Department of Medicine, Division of Hematology/Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
Clin Cancer Res. 2019 Apr 1;25(7):2072-2079. doi: 10.1158/1078-0432.CCR-18-0790. Epub 2019 Jan 11.
The CDK 4/6 inhibitor palbociclib rapidly and reversibly inhibits the cell cycle. The goal of this study was to exploit the cell cycle through intermittent, alternating dosing with palbociclib/paclitaxel to enhance efficacy. We determined the combination dose-limiting toxicity (DLT) in patients with Rb protein-expressing, advanced breast cancer.
This open-label, phase I trial (NCT01320592) enrolled patients to sequential cohorts of palbociclib orally dosed intermittently between days 1 and 19 of a 28-day cycle alternating with weekly paclitaxel. Dose escalation proceeded in a standard 3 + 3 design. Ten additional patients received the combination at the recommended phase II dose (RP2D). Those who reached response plateau ≥6 cycles could continue on palbociclib alone on a 3 week on/1 week off schedule at one dose level above their combination dose.
Twenty-seven patients enrolled. Although there was only 1 DLT (grade 3 alanine aminotransferase/aspartate aminotransferase at 125 mg), neutropenia (NTP) requiring dose modification in cycle 1 (C1) resulted in an RP2D of 75 mg palbociclib/80 mg/m paclitaxel. During C1, the most common adverse event was NTP, occurring in 15 patients (55.6%); grade 1 or 2 nausea and peripheral neuropathy were also observed in 8 patients each (29.6%). The clinical benefit rate was 55% at the RP2D; benefit was observed across all receptor subtypes.
Alternating sequential palbociclib/paclitaxel in patients with Rb advanced breast cancer is feasible and safe, without evidence of additive toxicity. This represents a new application for CDK 4/6 inhibitors in Rb breast cancer regardless of subtype; efficacy trials are warranted.
CDK4/6 抑制剂帕博西尼可快速、可逆地抑制细胞周期。本研究的目的是通过间歇性交替给予帕博西尼/紫杉醇来利用细胞周期，从而提高疗效。我们确定了表达 Rb 蛋白的晚期乳腺癌患者的联合剂量限制毒性（DLT）。
这项开放标签、I 期临床试验（NCT01320592）纳入了连续队列的患者，这些患者在 28 天周期的第 1 天至第 19 天之间间歇性口服帕博西尼给药，与每周紫杉醇交替。剂量递增采用标准的 3+3 设计。另外 10 名患者接受了推荐的 II 期剂量（RP2D）的联合治疗。达到反应平台≥6 个周期的患者可以继续使用帕博西尼，剂量水平高于联合剂量，方案为每 3 周使用 1 周停药。
共纳入 27 例患者。虽然只有 1 例 DLT（125mg 时为 3 级丙氨酸氨基转移酶/天冬氨酸氨基转移酶），但中性粒细胞减少症（NTP）需要在第 1 周期（C1）中调整剂量，导致 RP2D 为 75mg 帕博西尼/80mg/m 紫杉醇。在 C1 期间，最常见的不良反应是 NTP，发生在 15 例患者（55.6%）中；8 例患者各有 1 或 2 级恶心和周围神经病变。在 RP2D 时，临床获益率为 55%；在所有受体亚型中均观察到获益。
在表达 Rb 的晚期乳腺癌患者中，交替序贯给予帕博西尼/紫杉醇是可行且安全的，没有证据表明毒性增加。这代表了 CDK4/6 抑制剂在 Rb 乳腺癌中的新应用，无论亚型如何；有必要进行疗效试验。
