Krishnamurthy Jairam, Luo Jingqin, Suresh Rama, Ademuyiwa Foluso, Rigden Caron, Rearden Timothy, Clifton Katherine, Weilbaecher Katherine, Frith Ashley, Roshal Anna, Tandra Pavan K, Cherian Mathew, Summa Tracy, Haas Brittney, Thomas Shana, Hernandez-Aya Leonel, Bergqvist Mattias, Peterson Lindsey, Ma Cynthia X
Division of Oncology/Hematology, University of Nebraska Medical Center, Omaha, NE, USA.
Division of Public Health Science, Department of Surgery, Siteman Cancer Center, Biostatistics Shared Resource, Washington University School of Medicine, St. Louis, MO, USA.
NPJ Breast Cancer. 2022 Mar 21;8(1):35. doi: 10.1038/s41523-022-00399-w.
Palbociclib 3-weeks-on/1-week-off, combined with hormonal therapy, is approved for hormone receptor positive (HR+)/HER2-negative (HER2-) advanced/metastatic breast cancer (MBC). Neutropenia is the most frequent adverse event (AE). We aim to determine whether an alternative 5-days-on/2-days-off weekly schedule reduces grade 3 and above neutropenia (G3 + ANC) incidence. In this single-arm phase II trial, patients with HR+/HER2- MBC received palbociclib 125 mg, 5-days-on/2-days-off, plus letrozole or fulvestrant per physician, on a 28-day cycle (C), as their first- or second-line treatment. The primary endpoint was G3 + ANC in the first 29 days (C1). Secondary endpoints included AEs, efficacy, and serum thymidine kinase 1 (sTK1) activity. At data-cutoff, fifty-four patients received a median of 13 cycles (range 2.6-43.5). The rate of G3 + ANC was 21.3% (95% CI: 11.2-36.1%) without G4 in C1, and 40.7% (95% CI: 27.9-54.9%), including 38.9% G3 and 1.8% G4, in all cycles. The clinical benefit rate was 80.4% (95% CI: 66.5-89.7%). The median progression-free survival (mPFS) (95% CI) was 19.75 (12.11-34.89), 33.5 (17.25-not reached [NR]), and 11.96 (10.43-NR) months, in the overall, endocrine sensitive or resistant population, respectively. High sTK1 at baseline, C1 day 15 (C1D15), and C2D1 were independently prognostic for shorter PFS (p = 9.91 × 10, 0.001, 0.007, respectively). sTK1 decreased on C1D15 (p = 4.03 × 10), indicating target inhibition. Rise in sTK1 predicted progression, with the median lead time of 59.5 (inter-quartile range: -206.25-0) days. Palbociclib, 5-days-on/2-days-off weekly, met its primary endpoint with reduced G3 + ANC, without compromising efficacy. sTK1 is prognostic and shows promise in monitoring the palbociclib response. ClinicalTrials.gov#: NCT3007979.
帕博西尼采用3周用药/1周停药方案，联合激素疗法，已被批准用于激素受体阳性（HR+）/人表皮生长因子受体2阴性（HER2-）的晚期/转移性乳腺癌（MBC）。中性粒细胞减少是最常见的不良事件（AE）。我们旨在确定另一种每周5天用药/2天停药的方案是否能降低3级及以上中性粒细胞减少（G3+中性粒细胞绝对值计数[ANC]）的发生率。在这项单臂II期试验中，HR+/HER2-MBC患者接受帕博西尼125毫克，每周5天用药/2天停药，再根据医生的选择加用来曲唑或氟维司群，每28天为一个周期（C），作为一线或二线治疗。主要终点是前29天（C1）内的G3+ANC。次要终点包括不良事件、疗效和血清胸苷激酶1（sTK1）活性。在数据截止时，54例患者接受的周期数中位数为13个周期（范围2.6-43.5）。C1期G3+ANC的发生率为21.3%（95%置信区间：11.2-36.1%），无4级病例，而在所有周期中为40.7%（95%置信区间：27.9-54.9%），其中3级占38.9%，4级占1.8%。临床获益率为80.4%（95%置信区间：66.5-89.7%）。总体、内分泌敏感或耐药人群的中位无进展生存期（mPFS）（95%置信区间）分别为19.75（12.11-34.89）、33.5（17.25-未达到[NR]）和11.96（10.43-NR）个月。基线、C1期第15天（C1D15）和C2期第1天（C2D1）时sTK1水平较高是PFS较短的独立预后因素（p分别为9.91×10、0.001、0.007）。C1D15时sTK1水平下降（p=4.03×10），表明靶点受到抑制。sTK1升高预示疾病进展，中位提前期为59.5（四分位间距：-206.25-0）天。帕博西尼每周5天用药/2天停药方案达到了其主要终点，即降低了G3+ANC，且不影响疗效。sTK1具有预后价值，在监测帕博西尼反应方面显示出前景。临床试验注册号：NCT3007979。
