PO.CT01.05 · 临床试验
CDK4/6抑制剂达尔西利联合mFOLFOX6治疗经治的转移性结直肠癌：一项Simon两阶段II期研究结果
CDK4/6 inhibitor dalpiciclib combined with mFOLFOX6 in pretreated metastatic colorectal cancer: Results from a Simon two-stage phase II study
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：经治的转移性结直肠癌（mCRC）治疗选择仍然有限，突显了合理联合策略的必要性。细胞周期调控失调是结直肠癌的一个标志，可能导致治疗失败。细胞周期蛋白依赖性激酶4和6（CDK4/6）调控G1-S转换，是一个治疗靶点。临床前研究表明，CDK4/6抑制可增强细胞毒性化疗在结直肠癌模型中的抗肿瘤活性。我们开展了一项II期研究，评估口服CDK4/6抑制剂达尔西利联合mFOLFOX6治疗经治mCRC。
方法：这是一项开放标签、单臂、Simon两阶段II期研究，纳入在标准治疗（包括既往奥沙利铂类治疗）后进展的mCRC患者。达尔西利以125 mg口服每日一次给药（服药21天/停药7天），联合mFOLFOX6每2周一次的标准剂量。主要终点为按RECIST v1.1的客观缓解率（ORR）。次要终点包括疾病控制率（DCR）、安全性（CTCAE v5.0）、无进展生存期（PFS）和总生存期（OS）。预先设定的进入第2阶段的第1阶段标准为前18例患者中≥3例部分缓解。
结果：截至2025年12月10日的数据截止时间，共入组17例患者（中位年龄57.9岁；52.9%为女性）。所有患者均有多器官转移及既往抗EGFR和/或抗VEGF治疗；所有肿瘤均为pMMR，10例（58.8%）携带KRAS突变。在可评估患者（n=15；≥1次基线后评估）中，3例达到PR，4例达到SD，ORR为20.0%，DCR为46.7%，达到进入第2阶段的预设标准。中位PFS和OS分别为3.7和10.3个月；这些估计值为初步结果，生存数据尚不成熟。治疗相关不良事件可控，主要为血液学不良事件。3级中性粒细胞减少发生于29.4%的患者，3级血小板减少发生于17.6%；未观察到4-5级治疗相关不良事件或治疗相关死亡。
结论：达尔西利联合mFOLFOX6在经治mCRC中显示出可接受的耐受性和初步抗肿瘤活性，支持继续进入第二阶段。正在进行的入组和相关性分析将进一步明确获益的持久性，并识别最可能缓解的分子亚组。
临床试验信息：NCT05480280
查看英文原文 English abstract
Background: Treatment options for pretreated metastatic colorectal cancer (mCRC) remain limited, underscoring the need for rational combination strategies. Dysregulated cell-cycle control is a hallmark of colorectal cancer and may contribute to treatment failure. Cyclin-dependent kinases 4 and 6 (CDK4/6) regulate the G1-S transition and represent a therapeutic target. Preclinical studies have demonstrated that CDK4/6 inhibition can enhance the antitumor activity of cytotoxic chemotherapy in colorectal cancer models. We conducted a phase II study to evaluate dalpiciclib, an oral CDK4/6 inhibitor, combined with mFOLFOX6 in pretreated mCRC.
Methods: This was an open-label, single-arm, Simon two-stage phase II study in patients with mCRC who had progressed after standard therapies, including prior oxaliplatin-based therapy. Dalpiciclib was administered at 125 mg orally once daily (21 days on/7 days off) with mFOLFOX6 every 2 weeks at standard doses. The primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR), safety (CTCAE v5.0), progression-free survival (PFS), and overall survival (OS). The prespecified stage 1 criterion to proceed to stage 2 was ≥3 partial responses among the first 18 patients.
Results: At the data cutoff of December 10, 2025, 17 patients were enrolled (median age, 57.9 years; 52.9% female). All had multi-organ metastases and prior anti-EGFR and/or anti-VEGF therapy; all tumors were pMMR, and 10 (58.8%) harbored KRAS mutations. Among evaluable patients (n=15; ≥1 post-baseline assessment), 3 achieved PR and 4 achieved SD, yielding an ORR of 20.0% and a DCR of 46.7%, meeting the prespecified criterion to proceed to stage 2. Median PFS and OS were 3.7 and 10.3 months, respectively; these estimates are preliminary and survival data remain immature. Treatment-related adverse events were manageable and primarily hematologic. Grade 3 neutropenia occurred in 29.4% of patients and grade 3 thrombocytopenia in 17.6%; no grade 4-5 treatment-related adverse events or treatment-related deaths were observed.
Conclusions: Dalpiciclib plus mFOLFOX6 showed acceptable tolerability and preliminary antitumor activity in pretreated mCRC, supporting continuation to the second stage. Ongoing enrollment and correlative analyses will further define durability of benefit and identify molecular subgroups most likely to respond.
Clinical trial information: NCT05480280
利益披露 Disclosure
X. Xie, None..
Z. Yu, None..
Z. Lin, None..
W. Li, None..
D. Chen, None..
X. Zhai, None..
Y. Chen, None..
X. Wu, None.