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Prediction of pan-solid tumor pembrolizumab benefit by integrating tumor mutation and gene expression profiling

Research Square (Research Square)(2022)

Strata Oncology | Ochsner Cancer Institute | University of Wisconsin–Madison | University of Alabama at Birmingham | Prisma Health Greenville Memorial Hospital | Lineberger Comprehensive Cancer Center | ancer Care and Research Center | Aurora Cancer Care | Kaiser Permanente Southern California | SCL Health-CO | Kaiser Permanente Colorado | Gundersen Health System | Waukesha Memorial Hospital | Kaiser Permanente of the Mid-Atlantic States | Kaiser Permanente - Northern California | Bon Secours St. Franci | Lehigh Valley Health Network | MultiCare Regional Cancer Center

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Abstract
Abstract Pembrolizumab is approved in many advanced solid tumor types, however predictive biomarkers and the proportion of pembrolizumab-benefiting patients vary. Biomarkers beyond PD-L1 immunohistochemistry, microsatellite instability (MSI) status, and tumor mutation burden (TMB) may improve benefit prediction. Here, leveraging treatment data (time to next treatment [TTNT]) and comprehensive genomic and quantitative transcriptomic profiling on routine tumor tissue from 708 patients (24 tumor types) collected in an ongoing observational trial (NCT03061305), we report a multivariate, integrative predictor of pan-solid tumor pembrolizumab benefit. The Immune Response Score (IRS) model, which includes TMB and quantitative PD-1, PD-L2, ADAM12 and CD4 RNA expression, was confirmed as predictive through comparison of pembrolizumab TTNT with previous chemotherapy TTNT in a subset of 166 patients treated with both. Applying IRS to the entire NCT03061305 cohort (n=25,770 patients), 13.2-30.7% of patients (2.2-9.6% of patients outside of pembrolizumab approved tumor types [including TMB-High and MSI-High]) are predicted to benefit substantially from pembrolizumab. Hence, if prospectively validated, the IRS model may improve pembrolizumab benefit prediction across approved tumor types including patients outside of currently approved indications.
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gene expression profiling,gene expression,tumor mutation,pan-solid
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要点】:本研究提出了一种整合肿瘤突变和基因表达谱的免疫反应评分(IRS)模型,可以预测泛固体肿瘤患者从帕博利珠单抗治疗中获益的可能性,提高了预测准确性。

方法】:通过分析708名患者(24种肿瘤类型)的常规肿瘤组织,整合治疗数据(下一次治疗时间[TTNT])和全面的基因组及定量转录组数据,构建了一个多变量、综合性的IRS预测模型。

实验】:实验在NCT03061305观察性试验中收集的数据上进行,通过比较166名患者接受帕博利珠单抗治疗与之前化疗的TTNT,验证了IRS模型预测性。应用IRS模型于整个NCT03061305队列(25,770名患者),预测13.2-30.7%的患者(包括在未批准的肿瘤类型中2.2-9.6%的患者)可以从帕博利珠单抗治疗中获得显著益处。