Department of Internal Medicine, University of Kansas Medical Center, Westwood, Kansas.
Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
Clin Cancer Res. 2021 Jul 15;27(14):3896-3904. doi: 10.1158/1078-0432.CCR-20-4879. Epub 2021 Feb 18.
mutations are common in breast cancer and promote tumor progression and treatment resistance. We conducted a phase I/II trial of alpelisib (α-specific PI3K inhibitor) plus nab-paclitaxel in patients with HER2-negative metastatic breast cancer (MBC).
Eligible patients had HER2-negative MBC with any number of prior chemotherapies. Phase I was 3+3 dose-escalation design with three dose levels of alpelisib (250, 300, and 350 mg) daily plus nab-paclitaxel 100 mg/m administered on days 1, 8, and 15 every 28 days. Phase II was according to Simon's two-stage design. mutations in tumor/circulating tumor DNA (ctDNA) were assessed. Primary endpoints were recommended phase II dose (RP2D) and objective response rate (ORR). Additional endpoints included safety, pharmacokinetics, progression-free survival (PFS), and association of mutation with outcomes.
A total of 43 patients were enrolled (phase I, = 13 and phase II, = 30). A total of 84% had visceral disease and 84% had prior taxane. No dose-limiting toxicities occurred in phase I. RP2D was alpelisib 350 mg daily plus nab-paclitaxel 100 mg/m on days 1, 8, and 15. Hyperglycemia (grade 3, 26% and grade 4, 0%), neutropenia (grade 3, 23% and grade 4, 7%), diarrhea (grade 3, 5% and grade 4, 0%), and rash (grade 3, 7% and grade 4, 0%) were the most common adverse events. Among 42 evaluable patients, ORR was 59% (complete response, 7% and partial response, 52%), 21% of whom had response lasting >12 months; median PFS was 8.7 months. A total of 40% of patients demonstrated tumor and/or ctDNA mutation; patients with tumor/ctDNA mutation demonstrated better PFS compared with those without mutation (11.9 vs. 7.5 months; HR, 0.44; = 0.027). Patients with normal metabolic status had longer PFS compared with prediabetic/diabetic patients (12 vs. 7.5 months; = 0.014). No pharmacokinetics interactions were detected.
The alpelisib plus nab-paclitaxel combination was well tolerated and shows encouraging efficacy, especially in patients with -mutated tumor/ctDNA. The impact of metabolic status on response to this combination merits further investigation.
突变在乳腺癌中很常见，可促进肿瘤进展和治疗耐药。我们进行了一项 I/II 期试验，研究 alpelisib（α 特异性 PI3K 抑制剂）联合 nab-紫杉醇在 HER2 阴性转移性乳腺癌（MBC）患者中的应用。
符合条件的患者为 HER2 阴性 MBC，既往接受过任意数量的化疗。I 期采用 3+3 剂量递增设计，每日给予 alpelisib（250、300 和 350mg）三个剂量水平，联合 nab-紫杉醇 100mg/m2，于第 1、8 和 15 天给药，每 28 天一次。II 期根据 Simon 的两阶段设计进行。评估肿瘤/循环肿瘤 DNA（ctDNA）中的 突变。主要终点为推荐的 II 期剂量（RP2D）和客观缓解率（ORR）。其他终点包括安全性、药代动力学、无进展生存期（PFS）以及 突变与结局的相关性。
共纳入 43 例患者（I 期，n=13；II 期，n=30）。84%的患者有内脏疾病，84%的患者有既往紫杉烷类药物治疗。I 期未发生剂量限制性毒性。RP2D 为每日 alpelisib 350mg 联合 nab-紫杉醇 100mg/m2，于第 1、8 和 15 天给药。最常见的不良事件为高血糖（3 级，26%；4 级，0%）、中性粒细胞减少（3 级，23%；4 级，7%）、腹泻（3 级，5%；4 级，0%）和皮疹（3 级，7%；4 级，0%）。在 42 例可评估患者中，ORR 为 59%（完全缓解率，7%；部分缓解率，52%），其中 21%的患者缓解持续时间超过 12 个月；中位 PFS 为 8.7 个月。共有 40%的患者存在肿瘤和/或 ctDNA 突变；与无突变的患者相比，有突变的患者 PFS 更好（11.9 个月 vs. 7.5 个月；HR，0.44；P=0.027）。代谢状态正常的患者 PFS 长于 prediabetic/diabetic 患者（12 个月 vs. 7.5 个月；P=0.014）。未检测到药代动力学相互作用。
alpelisib 联合 nab-紫杉醇耐受性良好，疗效令人鼓舞，特别是在有 突变的肿瘤/ctDNA 患者中。代谢状态对该联合用药反应的影响值得进一步研究。
