Tumor mutational burden predicts the efficacy of pembrolizumab monotherapy: a pan-tumor retrospective analysis of participants with advanced solid tumors.
Tumor mutational burden predicts the efficacy of pembrolizumab monotherapy: a pan-tumor retrospective analysis of participants with advanced solid tumors.
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DOI：
10.1136/jitc-2021-003091
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发表时间：
2022-01
影响因子：
10.9
通讯作者：
Lunceford J
中科院分区：
文献类型：
--
作者：
Cristescu R;Aurora-Garg D;Albright A;Xu L;Liu XQ;Loboda A;Lang L;Jin F;Rubin EH;Snyder A;Lunceford J
几项研究评估了肿瘤突变负荷（TMB）与免疫检查点抑制剂结果之间的关系。在帕博利珠单抗单药治疗既往接受过治疗的复发性或转移性癌症的II期KEYNOTE-158研究中，由FoundationOne CDx评估的高TMB与改善的客观缓解率（ORR）相关。我们回顾性评估了TMB与既往接受过治疗的晚期实体瘤参与者的疗效之间的关系，这些参与者参加了12项评估pembrolizumab单药治疗的试验，其中包括3项比较pembrolizumab与化疗的随机试验。通过全外显子组测序在福尔马林固定、石蜡包埋的预处理肿瘤样品中评估TMB。高TMB定义为≥175个突变/外显子组。微卫星不稳定性（MSI）表型基于全外显子组测序结果。通过免疫组织化学评估程序性死亡配体1（PD-L1）表达。主要终点为独立中心审查根据RECIST V.1.1评估的ORR。其他终点包括独立中心审查根据RECIST V.1.1评估的无进展生存期（PFS）和总生存期（OS）。在分析的2234名参与者中，1772人接受了pembrolizumab单药治疗，462人接受了化疗。在接受帕博利珠单抗治疗的受试者中，433例TMB ≥175个突变/外显子组受试者的ORR为31.4%（95% CI 27.1 - 36.0），1339例TMB <175个突变/外显子组受试者的ORR为9.5%（95% CI 8.0 - 11.2）。无论PD-L1表达如何，均观察到TMB与ORR的相关性，并且不受特定肿瘤类型或极高TMB或高MSI受试者的影响。在3项随机对照试验中，TMB与帕博利珠单抗的ORR（p≤0.016）、PFS（p≤0.005）和OS（p≤0.029）相关，但与化疗无关（分别为p≥0.340、p≥0.643和p≥0.174），在TMB ≥175个突变/外显子组的受试者中，帕博利珠单抗与化疗相比改善了疗效。TMB ≥175个突变/外显子组与帕博利珠单抗单药治疗的疗效具有临床意义的改善相关，并且在多种既往接受过治疗的晚期实体瘤类型中，帕博利珠单抗与化疗相比的结局改善相关。这些数据表明，TMB具有广泛的临床实用性，无论肿瘤类型，PD-L1表达或MSI状态如何，并支持其作为既往接受过治疗的晚期实体瘤受试者中pembrolizumab单药治疗的预测生物标志物。
Several studies have evaluated the relationship between tumor mutational burden (TMB) and outcomes of immune checkpoint inhibitors. In the phase II KEYNOTE-158 study of pembrolizumab monotherapy for previously treated recurrent or metastatic cancer, high TMB as assessed by the FoundationOne CDx was associated with an improved objective response rate (ORR). We retrospectively assessed the relationship between TMB and efficacy in participants with previously treated advanced solid tumors enrolled in 12 trials that evaluated pembrolizumab monotherapy, including 3 randomized trials that compared pembrolizumab with chemotherapy. TMB was assessed in formalin-fixed, paraffin-embedded pretreatment tumor samples by whole-exome sequencing. High TMB was defined as ≥175 mutations/exome. Microsatellite instability (MSI) phenotype was based on whole-exome sequencing results. Programmed death ligand 1 (PD-L1) expression was assessed by immunohistochemistry. The primary end point was ORR assessed per RECIST V.1.1 by independent central review. Other end points included progression-free survival (PFS) assessed per RECIST V.1.1 by independent central review and overall survival (OS). Of the 2234 participants in the analysis, 1772 received pembrolizumab monotherapy and 462 received chemotherapy. Among the pembrolizumab-treated participants, ORR was 31.4% (95% CI 27.1 to 36.0) in the 433 participants with TMB ≥175 mutations/exome and 9.5% (95% CI 8.0 to 11.2) in the 1339 participants with TMB <175 mutations/exome. The association of TMB with ORR was observed regardless of PD-L1 expression and not driven by specific tumor types or participants with very high TMB or high MSI. In the 3 randomized controlled trials, TMB was associated with ORR (p≤0.016), PFS (p≤0.005), and OS (p≤0.029) of pembrolizumab but not of chemotherapy (p≥0.340, p≥0.643, and p≥0.174, respectively), and pembrolizumab improved efficacy versus chemotherapy in participants with TMB ≥175 mutations/exome. TMB ≥175 mutations/exome is associated with clinically meaningful improvement in the efficacy of pembrolizumab monotherapy and improved outcomes for pembrolizumab versus chemotherapy across a wide range of previously treated advanced solid tumor types. These data suggest TMB has broad clinical utility irrespective of tumor type, PD-L1 expression, or MSI status and support its use as a predictive biomarker for pembrolizumab monotherapy in participants with previously treated advanced solid tumors.
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针对 PD(L)1、CTLA-4 及其组合的免疫检查点抑制剂的肿瘤突变负担、毒性和反应：荟萃回归分析。
DOI：
10.1158/1078-0432.ccr-20-0458
发表时间：
2020-09-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Osipov A;Lim SJ;Popovic A;Azad NS;Laheru DA;Zheng L;Jaffee EM;Wang H;Yarchoan M
通讯作者：
Yarchoan M
影响因子：
51.1
作者：
Plimack, Elizabeth R.;Bellmunt, Joaquim;O'Donnell, Peter H.
通讯作者：
O'Donnell, Peter H.
影响因子：
4.6
作者：
Feliubadaló L;Tonda R;Gausachs M;Trotta JR;Castellanos E;López-Doriga A;Teulé À;Tornero E;Del Valle J;Gel B;Gut M;Pineda M;González S;Menéndez M;Navarro M;Capellá G;Gut I;Serra E;Brunet J;Beltran S;Lázaro C
通讯作者：
Lázaro C
影响因子：
45.3
作者：
Nanda, Rita;Chow, Laura Q. M.;Buisseret, Laurence
通讯作者：
Buisseret, Laurence
影响因子：
8.8
作者：
Mehra R;Seiwert TY;Gupta S;Weiss J;Gluck I;Eder JP;Burtness B;Tahara M;Keam B;Kang H;Muro K;Geva R;Chung HC;Lin CC;Aurora-Garg D;Ray A;Pathiraja K;Cheng J;Chow LQM;Haddad R
通讯作者：
Haddad R