曲拉西利是一款短效、高选择性且可逆的细胞周期蛋白依赖性激酶(CDK)4/6 抑制剂,它能够将骨髓造血干/祖细胞短暂阻滞于细胞周期的 G1 期,进而保护骨髓细胞免受化疗药物的杀伤。
G1T28-02、G1T28-03 和 G1T28-05 三项 II 期临床研究及其汇总分析结果表明,对于接受化疗的 SCLC 患者,使用曲拉西利可降低 CIM 发生率,曲拉西利具有多谱系骨髓保护作用,且不增加化疗风险,显著提升患者生活质量[8-11]。针对国内缺少预防化疗引起骨髓抑制或减轻骨髓抑制的有效疗法,我们牵头开展了在中国 ES-SCLC 化疗前给予曲拉西利的安全性、疗效和药代动力学的 3 期研究(TRACES)。TRACES 研究纳入了 95 例纳入了接受 1 线治疗和 2/3 线治疗的 ES-SCLC 患者,研究进一步证实了曲拉西利对接受卡铂联合依托泊苷或拓扑替康治疗的中国 ES-SCLC 患者的骨髓保护作用[12]。该研究结果显示,与对照组相比,化疗前给予曲拉西利可显著缩短第 1 周期 SN 的持续时间(0 天 vs 2 天,P = 0.0003),降低 SN(9.8% vs 47.6%)、FN(2.4% vs 16.7%)、3/4 级贫血(14.6% vs 31.0%)和 4 级血小板减少(9.8% vs 14.3%)的发生率,减少 G-CSF 使用率、ESA 使用率和血小板输注发生率,且患者耐受性良好[12]。
图 2. 中国 TRACES 研究结果
基于 TRACES 研究的积极结果,曲拉西利已于 2022 年获得国家药品监督管理局(NMPA)批准,用于既往未接受过系统性化疗的 ES-SCLC 患者,在接受含铂类药物联合依托泊苷方案治疗前预防性给药,以降低化疗引起的骨髓抑制的发生率。为了在更广泛的人群中验证曲拉西利的骨髓保护作用,我们牵头开展了多中心、前瞻性的曲拉西利在小细胞肺癌化疗骨髓保护的真实世界研究。2024 年 CSCO 年会上公布了这项真实世界研究研究计划和入组 7 例患者的初步结果,本次 AACR 上公布了这项真实世界研究的最终结果,曲拉西利表现亮眼。
纵览 G1T28 系列研究、TRACES 研究以及真实世界研究数据,共同验证了 ES-SCLC 患者在化疗前应用曲拉西利的明确骨髓保护作用和良好安全性。目前,曲拉西利已被美国国家综合癌症网络(NCCN)指南推荐作为 ES-SCLC 化疗前预防 CIM 的主要选择,并获得《中国临床肿瘤学会(CSCO)小细胞肺癌诊疗指南2025》的 I 级推荐(1A 类证据)[13,14]。而且,曲拉西利已经被纳入国家医保目录,极大地降低了患者的经济负担,提高了治疗可及性。
总体而言,曲拉西利在 ES-SCLC 领域具有重要的应用价值,是确保 ES-SCLC 患者按时、足量完成抗肿瘤治疗,保证化疗临床疗效并有效减少 CIM 的重要举措。随着循证医学证据的不断累积、临床医生对曲拉西利认识的加深和药物可及性的提高,未来越来越多的 ES-SCLC 患者将从中受益,进一步降低 CIM 的发生,改善患者整体治疗体验和生活质量,其在 ES-SCLC 治疗领域的应用前景将更加广阔。
参考文献
[1]Ying Cheng, et al. Preventive use of trilaciclib in Chinese patient with extensive-stage small cell lung cancer (ES-SCLC) receiving chemotherapy: A multi-center, single-arm, observational real-world study. 2025 AACR Abstract 7218 / 24.[2]中国临床肿瘤学会小细胞肺癌专家委员会, 中国医师协会肿瘤多学科诊疗专业委员会. 小细胞肺癌免疫治疗专家共识(2025版)[J]. 中华肿瘤杂志, 2025, 47(1): 65-75.[3]Cheng Y, Spigel DR, Cho BC, et al. Durvalumab after Chemoradiotherapy in Limited-Stage Small-Cell Lung Cancer. N Engl J Med. 2024 Oct 10;391(14):1313-1327.[4]Christine Hann, et al. Durvalumab (D) vs placebo (P) after concurrent chemoradiotherapy (cCRT) in limited-stage small-cell lung cancer (LS-SCLC): Outcomes by PD-L1 expression in ADRIATIC. 2025 AACR Abstract CT094 / 12.[5]Yanli Xing, et al. BCL-2 selective inhibitor venetoclax combined with topoisomerase I inhibitor irinotecan is effective in small cell lung cancer (SCLC). 2025 AACR Abstract 1381 / 3.[6]Debdatta Halder, et al. Targeting ATM modulates oncogenic pathways and amplifies chemotherapy efficacy in small cell lung cancer. 2025 AACR Abstract LB016 / 16.