雌激素受体阳性乳腺癌耐药新疗法
磷脂肌醇3-激酶（PI3K）是重要的生长因子信号转导通路之一，可活化细胞质膜成分磷脂肌醇，使蛋白激酶B（PKB或AKT）由细胞质定位于细胞膜，继而被磷酸化激活，参与信号转导，对细胞的存活和增殖起重要的作用。PI3K通路激活常见于雌激素受体阳性、内分泌治疗耐药的乳腺癌患者。
2019年2月14日，《美国医学会杂志》肿瘤学分册正式发表哈佛大学医学院、麻省总医院癌症中心、德克萨斯大学MD安德森癌症中心、范德堡大学英格拉姆癌症中心、莎拉坎农研究所、纽约纪念医院斯隆凯特林癌症中心、诺华生物医学研究中心、旧金山加利福尼亚大学海伦迪勒家族综合癌症中心、西班牙巴塞罗那大学瓦尔德希布伦肿瘤研究所、加泰罗尼亚肿瘤研究所、德国癌症联盟、西德癌症中心、埃森大学医院、维尔茨堡大学医院、美茵法兰肯综合癌症中心、班贝格社保基金会、英国牛津大学丘吉尔医院癌症中心、瑞士诺华的研究报告，评定了口服PI3Kα特异抑制剂阿尔卑利昔（BYL719、阿吡利塞、阿培利司）＋氟维司群用于雌激素受体阳性晚期乳腺癌患者的最大耐受剂量、安全性和活性。
CBYL719X2101: A Study of BYL719 in Adult Patients With Advanced Solid Malignancies, Whose Tumors Have an Alteration of the PIK3CA Gene (NCT01219699)
该国际多中心非盲单组1b期研究于2010年10月5日～2017年3月22日从5个国家10个中心入组PIK3CA突变型或野生型雌激素受体阳性晚期乳腺癌抗雌激素治疗期间或之后疾病进展的87例绝经后女性（年龄中位58岁、范围37～79岁，既往抗肿瘤治疗：中位5线、范围1～16线）。剂量递增阶段：阿尔卑利昔从每天300毫克开始递增剂量（9例300毫克、8例350毫克、70例400毫克）＋氟维司群每天500毫克固定剂量；剂量扩大阶段：阿尔卑利昔2期推荐剂量＋氟维司群。主要研究终点为阿尔卑利昔＋氟维司群的最大耐受剂量。次要终点包括安全性和初步活性。
结果，剂量递增期间，报告限制剂量毒性反应患者1例（阿尔卑利昔400毫克时：2级腹泻，3级呕吐、疲劳和食欲减退）。
联合氟维司群的阿尔卑利昔最大耐受剂量为每天400毫克、2期推荐剂量为每天300毫克。
总体而言，阿尔卑利昔每天400毫克时，无论因果关系、发生率≥10%的最常见3～4级不良事件：高血糖19例（22%）、斑丘疹11例（13%），由于不良事件而永久停药患者9例。
阿尔卑利昔最大耐受剂量的中位无进展生存5.4个月（95%置信区间：4.6～9.0个月）。
阿尔卑利昔每天300→400毫克＋氟维司群的中位无进展生存：
PIK3CA突变型：9.1个月（95%置信区间：6.6～14.6个月）
PIK3CA野生型：4.7个月（95%置信区间：1.9～5.6个月）
肿瘤客观缓解率：
PIK3CA突变型：29%（95%置信区间：17%～43%）
PIK3CA野生型：0
因此，该研究结果表明，对于雌激素受体阳性晚期乳腺癌患者，阿尔卑利昔＋氟维司群的安全性可控，PIK3CA突变型与野生型相比，临床效果更好。
相关阅读
JAMA Oncol. 2019 Feb 14;5(2):e184475.
Alpelisib Plus Fulvestrant in PIK3CA-Altered and PIK3CA-Wild-Type Estrogen Receptor-Positive Advanced Breast Cancer: A Phase 1b Clinical Trial.
Juric D, Janku F, Rodón J, Burris HA, Mayer IA, Schuler M, Seggewiss-Bernhardt R, Gil-Martin M, Middleton MR, Baselga J, Bootle D, Demanse D, Blumenstein L, Schumacher K, Huang A, Quadt C, Rugo HS.
