| 纪 青,莫 淼.T-VEC联合依匹木单抗治疗晚期恶性黑色素瘤的多中心随机Ⅱ期临床试验的5年随访结果解读[J].肿瘤学杂志,2023,29(7):626-634. |
| T-VEC联合依匹木单抗治疗晚期恶性黑色素瘤的多中心随机Ⅱ期临床试验的5年随访结果解读 |
| Talimogene Laherparepvec in Combination with Ipilimumab Versus Ipilimumab Alone for Advanced Melanoma： Interpretation of A Multicenter， Randomized， Open-Label， Phase Ⅱ Trial |
| 投稿时间：2023-07-18 |
| DOI：10.11735/j.issn.1671-170X.2023.07.B013 |
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| 中文关键词: 溶瘤病毒 T-VEC 黑色素瘤 免疫检查点抑制剂 |
| 英文关键词:oncolytic virus talimogene laherparepvec melanoma immune checkpoint inhibitor |
| 基金项目: |
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| 中文摘要: |
| 摘 要：溶瘤病毒联合免疫检查点抑制剂方案一直是恶性黑色素瘤治疗的研究热点。一项多中心、开放标签的随机Ⅰb/Ⅱ期临床试验（NCT01740297）对比了溶瘤病毒talimogene laherparepvec（T-VEC）联合依匹木单抗对比依匹木单抗单药在不可切除的ⅢB~ⅣM1c期恶性黑色素瘤患者中的疗效和安全性。该研究的Ⅱ期于2013年8月至2021年3月在美国、法国和德国的33个中心进行，筛选入组198例患者，以1∶1的比例随机接受T-VEC联合依匹木单抗或依匹木单抗单药治疗。主要研究终点是根据免疫相关应答标准评估的客观缓解率(objective response rate，ORR)，关键次要终点包括持久反应率(durable response rate，DRR)、反应持续时间(duration of response，DOR)、无进展生存期(progression-free survival，PFS)、总生存期(overall survival，OS)和安全性。与依匹木单抗单药相比，联合用药组显著性改善了患者的ORR（35.7% vs 16.0%；OR=2.9，95%CI：1.5~5.7，P=0.003）。两组的DRR分别为33.7%和13.0%（P=0.001）。在达到客观缓解的患者中，联合用药组的中位DOR为69.2个月（95%CI：38.5~NA)，单药组尚未达到。联合用药组的中位PFS为13.5个月，单药组为6.4个月（HR=0.78，95%CI：0.55~1.09，P=0.14）。联合用药组的5年OS率为54.7%，单药组为48.4%。5年随访中未发现新的安全性事件。这是首个达到主要研究终点的溶瘤病毒联合免疫检查点抑制剂的随机对照研究。5年随访数据提示T-VEC联合依匹木单抗能安全有效地改善晚期恶性黑色素瘤患者的治疗有效率，但从长期生存角度，联合用药并未给患者带来具有统计学差异的生存获益。 |
| 英文摘要: |
| Abstract： Oncolytic viruses combined with immune checkpoint inhibitors have been a hot research topic in treatment of melanoma. A multicentre， open-label， randomized phase Ⅰb/Ⅱ trial(NCT01740297) compared the efficacy and safety of talimogene laherparepvec(T-VEC) with ipilimumab and ipilimumab alone in treatment of patients with unresectable stage ⅢB~ⅣM1c melanoma. The phase Ⅱ part of this study was conducted from August 2013 to March 2021 at 33 centers in the United States， France and Germany and enrolled 198 patients who were randomized 1∶1 to receive either T-VEC plus ipilimumab or ipilimumab alone. The primary end point was investigator-assessed objective response rate(ORR) per immune-related response criteria. Key secondary endpoints included durable response rate(ORR)， duration of response(DRR)， duration of response(DOR)， progression-free survival(PFS)， overall survival(OS) and safety. Compared to ipilimumab alone， ORR was significantly improved in the combination arm(35.7% vs 16.0%； OR=2.9， 95%CI：1.5~5.7， P=0.003). DRR was 33.7% and 13.0% respectively(P=0.001). Among the objective responders， the median DOR was 69.2 months(95%CI：38.5~NA) in the combination arm and was not reached in ipilimumab arm. Median PFS was 13.5 months in the combination arm and 6.4 months in the ipilimumab arm(HR=0.78，95%CI：0.55~1.09， P=0.14). Estimated 5-year OS was 54.7% in the combination arm and 48.4% in the ipilimumab arm. No new safety events were observed. This is the first randomized controlled trial of the combination of an oncolytic virus and an immune checkpoint inhibitor therapy that meets its primary endpoint. The 5-year follow-up data suggests that T-VEC in combination with ipilimumab can safely and effectively improve the treatment response in patients with advanced melanoma， but the combination does not provide a significant survival benefit in terms of long-term survival. |
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