Tolaney Sara, Burris Howard, Gartner Elaina, Mayer Ingrid A, Saura Cristina, Maurer Matthew, Ciruelos Eva, Garcia Agustin A, Campana Frank, Wu Bin, Xu Yi, Jiang Jason, Winer Eric, Krop Ian
Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA,
Breast Cancer Res Treat. 2015 Jan;149(1):151-61. doi: 10.1007/s10549-014-3248-4. Epub 2014 Dec 24.
This phase I/II dose-escalation study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, and efficacy of the pan-class I phosphoinositide 3-kinase inhibitor pilaralisib in combination with trastuzumab (Arm 1) or trastuzumab plus paclitaxel (Arm 2) in patients with HER2-positive metastatic breast cancer. Patients had progressed on prior trastuzumab (Arms 1 and 2) and received prior taxane (Arm 2). The MTD of pilaralisib was determined using a 3 + 3 dose-escalation design (starting dose 200 mg once daily). Forty-two patients were enrolled (21 in each arm). Five patients had a dose-limiting toxicity (DLT; three in Arm 1 and two in Arm 2). Dose-limiting toxicities were rash (three patients) and neutropenia (two patients). The MTD of pilaralisib was determined at 400 mg once daily in both arms. The most frequently reported treatment-related adverse events (AEs) were diarrhea (23.8 % in Arm 1 vs. 66.7 % in Arm 2), fatigue (14.3 vs. 42.9 %), and rash (33.3 vs. 38.1 %). The most frequently reported treatment-related grade ≥3 AEs were erythematous rash (9.5 %) in Arm 1 and diarrhea, peripheral neuropathy, and neutropenia (14.3 % each) in Arm 2. Steady-state pilaralisib exposure was similar to previous studies with pilaralisib monotherapy. No responses occurred in Arm 1; four of 20 evaluable patients (20 %) in Arm 2 had a partial response. Observed PIK3CA mutations in cell-free circulating DNA did not correlate with response. Pilaralisib in combination with trastuzumab with or without paclitaxel had an acceptable safety profile in metastatic HER2-positive breast cancer, with clinical activity in the paclitaxel arm.
这项I/II期剂量递增研究调查了泛I类磷酸肌醇3激酶抑制剂哌柏西利与曲妥珠单抗联合使用（第1组）或曲妥珠单抗加紫杉醇联合使用（第2组）治疗HER2阳性转移性乳腺癌患者时的最大耐受剂量（MTD）、安全性、药代动力学和疗效。患者既往接受曲妥珠单抗治疗后病情进展（第1组和第2组），且第2组患者既往接受过紫杉烷治疗。采用3 + 3剂量递增设计（起始剂量为每日一次200 mg）确定哌柏西利的MTD。共入组42例患者（每组21例）。5例患者出现剂量限制性毒性（DLT；第1组3例，第2组2例）。剂量限制性毒性为皮疹（3例患者）和中性粒细胞减少（2例患者）。两组中哌柏西利的MTD均确定为每日一次400 mg。最常报告的与治疗相关的不良事件（AE）为腹泻（第1组为23.8%，第2组为66.7%）、疲劳（14.3%对42.9%）和皮疹（33.3%对38.1%）。最常报告的与治疗相关的≥3级AE在第1组为红斑性皮疹（9.5%），在第2组为腹泻、周围神经病变和中性粒细胞减少（各14.3%）。哌柏西利的稳态暴露与既往哌柏西利单药治疗研究相似。第1组未出现缓解；第2组20例可评估患者中有4例（20%）出现部分缓解。在游离循环DNA中观察到的PIK3CA突变与缓解无关。哌柏西利联合曲妥珠单抗加或不加紫杉醇在转移性HER2阳性乳腺癌中具有可接受的安全性，且在紫杉醇组具有临床活性。
