Tumor Mutational Burden, Toxicity, and Response of Immune Checkpoint Inhibitors Targeting PD(L)1, CTLA-4, and Combination: A Meta-regression Analysis.
Tumor Mutational Burden, Toxicity, and Response of Immune Checkpoint Inhibitors Targeting PD(L)1, CTLA-4, and Combination: A Meta-regression Analysis.
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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
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发表时间：
2020-09-15
期刊：
影响因子：
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通讯作者：
Yarchoan M
中科院分区：
文献类型：
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作者：
Osipov A;Lim SJ;Popovic A;Azad NS;Laheru DA;Zheng L;Jaffee EM;Wang H;Yarchoan M
肿瘤突变负荷(TMB)已成为ICI治疗临床反应的潜在预测生物标志物，但TMB是否也能预测毒性尚不清楚。我们调查了多种癌症类型ICI治疗的TMB、客观有效率(ORR)、总生存期(OS)和毒性之间的关系。我们在MEDLINE、PubMed和ASCO/ESMO/AACR会议上搜索29种癌症类型的抗PD(L)1、CTLA-4或联合的临床试验。我们评估了ICI的实施情况、有效率(完全或部分有效)、中位数OS、OS风险比和3/4级毒性。我们使用来自基础医学的肿瘤水平的TMB数据进行了系统回顾、荟萃分析和荟萃回归。对12450例脑梗塞患者的临床试验进行了分析。Meta回归分析显示，在所有治疗组中，TMB与抗PD(L)1、抗CTLA-4和联合用药(P<；0.0001)的ORR显著相关，但与毒性无关。我们的Meta分析中包括的大多数研究都没有OS数据，TMB和OS在这个子集中的关系不显著(p=0.26)。在高转移率肿瘤类型(≥10mut/兆基)中，与PD(L)1单药治疗相比，联合化疗的ORR改善和3/4级毒性增加分别为21.13%和25.41%，而低转移性肿瘤类型(Lt；10mut/兆基数)的ORR改善和3/4级毒性增加分别为3.73%和18.78%。TMB与抗PD(L)1、抗CTLA-4和联合ICIS的临床疗效呈正相关，但与毒性无关。这些结果表明，对于TMB较高的肿瘤，ICIS具有良好的风险/收益比。
Tumor mutational burden (TMB) has emerged as a potential predictive biomarker for clinical response to ICI therapy, but whether TMB also predicts toxicity remains unknown. We investigated the relationship between TMB, objective response rate (ORR), overall survival (OS), and toxicity for ICI therapy across multiple cancer types. We searched MEDLINE, PubMed, and ASCO/ESMO/AACR meetings for clinical trials of anti-PD(L)1, CTLA-4, or combination in 29 cancer types. We assessed ICI administered, responses (complete or partial response), median OS, OS hazard ratio, and grade 3/4 toxicity. We conducted a systematic review, meta-analysis and meta-regression using tumor level TMB data from Foundation Medicine. 117 clinical trials, which included 12450 patients treated ICI therapy, were analyzed. Meta-regression analysis revealed that TMB was significantly associated with ORR for anti-PD(L)1, anti-CTLA-4, and combination (p<0.0001 for all), but not associated with toxicity in all treatment groups. OS data were unavailable for most studies included in our meta-analysis, and the relationship between TMB and OS in this subset was not significant (p=0.26). In high TMB tumor types (≥10 mut/megabase) the improvement of ORR and increase in grade 3/4 toxicity with combination ICI therapy as compared to PD(L)1 monotherapy were 21.13% and 25.41%, respectively, as compared to 3.73% and 18.78% in low TMB tumor types (<10 mut/megabase). There is a positive association between TMB and clinical response with anti-PD(L)1, anti-CTLA-4, and combination ICIs, but no association between TMB and toxicity. These results imply a favorable risk/benefit ratio for ICIs in tumors with a higher TMB.