Hematology and Medical Oncology, Weill Cornell Medicine, New York, New York.
Oncology Department, Hospital Universitario 12 de Octubre, Imas12, UCM, CNIO, CIBERONC, Madrid, Spain.
Cancer Res Commun. 2022 Nov 2;2(11):1326-1333. doi: 10.1158/2767-9764.CRC-22-0072. eCollection 2022 Nov.
To assess the preclinical efficacy, clinical safety and efficacy, and MTD of palbociclib plus nab-paclitaxel in patients with advanced pancreatic ductal adenocarcinoma (PDAC).
Preclinical activity was tested in patient-derived xenograft (PDX) models of PDAC. In the open-label, phase I clinical study, the dose-escalation cohort received oral palbociclib initially at 75 mg/day (range, 50‒125 mg/day; modified 3+3 design; 3/1 schedule); intravenous nab-paclitaxel was administered weekly for 3 weeks/28-day cycle at 100‒125 mg/m. The modified dose-regimen cohorts received palbociclib 75 mg/day (3/1 schedule or continuously) plus nab-paclitaxel (biweekly 125 or 100 mg/m, respectively). The prespecified efficacy threshold was 12-month survival probability of ≥65% at the MTD.
Palbociclib plus nab-paclitaxel was more effective than gemcitabine plus nab-paclitaxel in three of four PDX models tested; the combination was not inferior to paclitaxel plus gemcitabine. In the clinical trial, 76 patients (80% received prior treatment for advanced disease) were enrolled. Four dose-limiting toxicities were observed [mucositis ( = 1), neutropenia ( = 2), febrile neutropenia ( = 1)]. The MTD was palbociclib 100 mg for 21 of every 28 days and nab-paclitaxel 125 mg/m weekly for 3 weeks in a 28-day cycle. Among all patients, the most common all-causality any-grade adverse events were neutropenia (76.3%), asthenia/fatigue (52.6%), nausea (42.1%), and anemia (40.8%). At the MTD ( = 27), the 12-month survival probability was 50% (95% confidence interval, 29.9-67.2).
This study showed the tolerability and antitumor activity of palbociclib plus nab-paclitaxel treatment in patients with PDAC; however, the prespecified efficacy threshold was not met.
Pfizer Inc (NCT02501902).
In this article, the combination of palbociclib, a CDK4/6 inhibitor, and nab-paclitaxel in advanced pancreatic cancer evaluates an important drug combination using translational science. In addition, the work presented combines preclinical and clinical data along with pharmacokinetic and pharmacodynamic assessments to find alternative treatments for this patient population.
评估帕博西尼联合 nab-紫杉醇治疗晚期胰腺导管腺癌（PDAC）患者的临床前疗效、临床安全性和疗效以及最大耐受剂量（MTD）。
在 PDAC 的患者来源异种移植（PDX）模型中测试了临床前活性。在开放标签、I 期临床研究中，剂量递增队列最初每天口服帕博西尼 75 mg（范围 50-125 mg/天；改良 3+3 设计；3/1 方案）；静脉注射 nab-紫杉醇每周一次，每 28 天周期内使用 3 周，剂量为 100-125 mg/m。改良剂量方案队列接受每天 75 mg 的帕博西尼（3/1 方案或连续）加 nab-紫杉醇（分别为每 2 周 125 或 100 mg/m）。预定的疗效阈值是 MTD 时 12 个月生存率≥65%。
在四个经过测试的 PDX 模型中，有三个模型中帕博西尼联合 nab-紫杉醇比吉西他滨联合 nab-紫杉醇更有效；该联合方案与紫杉醇联合吉西他滨相比没有劣势。在临床试验中，共纳入 76 名患者（80%接受过晚期疾病的治疗）。观察到 4 例剂量限制毒性（=1 例粘膜炎，=2 例中性粒细胞减少症，=1 例发热性中性粒细胞减少症）。MTD 为帕博西尼 100 mg 每 28 天使用 21 天，每周 nab-紫杉醇 125 mg/m 静脉滴注 3 周，每 28 天一个周期。在所有患者中，最常见的任何病因的任何级别不良事件为中性粒细胞减少症（76.3%）、乏力/疲劳（52.6%）、恶心（42.1%）和贫血（40.8%）。在 MTD（=27）时，12 个月生存率为 50%（95%置信区间，29.9-67.2）。
本研究显示了帕博西尼联合 nab-紫杉醇治疗 PDAC 患者的耐受性和抗肿瘤活性；然而，未达到预定的疗效阈值。
辉瑞公司（NCT02501902）。
本文通过转化科学评估了 CDK4/6 抑制剂帕博西尼联合 nab-紫杉醇在晚期胰腺癌中的联合应用，为这一患者群体提供了替代治疗方法。此外，本研究结合了临床前和临床数据以及药代动力学和药效学评估，为这一药物组合提供了支持。
