Dejan Juric, Massachusetts General Hospital Cancer Center, Boston; Alan Huang, Novartis Institutes for BioMedical Research, Cambridge, MA; Jordi Rodon and Josep Tabernero, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona; Marta Gil-Martin, Catalan Institute of Oncology - Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain; Filip Janku, The University of Texas MD Anderson Cancer Center, Houston, TX; Howard A. Burris, Sarah Cannon Research Institute and Tennessee Oncology; Jordan Berlin, Vanderbilt-Ingram Cancer Center, Nashville, TN; Jan H.M. Schellens, Netherlands Cancer Institute, Amsterdam, the Netherlands; Mark R. Middleton, National Institute for Health Research, Oxford Biomedical Research Centre, Churchill Hospital, Oxford, United Kingdom; Martin Schuler, West German Cancer Center, University Duisburg-Essen, and German Cancer Consortium, Partner Site University Hospital Essen, Essen; Ruth Seggewiss-Bernhardt, Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, Würzburg, Germany; Hope S. Rugo, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; Douglas Bootle, David Demanse, Lars Blumenstein, and Cornelia Quadt, Novartis Pharma AG, Basel, Switzerland; Christina Coughlin, Novartis Pharmaceuticals Corporation, East Hanover, NJ; and José Baselga, Memorial Sloan Kettering Cancer Center, New York, NY.
J Clin Oncol. 2018 May 1;36(13):1291-1299. doi: 10.1200/JCO.2017.72.7107. Epub 2018 Feb 5.
Purpose 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. Patients and Methods 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. Results 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%). Conclusion 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.
目的 我们报告了首例人体 Ia 期研究（ClinicalTrials.gov 标识符：NCT01219699），确定了最大耐受剂量，并评估了单一药物 alpelisib（BYL719）的安全性和初步疗效，alpelisib 是一种口服磷脂酰肌醇 3-激酶 α（PI3Kα）选择性抑制剂。
方法 在剂量递增阶段，接受过治疗的 PIK3CA 改变的晚期实体瘤患者接受每日一次或两次口服 alpelisib 连续治疗。在剂量扩展阶段，PIK3CA 改变的实体瘤和 PIK3CA 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 400mg 每日一次。
结果 共有 134 名患者接受了治疗。alpelisib 的最大耐受剂量确定为每日一次 400mg 和每日两次 150mg。剂量递增阶段有 9 名患者（13.2%）发生剂量限制毒性，包括高血糖（n=6）、恶心（n=2）和高血糖伴低磷血症（n=1）。常见的所有级别、与治疗相关的不良事件包括高血糖（51.5%）、恶心（50.0%）、食欲下降（41.8%）、腹泻（40.3%）和呕吐（31.3%）。alpelisib 吸收迅速；每日一次 400mg 时半衰期为 7.6 小时，几乎没有蓄积。在剂量≥270mg 时观察到肿瘤客观缓解；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%）患者病情稳定超过 24 周；疾病控制率（完全和部分缓解及病情稳定）为 58.2%。在雌激素受体阳性/人表皮生长因子受体 2 阴性乳腺癌患者中，中位无进展生存期为 5.5 个月。常见突变基因（≥10%肿瘤）包括 TP53（51.3%）、APC（23.7%）、KRAS（22.4%）、ARID1A（13.2%）和 FBXW7（10.5%）。
结论 alpelisib 在 PIK3CA 改变的实体瘤患者中显示出可耐受的安全性和令人鼓舞的初步疗效，支持选择性 PI3Kα 抑制与其他药物联合用于治疗 PIK3CA 突变肿瘤的原理。
