编者按:癌症常见磷脂酰肌醇-3-羟激酶(PI3K)失调,其大多由于PI3K催化亚基p110α蛋白编码基因PIK3CA扩增或突变激活引起。PIK3CA突变为实体肿瘤最常见的变化之一,分别占子宫内膜癌的42%~55%、宫颈癌的42%,乳腺癌的27%~36%、结直肠癌的18%、头颈部癌的13%、卵巢癌的12%。因此,PI3K靶向治疗对于PIK3CA改变型癌症特别有效。瑞士诺华的阿尔卑利昔(BYL719)为口服选择性p110α抑制剂,对p110α、β、γ、δ的50%最大抑制浓度(体外生化测定)分别为4.6、1156、250、290nM,对于多种癌细胞株和肿瘤异种移植模型具有抗肿瘤活性,尤其对于携带PIK3CA突变或扩增模型,突显PIK3CA改变型肿瘤患者临床效果可能增强。
2018年2月5日,美国临床肿瘤学会《临床肿瘤学杂志》在线发表美国麻省总医院、诺华生物医学研究中心、德克萨斯大学MD安德森癌症中心、萨拉·坎农研究所、田纳西肿瘤专科网络、范德堡大学、旧金山加利福尼亚大学、美国诺华、纽约纪念医院斯隆-凯特林癌症中心、西班牙巴塞罗那自治大学瓦尔·希伯伦医院和肿瘤研究所、加泰罗尼亚肿瘤研究院和贝尔维戈生物医学研究所、荷兰癌症研究所、英国国家卫生研究院、丘吉尔医院、牛津生物医学研究中心、德国癌症联盟、西德癌症中心、杜伊斯堡埃森大学、埃森大学医院、维尔茨堡大学医院、美茵弗兰肯综合癌症中心、瑞士诺华的首次人体研究最终结果报告,探讨了阿尔卑利昔单药治疗PIK3CA改变型晚期实体肿瘤患者、PIK3CA改变型和野生型雌激素受体(ER)阳性且人表皮生长因子受体2(HER2)阴性乳腺癌患者的最大耐受剂量、安全性和初步疗效。
该多中心非盲Ia期研究(NCT01219699)于2010年10月~2014年3月从11个中心入组患者134例:
中位年龄59岁(范围:21~82)
女性98例(73%)
男性36例(27%)
乳腺癌36例(26.9%)
大肠癌35例(26.1%)
头颈癌19例(14.2%)
卵巢癌14例(10.4%)
其他癌30例(22.4%)
PIK3CA改变型:125例(93.3%)
PIK3CA野生型:7例(5.2%)
PIK3CA未知型:2例(1.5%)
该研究分为两个阶段:
剂量递增阶段(76例)PIK3CA改变型晚期实体肿瘤患者连续接受口服阿尔卑利昔每天一次或两次,确定最大耐受剂量为每天一次400mg或每天两次150mg。
剂量固定阶段(51例)PIK3CA改变型晚期实体肿瘤、PIK3CA野生型ER阳性且HER2阴性乳腺癌患者接受阿尔卑利昔每天一次400mg。
剂量递增阶段发生剂量限制性毒性反应9例,占13.2%。其中:
高血糖6例
恶心2例
高血糖且低血磷1例
常见所有级别治疗相关不良事件包括:
高血糖(51.5%)
恶心(50.0%)
食欲下降(41.8%)
腹泻(40.3%)
呕吐(31.3%)
阿尔卑利昔吸收迅速;每天一次400mg的半衰期为7.6小时,体内蓄积极少。
肿瘤客观缓解见于剂量≥每天一次270mg,共8例,占6.0%,其中:
完全缓解1例(子宫内膜癌)
部分缓解7例(宫颈癌3例、乳腺癌1例、子宫内膜癌1例、结肠癌1例、直肠癌1例)。
疾病稳定70例(52.2%),疾病稳定保持>24周13例(9.7%);疾病控制率为58.2%。
晚期乳腺癌患者27例,其中肿瘤缩小15例(55.6%,大多数为PIK3CA突变型ER阳性且HER2阴性病变,2例肿瘤缩小25.0%和23.5%)。22例ER阳性且HER2阴性乳腺癌患者的中位无进展生存5.5个月(95%置信区间:3.0~7.0)。
常见(≥10%)突变基因包括:
TP53(51.3%)
APC(23.7%)
KRAS(22.4%)
ARID1A(13.2%)
FBXW7(10.5%)
因此,对于PIK3CA改变型实体肿瘤患者,阿尔卑利昔的安全性可以耐受,初步疗效令人鼓舞,为选择性PI3Kα抑制剂联合其他药物治疗PIK3CA突变肿瘤奠定了基础。
编者按:由于阿尔卑利昔300mg每天一次与400mg每天一次相比,耐受性提高且有效性相似,氟维司群±阿尔卑利昔300mg每天一次治疗芳香酶抑制剂耐药晚期乳腺癌患者的III期研究(SOLAR-1,NCT02437318)已于2015年7月23日启动,预计2018年5月31日抵达主要终点、2020年4月15日抵达全部终点。
J Clin Oncol. 2018 Feb 5. [Epub ahead of print]
Phosphatidylinositol 3-Kinase α-Selective Inhibition With Alpelisib (BYL719) in PIK3CA-Altered Solid Tumors: Results From the First-in-Human Study.
Dejan Juric, Jordi Rodon, Josep Tabernero, Filip Janku, Howard A. Burris, Jan H.M. Schellens, Mark R. Middleton, Jordan Berlin, Martin Schuler, Marta Gil-Martin, Hope S. Rugo, Ruth Seggewiss-Bernhardt, Alan Huang, Douglas Bootle, David Demanse, Lars Blumenstein, Christina Coughlin, Cornelia Quadt, José Baselga.
Massachusetts General Hospital Cancer Center, Boston; Novartis Institutes for BioMedical Research, Cambridge, MA; Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona; Catalan Institute of Oncology - Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain; The University of Texas MD Anderson Cancer Center, Houston, TX; Sarah Cannon Research Institute and Tennessee Oncology; Vanderbilt-Ingram Cancer Center, Nashville, TN; Netherlands Cancer Institute, Amsterdam, the Netherlands; National Institute for Health Research, Oxford Biomedical Research Centre, Churchill Hospital, Oxford, United Kingdom; West German Cancer Center, University Duisburg-Essen, and German Cancer Consortium, Partner Site University Hospital Essen, Essen; Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, Würzburg, Germany; University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; Novartis Pharma AG, Basel, Switzerland; Novartis Pharmaceuticals Corporation, East Hanover, NJ; Memorial Sloan Kettering Cancer Center, New York, NY.
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.
PMID: 29401002
DOI: 10.1200/JCO.2017.72.7107
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