了治疗。Alpelisib最大耐受剂量确定为400 mg每日一次和150 mg每日两次。剂量递增阶段的9例患者（13.2%）出现剂量限制性毒性，包括高血糖症（n = 6）、恶心（n = 2）以及高血糖症和低磷血症（n = 1）。常见的所有级别的治疗相关不良事件包括高血糖症（51.5%）、恶心（50.0%）、食欲下降（41.8%）、腹泻（40.3%）和呕吐（31.3%）。Alpelisib被迅速吸收; 400 mg每日一次的半衰期为7.6小时，蓄积最小。在≥ 270 mg每日一次剂量下观察到客观肿瘤缓解;总缓解率为6.0%（n = 8; 1例子宫内膜癌患者完全缓解，7例宫颈癌、乳腺癌、子宫内膜癌、结肠癌和直肠癌患者部分缓解）。70例（52.2%）患者病情稳定，13例（9.7%）患者病情维持> 24周;疾病控制率（完全和部分缓解以及病情稳定）为58.2%。雌激素受体阳性/人表皮生长因子受体2阴性乳腺癌患者的中位无进展生存期为5.5个月。常见突变基因（≥ 10%肿瘤）包括TP 53（51.3%）、APC（23.7%）、KRAS（22.4%）、ARID 1A（13.2%）和FBXW 7（10.5%）。Alpelisib在PIK 3CA改变的实体瘤患者中表现出可耐受的安全性特征和令人鼓舞的初步活性，支持选择性PI 3 K α抑制与其他药物联合治疗PIK 3CA突变型肿瘤的基本原理。
We report the first-in-human phase Ia study to our knowledge (ClinicalTrials.gov identifier: NCT01219699) identifying the maximum tolerated dose and assessing safety and preliminary efficacy of single-agent alpelisib (BYL719), an oral phosphatidylinositol 3-kinase α (PI3Kα)–selective inhibitor. In the dose-escalation phase, patients with PIK3CA-altered advanced solid tumors received once-daily or twice-daily oral alpelisib on a continuous schedule. In the dose-expansion phase, patients with PIK3CA-altered solid tumors and PIK3CA-wild-type, estrogen receptor–positive/human epidermal growth factor receptor 2–negative breast cancer received alpelisib 400 mg once daily. One hundred thirty-four patients received treatment. Alpelisib maximum tolerated doses were established as 400 mg once daily and 150 mg twice daily. Nine patients (13.2%) in the dose-escalation phase had dose-limiting toxicities of hyperglycemia (n = 6), nausea (n = 2), and both hyperglycemia and hypophosphatemia (n = 1). Frequent all-grade, treatment-related adverse events included hyperglycemia (51.5%), nausea (50.0%), decreased appetite (41.8%), diarrhea (40.3%), and vomiting (31.3%). Alpelisib was rapidly absorbed; half-life was 7.6 hours at 400 mg once daily with minimal accumulation. Objective tumor responses were observed at doses ≥ 270 mg once daily; overall response rate was 6.0% (n = 8; one patient with endometrial cancer had a complete response, and seven patients with cervical, breast, endometrial, colon, and rectal cancers had partial responses). Stable disease was achieved in 70 (52.2%) patients and was maintained > 24 weeks in 13 (9.7%) patients; disease control rate (complete and partial responses and stable disease) was 58.2%. In patients with estrogen receptor–positive/human epidermal growth factor receptor 2–negative breast cancer, median progression-free survival was 5.5 months. Frequently mutated genes (≥ 10% tumors) included TP53 (51.3%), APC (23.7%), KRAS (22.4%), ARID1A (13.2%), and FBXW7 (10.5%). Alpelisib demonstrated a tolerable safety profile and encouraging preliminary activity in patients with PIK3CA-altered solid tumors, supporting the rationale for selective PI3Kα inhibition in combination with other agents for the treatment of PIK3CA-mutant tumors.