Stand Up to Cancer Phase Ib Study of Pan-Phosphoinositide-3-Kinase Inhibitor Buparlisib With Letrozole in Estrogen Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer
Stand Up to Cancer Phase Ib Study of Pan-Phosphoinositide-3-Kinase Inhibitor Buparlisib With Letrozole in Estrogen Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer
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DOI：
10.1200/jco.2013.54.0518
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发表时间：
2014-04-20
影响因子：
45.3
通讯作者：
Arteaga, Carlos L.
中科院分区：
文献类型：
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作者：
Mayer, Ingrid A.;Abramson, Vandana G.;Arteaga, Carlos L.
目的Buparlisib是一种口服可逆的I类磷酸肌醇-3-激酶抑制剂，在单独使用和与内分泌治疗联合使用时，对雌激素受体（ER）阳性乳腺癌细胞系和异种移植物显示出抗肿瘤活性。这Ib期研究评估buparlisib加来曲唑的安全性，耐受性，和初步活动在转移性ER阳性乳腺癌患者难治性内分泌therapy.Patients和方法患者接受来曲唑和buparlisib在两个不同的管理时间表。通过标准实体瘤I期方法评估结局。在基线和治疗开始后2周进行[F-18]氟脱氧葡萄糖-正电子发射断层扫描/计算机断层扫描（[F-18]FDG-PET/CT）。肿瘤块收集磷酸肌醇-3-激酶途径突变analysis.Results五十一例患者被分配到连续或间歇（五个/两个关闭天）buparlisib管理每4周的时间表。Buparlisib的最大耐受剂量（MTD）为100 mg/d。常见的药物相关不良事件包括2级高血糖、恶心、疲劳、转氨酶升高和情绪障碍。在MTD治疗的所有患者中，临床获益率（6个月无进展）为31%，包括连续剂量组中的2例客观缓解。在治疗12个月的7例患者中，3例患有PIK 3CA热点突变肿瘤。患者表现出代谢性疾病进展[F-18]FDG-PET/CT扫描在2 wk进展迅速therapeutic.Conclusion来曲唑和buparlisib组合是安全的，与可逆的毒性，无论时间表管理。观察到的临床活性与PIK 3CA突变状态无关。2周时[F-18]FDG-PET/CT扫描无代谢反应与疾病快速进展相关。buparlisib和内分泌治疗ER阳性乳腺癌患者的III期试验正在进行中。
Purpose Buparlisib, an oral reversible inhibitor of all class I phosphoinositide-3-kinases, has shown antitumoral activity against estrogen receptor (ER)-positive breast cancer cell lines and xenografts, alone and with endocrine therapy. This phase Ib study evaluated buparlisib plus letrozole's safety, tolerability, and preliminary activity in patients with metastatic ER-positive breast cancer refractory to endocrine therapy.Patients and Methods Patients received letrozole and buparlisib in two different administration schedules. Outcomes were assessed by standard solid-tumor phase I methods. [F-18]fluorodeoxyglucose-positron emission tomography/computed tomography ([F-18]FDG-PET/CT) scans were done at baseline and 2 weeks after treatment initiation. Tumor blocks were collected for phosphoinositide-3-kinase pathway mutation analysis.Results Fifty-one patients were allocated sequentially to continuous or intermittent (five on/two off days) buparlisib administration on an every-4-week schedule. Buparlisib's maximum-tolerated dose (MTD) was 100 mg/d. Common drug-related adverse events included grade 2 hyperglycemia, nausea, fatigue, transaminitis, and mood disorders. The clinical benefit rate (lack of progression 6 months) among all patients treated at the MTD was 31%, including two objective responses in the continuous dose arm. Of seven patients remaining on treatment 12 months, three had tumors with PIK3CA hot-spot mutation. Patients exhibiting metabolic disease progression by [F-18]FDG-PET/CT scan at 2 weeks progressed rapidly on therapy.Conclusion The letrozole and buparlisib combination was safe, with reversible toxicities regardless of schedule administration. Clinical activity was observed independent of PIK3CA mutation status. No metabolic response by [F-18]FDG-PET/CT scan at 2 weeks was associated with rapid disease progression. Phase III trials of buparlisib and endocrine therapy in patients with ER-positive breast cancer are ongoing.