检查点抑制剂疗法已证明对多种肿瘤类型具有总体生存获益。肿瘤突变负荷（TMB）是免疫疗法反应的预测生物标志物。本研究根据使用肿瘤组织 (tTMB) 或血液中循环肿瘤 DNA (bTMB) 评估的 TMB 状态，评估了纳武单抗易普利姆玛 (nivolumab ipilimumab) 在多种肿瘤类型中的疗效。患有高突变（每兆碱基≥10 个突变）的转移性或不可切除实体瘤患者) 在一项开放标签 2 期研究 (CheckMate 848；NCT03668119) 中，对标准疗法耐药的 tTMB (tTMB-H) 和/或 bTMB (bTMB-H) 以 2:1 的比例随机接受纳武单抗 ipilimumab 或纳武单抗单药治疗。 tTMB 和 bTMB 分别通过 Foundation Medicine FoundationOne® CDx 测试和 bTMB 临床试验测定来确定。双重主要终点是接受 nivolumab ipilimumab 治疗的 tTMB-H 和/或 bTMB-H 肿瘤患者的客观缓解率 (ORR)。总共 201 名标准疗法难治的患者被随机分组​​：135 名患有 tTMB-H，125 名患有 bTMB -H; 82 名患者具有双重 tTMB-H/bTMB-H。在 tTMB-H 患者中，纳武单抗 ipilimumab 治疗的 ORR 为 38.6%（95% CI 28.4% 至 49.6%），纳武单抗单药治疗的 ORR 为 29.8%（95% CI 17.3% 至 44.9%）。在 bTMB-H 患者中，纳武单抗易普利姆玛 的 ORR 为 22.5%（95% CI 13.9% 至 33.2%），纳武单抗单药治疗的 ORR 为 15.6%（95% CI 6.5% 至 29.5%）。在 tTMB-H 或 bTMB-H 患者中观察到对 nivolumab ipilimumab 治疗的早期和持久反应。纳武单抗易普利姆玛的安全性是可控的，没有新的安全信号。通过组织活检或无法进行组织活检时通过血液样本确定的患有 TMB-H 转移性或不可切除实体瘤的患者，如果没有其他治疗选择，可能会出现这种情况。受益于 nivolumab ipilimumab.NCT03668119.© 作者（或其雇主）2024。根据 CC BY-NC 允许重复使用。禁止商业再利用。请参阅权利和权限。英国医学杂志出版。

Checkpoint inhibitor therapy has demonstrated overall survival benefit in multiple tumor types. Tumor mutational burden (TMB) is a predictive biomarker for response to immunotherapies. This study evaluated the efficacy of nivolumab+ipilimumab in multiple tumor types based on TMB status evaluated using either tumor tissue (tTMB) or circulating tumor DNA in the blood (bTMB).Patients with metastatic or unresectable solid tumors with high (≥10 mutations per megabase) tTMB (tTMB-H) and/or bTMB (bTMB-H) who were refractory to standard therapies were randomized 2:1 to receive nivolumab+ipilimumab or nivolumab monotherapy in an open-label, phase 2 study (CheckMate 848; NCT03668119). tTMB and bTMB were determined by the Foundation Medicine FoundationOne® CDx test and bTMB Clinical Trial Assay, respectively. The dual primary endpoints were objective response rate (ORR) in patients with tTMB-H and/or bTMB-H tumors treated with nivolumab+ipilimumab.In total, 201 patients refractory to standard therapies were randomized: 135 had tTMB-H and 125 had bTMB-H; 82 patients had dual tTMB-H/bTMB-H. In patients with tTMB-H, ORR was 38.6% (95% CI 28.4% to 49.6%) with nivolumab+ipilimumab and 29.8% (95% CI 17.3% to 44.9%) with nivolumab monotherapy. In patients with bTMB-H, ORR was 22.5% (95% CI 13.9% to 33.2%) with nivolumab+ipilimumab and 15.6% (95% CI 6.5% to 29.5%) with nivolumab monotherapy. Early and durable responses to treatment with nivolumab+ipilimumab were seen in patients with tTMB-H or bTMB-H. The safety profile of nivolumab+ipilimumab was manageable, with no new safety signals.Patients with metastatic or unresectable solid tumors with TMB-H, as determined by tissue biopsy or by blood sample when tissue biopsy is unavailable, who have no other treatment options, may benefit from nivolumab+ipilimumab.NCT03668119.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.