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston; The University of Texas MD Anderson Cancer Center, Houston; Vall d'Hebron Institute of Oncology, Barcelona, Spain; Sarah Cannon Research Institute, Tennessee Oncology Professional Limited Liability Corporation, Nashville; Vanderbilt-Ingram Cancer Center, Nashville, Tennessee; West German Cancer Center, University Hospital Essen, Essen, German Cancer Consortium, Germany; University Hospital Würzburg, Würzburg, Germany; SozialStiftung Bamberg, Bamberg, Germany; Catalan Institute of Oncology-Bellvitge Biomedical Research Institute, Barcelona, Spain; Churchill Hospital Cancer Centre, Oxford, United Kingdom; Memorial Sloan-Kettering Cancer Center, New York, New York; Vall d'Hebron Institute of Oncology, Cellex Center, Barcelona, Spain; Novartis Pharma AG, Basel, Switzerland; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts; Tango Therapeutics, Cambridge, Massachusetts; University of California at San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco.
This phase 1b clinical trial evaluates the dose response and safety of alpelisib plus fulvestrant treatment in women with advanced breast cancer.
QUESTION: Is alpelisib, an oral α-specific phosphatidylinositol-3-kinase inhibitor, plus fulvestrant tolerable, and is there evidence of differential activity in patients with PIK3CA-altered vs PIK3CA-wild-type, estrogen receptor-positive advanced breast cancer that has progressed during or after antiestrogen therapies?
FINDINGS: In this phase 1b clinical trial of 87 women, alpelisib plus fulvestrant had a manageable safety profile with the alpelisib maximum tolerated dose of 400 mg and a recommended phase 2 dose of 300 mg once daily. Median progression-free survival was longer (9.1 vs 4.7 months) and objective response rate was higher (29% vs 0%) in patients with PIK3CA-altered vs PIK3CA-wild-type tumors.
MEANING: Oral α-specific phosphatidylinositol-3-kinase inhibition is a promising treatment strategy in estrogen receptor-positive PIK3CA-altered advanced breast cancer.
IMPORTANCE: The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in patients with estrogen receptor-positive (ER+), endocrine therapy-resistant breast cancers.
OBJECTIVE: To assess the maximum tolerated dose (MTD), safety, and activity of alpelisib, an oral, PI3Kα-specific inhibitor, plus fulvestrant in patients with ER+ advanced breast cancer (ABC).
DESIGN, SETTING, AND PARTICIPANTS: An open-label, single-arm, phase 1b study of alpelisib plus fulvestrant was conducted at 10 centers in 5 countries. Participants were 87 postmenopausal women with PIK3CA-altered or PIK3CA-wild-type ER+ ABC, whose cancer progressed during or after antiestrogen therapy. The study began enrolling patients October 5, 2010, and the data cutoff was March 22, 2017.
INTERVENTIONS: Escalating doses of alpelisib were administered once daily, starting at 300 mg, plus fixed-dose fulvestrant, 500 mg, in the dose-escalation phase; alpelisib at the recommended phase 2 dose plus fulvestrant in the dose-expansion phase.
MAIN OUTCOMES AND MEASURES: The primary end point was determination of the MTD of once-daily alpelisib plus fulvestrant. Secondary end points included safety and preliminary activity.
RESULTS: From October 5, 2010, to March 22, 2017, 87 women (median age: 58 years [range, 37-79 years]; median of 5 prior lines of antineoplastic therapy) received escalating once-daily doses of alpelisib (300 mg, n=9; 350 mg, n=8; 400 mg, n=70) plus fixed-dose fulvestrant (500 mg). During dose escalation, dose-limiting toxic effects were reported in 1 patient (alpelisib, 400 mg): diarrhea (grade 2), vomiting, fatigue, and decreased appetite (all grade 3). The MTD of alpelisib when combined with fulvestrant was 400 mg once daily, and the recommended phase 2 dose was 300 mg once daily. Overall, the most frequent grade 3/4 adverse events with alpelisib, 400 mg, once daily (≥10% of patients), regardless of causality, were hyperglycemia (19 [22%]) and maculopapular rash (11 [13%]); 9 patients permanently discontinued therapy owing to adverse events. Median progression-free survival at the MTD was 5.4 months (95% CI, 4.6-9.0 months). Median progression-free survival with alpelisib, 300 to 400 mg, once daily plus fulvestrant was longer in patients with PIK3CA-altered tumors (9.1 months; 95% CI, 6.6-14.6 months) vs wild-type tumors (4.7 months; 95% CI, 1.9-5.6 months). Overall response rate in the PIK3CA-altered group was 29% (95% CI, 17%-43%), with no objective tumor responses in the wild-type group.
CONCLUSIONS AND RELEVANCE: Alpelisib plus fulvestrant has a manageable safety profile in patients with ER+ ABC, and data suggest that this combination may have greater clinical activity in PIK3CA-altered vs wild-type tumors.
TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01219699
PMID: 30543347
DOI: 10.1001/jamaoncol.2018.4475
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