[7]Zhou Yu, et al. APG-2449, a novel focal adhesion kinase (FAK) inhibitor, enhances the antitumor activity of chemotherapy in preclinical models of small-cell lung cancer (SCLC) with activated FAK. 2025 AACR Abstract 1679 / 10.[8]Weiss JM, Csoszi T, Maglakelidze M, et al. Myelopreservation with the CDK4/6 inhibitor trilaciclib in patients with small-cell lung cancer receiving first-line chemotherapy: a phase Ib/randomized phase II trial[J]. Ann Oncol. 2019;30(10):1613-1621.[9]Hart LL, Ferrarotto R, Andric ZG, et al. Myelopreservation with Trilaciclib in Patients Receiving Topotecan for Small Cell Lung Cancer: Results from a Randomized, Double-Blind, Placebo-Controlled Phase II Study[J]. Adv Ther. 2021;38(1):350-365.[10]Daniel D, Kuchava V, Bondarenko I, et al.Trilaciclib prior to chemotherapy and atezolizumab in patients with newly diagnosed extensive‐stage small cell lung cancer: a multicentre, randomised, double‐blind, placebo‐controlled phase II trial[J]. Int J Cancer. 2020;148:2557‐2570.[11]Weiss J, Goldschmidt J, Andric Z, et al. Effects of Trilaciclib on Chemotherapy-Induced Myelosuppression and Patient-Reported Outcomes in Patients with Extensive-Stage Small Cell Lung Cancer: Pooled Results from Three Phase II Randomized, Double-Blind, Placebo-Controlled Studies[J]. Clin Lung Cancer. 2021 Sep;22(5):449-460.[12]Cheng Y, Wu L, Huang D, et al. Myeloprotection with trilaciclib in Chinese patients with extensive-stage small cell lung cancer receiving chemotherapy: Results from a randomized, double-blind, placebo-controlled phase III study (TRACES)[J]. Lung Cancer, 2024, 188: 107455.[13]中国临床肿瘤学会指南工作委员会. 中国临床肿瘤学会(CSCO)小细胞肺癌诊疗指南 2025[M]. 北京: 人民卫生出版社, 2025.[14]NCCN Clinical Practice Guidelines in Small Cell Lung Cancer. Version 4. 2025.[15]Kaiqing Zhang, et al. Preclinical study of bispecific antibody drug conjugates (bsADCs) targeting DLL3 and SEZ6 demonstrated potent anti-tumor activity in small cell lung cancer (SCLC) xenograft models. 2025 AACR Abstract 4776 / 12.[16]Frank An, et al. Bispecific antibody drug conjugates (bsADCs) targeting DLL3 and B7-H3 demonstrated potent anti-tumor activity in preclinical models of small cell lung cancer (SCLC). 2025 AACR Abstract 6081 / 22.[17]Yingdong Lu, et al. PLB-001, a novel anti-dll3 ADC with topoisomerase 1 inhibitor-based linker-payload for treatment of SCLC. 2025 AACR Abstract 4746 / 13.[18]Zhuoxiao Cao, et al. A novel allogeneic anti-DLL3 CAR-NK cell therapy in treating small cell lung cancer. 2025 AACR Abstract 6121 / 29.
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