A Phase I Study of Ribociclib Plus Everolimus in Patients with Metastatic Pancreatic Adenocarcinoma Refractory to Chemotherapy.
A Phase I Study of Ribociclib Plus Everolimus in Patients with Metastatic Pancreatic Adenocarcinoma Refractory to Chemotherapy.
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Ribociclib 加依维莫司治疗化疗难治性转移性胰腺癌患者的 I 期研究。
DOI：
10.1089/pancan.2020.0005
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发表时间：
2020
影响因子：
2
通讯作者：
Pishvaian,MichaelJ
中科院分区：
文献类型：
--
作者：
Weinberg,BenjaminA;Wang,Hongkun;Witkiewicz,AgnieszkaK;Marshall,JohnL;He,AiwuR;Vail,Paris;Knudsen,ErikS;Pishvaian,MichaelJ
目的：转移性胰腺癌（mPC）预后差。CDK 4/6在mPC中通常由于CDKN 2A丢失而失调，导致抑制CDK 4/6的p16 INK 4a的丢失。CDK 4/6抑制剂单一疗法由于RAS介导的替代途径的激活而无效，包括磷脂酰肌醇3-激酶-哺乳动物雷帕霉素靶蛋白（PI 3 K-mTOR）。我们进行了一项I期研究，结合CDK 4/6和mTOR抑制的mPC患者难治性标准chemotherapy.Materials and Methods：ribociclib（CDK 4/6抑制剂）和依维莫司（mTOR抑制剂）的组合进行了研究，在一项I期研究中的mPC患者和进展的5-氟尿嘧啶和吉西他滨为基础的化疗。采用3 + 3设计确定ribociclib（250或300 mg/天，第1-21天）联合依维莫司（2.5 mg/天，第1-28天）每28天一次的推荐II期剂量（RP 2D）。次要终点是中位无进展生存期（mPFS），中位总生存期（mOS），反应率，安全性和对视网膜母细胞瘤pathway.Results的影响：12例患者入组，每个剂量水平6例。在250 mg剂量下，仅1例患者出现3级皮疹的剂量限制性毒性。ribociclib的RP 2D为300 mg。mPFS为1.8个月（95%置信区间[CI] [0.6-2.1]），mOS为3.7个月（95% CI [2.3-5.6]）。2例患者（17%）在8周时病情稳定。药效学评价表明，CDK 4/6调节基因表达在治疗期间显著降低（n= 6，p< 0.001）。结论：Ribociclib 300 mg/天，持续第1-21天，联合依维莫司2.5 mg/天耐受性良好，与CDK 4/6调节基因表达降低相关。这种组合作为三线治疗无效，但在mPC中确实靶向CDK 4/6，揭示了在其他环境中获益的潜力。
Purpose:Metastatic pancreatic adenocarcinoma (mPC) has a poor prognosis. CDK4/6 is often deregulated in mPC due toCDKN2Aloss, resulting in the loss of p16INK4a that inhibits CDK4/6. CDK4/6 inhibitor monotherapy is ineffective due to RAS-mediated activation of alternative pathways, including phosphatidylinositol 3-kinase–mammalian target of rapamycin (PI3K-mTOR). We conducted a phase I study combining CDK4/6 and mTOR inhibition in patients with mPC refractory to standard chemotherapy.Materials and Methods:The combination of ribociclib (a CDK4/6 inhibitor) and everolimus (an mTOR inhibitor) was investigated in a phase I study in patients with mPC and progression on 5-fluorouracil- and gemcitabine-based chemotherapy. A 3 + 3 design was used to find the recommended phase II dose (RP2D) of ribociclib (250 or 300 mg daily for days 1–21) in combination with everolimus (2.5 mg daily for days 1–28) every 28 days. Secondary endpoints were median progression-free survival (mPFS), median overall survival (mOS), response rate, safety, and effect on the retinoblastoma pathway.Results:Twelve patients were enrolled, six at each dose level. Only one patient had a dose-limiting toxicity of a grade 3 rash at the 250 mg dose. The RP2D of ribociclib was 300 mg. mPFS was 1.8 months (95% confidence interval [CI] [0.6–2.1]), and mOS was 3.7 months (95% CI [2.3–5.6]). Two patients (17%) had stable disease at 8 weeks. Pharmacodynamic evaluation demonstrated that CDK4/6-regulated gene expression was significantly decreased on treatment (n= 6,p< 0.001).Conclusion:Ribociclib 300 mg daily for days 1–21 plus everolimus 2.5 mg daily was well tolerated and associated with decreased CDK4/6-regulated gene expression. This combination was not effective as a third-line therapy but does pharmacologically target CDK4/6 in mPC, revealing the potential for benefit in other settings.