DNA低甲基化识别小细胞肺癌临床获益亚组：durvalumab联合olaparib维持治疗的II期试验多组学分析
DNA hypomethylation identifying clinical benefit subgroup of small-cell lung cancer: multi-omics analysis of a phase II trial with durvalumab plus olaparib as maintenance therapy.
作者
作者单位
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China.
- Department of Internal Medicine, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Institute of Cancer Research, Henan Academy of Innovations in Medical Science, Zhengzhou, China.
- Affiliated Dongguan Hospital of Southern Medical university, Dongguan People Hospital, Dongguan, China.
- Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, China.
- Department of Medical Oncology, Zhujiang Hospital of Southern Medical University, Guangzhou, China.
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China huangyan@sysucc.org.cn zhangli@sysucc.org.cn.
摘要
中文
广泛期小细胞肺癌（ES-SCLC）的长期生存仍然罕见，大多数患者在维持治疗期间出现疾病进展。聚（ADP-核糖）聚合酶（PARP）抑制剂具有抗肿瘤活性、修饰肿瘤免疫原性并使肿瘤对抗程序性细胞死亡蛋白1/程序性死亡配体1治疗敏感的潜力。我们进行了这项2期试验，以研究durvalumab联合olaparib作为ES-SCLC患者维持治疗的有效性和安全性。这是一项多中心、单臂、II期试验，纳入了60名先前未经治疗的ES-SCLC患者（NCT05245994）。患者接受durvalumab（1500 mg）联合铂-依托泊苷化疗静脉给药，每21天一次，最多四个周期，随后进行durvalumab（1500 mg，每28天一次）和口服olaparib（300 mg，每日两次）的维持治疗，直至疾病进展或出现不可接受的毒性。进行了多组学分析以表征与临床结果相关的分子亚型。该联合方案显示出有前景的疗效，12个月生存且无进展率为25.0%，客观缓解率为73.3%，中位无进展生存期为6.8个月，中位总生存期为14.6个月。多组学分析确定了一个低甲基化亚组（聚类1），与显著改善的生存结果相关。进一步分析显示，该亚型表现出增强的抗原呈递机制、有利的细胞因子谱，以及通过启动子甲基化升高和特定DDR基因转录沉默抑制DNA损伤修复（DDR）通路，这些共同与良好的结果相关。本研究提供了durvalumab联合olaparib作为ES-SCLC维持治疗的第一个前瞻性证据。多组学分析表明，DNA低甲基化状态可能富集于从PARP抑制和免疫治疗中获益的患者。NCT05245994。
English
Long-term survival of extensive-stage small-cell lung cancer (ES-SCLC) remains rare, with most patients experiencing disease progression during maintenance therapy. Poly (ADP-ribose) polymerase (PARP) inhibitors have the potential to confer antitumor activity, modify tumor immunogenicity, and sensitize tumors to anti-programmed cell death protein 1/programmed death-ligand 1 therapy. We conducted this phase 2 trial to investigate the efficacy and safety of durvalumab plus olaparib as maintenance therapy in patients with ES-SCLC. This was a multicenter, single-arm, phase II trial that enrolled 60 patients with previously untreated ES-SCLC (NCT05245994). Patients received durvalumab (1,500 mg) combined with platinum-etoposide chemotherapy intravenously every 21 days for up to four cycles, followed by maintenance therapy with durvalumab (1,500 mg every 28 days) and oral olaparib (300 mg two times a day) until disease progression or unacceptable toxicity. Multi-omics analyses were performed to characterize molecular subtypes associated with clinical outcomes. The combination regimen demonstrated promising efficacy, with an alive and progression-free at 12 months rate of 25.0%, an objective response rate of 73.3%, a median progression-free survival of 6.8 months, and a median overall survival of 14.6 months. Multi-omics profiling identified a hypomethylation subgroup (cluster 1) that was associated with significantly improved survival outcomes. Further analysis revealed that this subtype exhibited enhanced antigen presentation machinery, a favorable cytokine profile, and suppression of DNA damage repair (DDR) pathways, potentially through elevated promoter methylation and transcriptional silencing of specific DDR genes, which together were associated with the favorable outcomes. This study presents the first prospective evidence supporting durvalumab plus olaparib as maintenance therapy in ES-SCLC. Multi-omics analysis identifies that DNA hypomethylation status may enrich for patients who benefit from PARP inhibition and immunotherapy. NCT05245994.
分类与指标
- 研究类型
- 临床研究
- 病种
- 肺癌
- JCR 分区
- Q1
- 影响因子
- 11.7
- 新锐分区
- 1区