Sorich Michael J, Manning-Bennett Arkady T, Li Lee X, Shahnam Adel, Kichenadasse Ganessan, Karapetis Christos S, Abuhelwa Ahmad Y, McKinnon Ross A, Rowland Andrew, Hopkins Ashley M
College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia.
Department of Medical Oncology, Peter McCallum Cancer Centre, Melbourne, VIC, Australia.
Target Oncol. 2025 Mar;20(2):361-369. doi: 10.1007/s11523-024-01124-2. Epub 2025 Jan 7.
BACKGROUND: Tumour mutational burden (TMB) is an established biomarker for patients treated with immune checkpoint inhibitors (ICIs). The optimal TMB cut-off is uncertain. It is also uncertain whether there is a sharp TMB threshold or a more graduated change in clinical outcomes as TMB increases. OBJECTIVE: We aimed to determine the relationship between TMB and ICI treatment outcomes using alternative statistical approaches in patients with non-small cell lung cancer. METHODS: Tumour mutational burden was evaluated as a prognostic and predictive biomarker in advanced non-small cell lung cancer utilising data from two real-world cohorts of ICI use (n = 968) and three randomised controlled trials evaluating ICIs (n = 1588). The non-linear relationship between continuous TMB and response/survival/efficacy outcomes was evaluated using statistical methods that do not require specifying a TMB cut-off. RESULTS: Median TMB for all cohorts was seven mutations/megabase, excluding MYSTIC, where the median was 13 mutations/megabase. Progressively higher TMB was significantly associated with a progressively higher objective response rate and progression-free survival in ICI-treated patients in Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets [MSK-IMPACT] (objective response rate: p < 0.001, progression-free survival: p < 0.001), Strata Clinical Molecular Database [SCMD] (progression-free survival: p = 0.023) and OAK/POPLAR (objective response rate: p = 0.017, progression-free survival: p < 0.001) This relationship was not apparent for patients treated with chemotherapy. There was no obvious TMB threshold for ICI response. The relationship between TMB and overall survival was more complex and heterogeneous. CONCLUSIONS: Using a single cut-off to analyse a continuous biomarker may hide important information. Methods that provide more nuance to the underlying relationship between TMB and outcomes enable readers to judge for themselves the value and limitations of TMB cut-offs proposed for clinical practice.
背景：肿瘤突变负荷（TMB）是接受免疫检查点抑制剂（ICI）治疗患者的一种既定生物标志物。最佳TMB临界值尚不确定。随着TMB升高，临床结局是存在一个明显的TMB阈值还是有更渐进的变化也不确定。 目的：我们旨在使用替代统计方法确定非小细胞肺癌患者中TMB与ICI治疗结局之间的关系。 方法：利用两个ICI实际应用队列（n = 968）和三项评估ICI的随机对照试验（n = 1588）的数据，评估肿瘤突变负荷作为晚期非小细胞肺癌的预后和预测生物标志物。使用不需要指定TMB临界值的统计方法评估连续TMB与反应/生存/疗效结局之间的非线性关系。 结果：所有队列的TMB中位数为每兆碱基7个突变，但纪念斯隆凯特琳癌症中心可操作癌症靶点综合突变分析（MSK-IMPACT）队列除外，该队列的TMB中位数为每兆碱基13个突变。在纪念斯隆凯特琳癌症中心可操作癌症靶点综合突变分析（MSK-IMPACT）队列（客观缓解率：p < 0.001，无进展生存期：p < 0.001）、Strata临床分子数据库（SCMD）队列（无进展生存期：p = 0.023）以及OAK/POPLAR队列（客观缓解率：p = 0.017，无进展生存期：p < 0.001）中，接受ICI治疗的患者TMB逐渐升高与客观缓解率和无进展生存期逐渐升高显著相关。化疗患者中未观察到这种关系。ICI反应不存在明显的TMB阈值。TMB与总生存期之间的关系更为复杂且具有异质性。 结论：使用单一临界值分析连续生物标志物可能会掩盖重要信息。能更细微地呈现TMB与结局之间潜在关系的方法，使读者能够自行判断临床实践中提出的TMB临界值的价值和局限性。
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