A Phase Ib Dose-Escalation and Expansion Study of the BCL2 Inhibitor Venetoclax Combined with Tamoxifen in ER and BCL2-Positive Metastatic Breast Cancer
A Phase Ib Dose-Escalation and Expansion Study of the BCL2 Inhibitor Venetoclax Combined with Tamoxifen in ER and BCL2-Positive Metastatic Breast Cancer
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DOI：
10.1158/2159-8290.cd-18-1151
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发表时间：
2019-03-01
期刊：
影响因子：
28.2
通讯作者：
Lindeman, Geoffrey J.
中科院分区：
文献类型：
--
作者：
Lok, Sheau W.;Whittle, James R.;Lindeman, Geoffrey J.
文奈德是一种有效和选择性的bcl2抑制剂，在ER阳性乳腺癌的临床前模型中与内分泌治疗具有协同作用。采用Ib3+3期剂量递增和扩展研究设计，33例ER和BCL2阳性转移性疾病患者(以前的方案平均2个，范围0~8个月)接受三苯氧胺(20 Mg)和万乃洛(200~800 mg)每日治疗。除了不复杂的“靶向”淋巴细胞减少，在升级阶段(15名患者)没有观察到剂量限制性毒性或高度不良事件，800毫克被选为推荐的II期剂量(RP2D)。在扩展阶段(18名患者)，几乎没有观察到与高级治疗相关的不良事件。在RP2D治疗的24名患者中，确认的放射学应答率为54%，临床受益率为75%。治疗反应在4周时被代谢反应(FDG-PET)抢先，并与循环肿瘤DNA的一系列变化相关。在10名血浆检测到ESR1基因突变的患者中，观察到了放射学反应(40%)和临床受益(70%)。意义：在第一项评估静脉滴注治疗实体瘤的临床研究中，我们证明了静脉滴注与内分泌治疗相结合具有可耐受的安全性，并在ER和BCL2阳性的转移性乳腺癌中引起显著的活性。这些发现支持对bcl2阳性肿瘤患者进行联合治疗的进一步研究。
Venetoclax, a potent and selective BCL2 inhibitor, synergizes with endocrine therapy in preclinical models of ER-positive breast cancer. Using a phase Ib 3 + 3 dose-escalation and expansion study design, 33 patients with ER and BCL2-positive metastatic disease (mean prior regimens, 2; range, 0-8) were treated with daily tamoxifen (20 mg) and venetoclax (200-800 mg). Apart from uncomplicated "on-target" lymphopenia, no dose-limiting toxicities or high-grade adverse events were observed in the escalation phase (15 patients), and 800 mg was selected as the recommended phase II dose (RP2D). In the expansion phase (18 patients), few high-grade treatment-related adverse events were observed. For 24 patients treated at the RP2D, the confirmed radiologic response rate was 54% and the clinical benefit rate was 75%. Treatment responses were preempted by metabolic responses (FDG-PET) at 4 weeks and correlated with serial changes in circulating tumor DNA. Radiologic responses (40%) and clinical benefit (70%) were observed in 10 patients with plasma-detected ESR1 mutations.SIGNIFICANCE: In the first clinical study to evaluate venetoclax in a solid tumor, we demonstrate that combining venetoclax with endocrine therapy has a tolerable safety profile and elicits notable activity in ER and BCL2-positive metastatic breast cancer. These findings support further investigation of combination therapy for patients with BCL2-positive tumors.