Ingrid A. Mayer, Vandana G. Abramson, Justin M. Balko, María Gabriela Kuba, Melinda E. Sanders, and Carlos L. Arteaga, Vanderbilt University, Nashville, TN; Steven J. Isakoff, Massachusetts General Hospital, Boston, MA; Andres Forero, University of Alabama, Birmingham, AL; Jeffrey T. Yap, Huntsman Cancer Institute, Salt Lake City, UT; Annick D. Van den Abbeele and Eric Winer, Dana-Farber Cancer Institute, Boston, MA; Yisheng Li, MD Anderson Cancer Center, Houston, TX; and Lewis C. Cantley, Weill Cornell Medical College, New York, NY.
J Clin Oncol. 2014 Apr 20;32(12):1202-9. doi: 10.1200/JCO.2013.54.0518. Epub 2014 Mar 24.
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 received letrozole and buparlisib in two different administration schedules. Outcomes were assessed by standard solid-tumor phase I methods. [(18)F]fluorodeoxyglucose-positron emission tomography/computed tomography ([(18)F]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.
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 [(18)F]FDG-PET/CT scan at 2 weeks progressed rapidly on therapy.
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 [(18)F]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.
Buparlisib 是一种口服可逆的所有 I 类磷酸肌醇-3-激酶抑制剂，已显示出对雌激素受体（ER）阳性乳腺癌细胞系和异种移植物的抗肿瘤活性，单独使用和与内分泌治疗联合使用均有效果。这项 Ib 期研究评估了 buparlisib 加 letrozole 对内分泌治疗耐药的转移性 ER 阳性乳腺癌患者的安全性、耐受性和初步疗效。
患者接受 letrozole 和 buparlisib 两种不同的给药方案。采用标准实体瘤 I 期方法评估结果。在治疗开始后 2 周进行 [(18)F]氟脱氧葡萄糖正电子发射断层扫描/计算机断层扫描（[(18)F]FDG-PET/CT）扫描。收集肿瘤块进行磷酸肌醇-3-激酶通路突变分析。
51 例患者按序接受连续或间歇（每 5 天/2 天停药）给药方案的 buparlisib 给药，每 4 周一次。buparlisib 的最大耐受剂量（MTD）为 100mg/d。常见的药物相关不良反应包括≤2 级高血糖、恶心、疲劳、转氨酸升高和情绪障碍。在接受 MTD 治疗的所有患者中，临床获益率（无进展≥6 个月）为 31%，其中连续剂量组有 2 例客观缓解。在继续治疗≥12 个月的 7 例患者中，有 3 例肿瘤有 PIK3CA 热点突变。在 2 周时通过 [(18)F]FDG-PET/CT 扫描显示代谢疾病进展的患者在治疗上进展迅速。
letrozole 和 buparlisib 联合治疗安全，无论给药方案如何，毒性均可逆转。临床活性与 PIK3CA 突变状态无关。在 2 周时通过 [(18)F]FDG-PET/CT 扫描无代谢反应与疾病快速进展有关。正在进行 buparlisib 和内分泌治疗联合治疗 ER 阳性乳腺癌的 III 期试验。
