Tumour Mutational Burden and Immune Checkpoint Inhibitor Response in Non-small Cell Lung Cancer: A Continuous Modelling Approach.

IF 4.4 3区医学 Q2 ONCOLOGY Targeted Oncology Pub Date : 2025-01-07 DOI:10.1007/s11523-024-01124-2

Michael J Sorich, Arkady T Manning-Bennett, Lee X Li, Adel Shahnam, Ganessan Kichenadasse, Christos S Karapetis, Ahmad Y Abuhelwa, Ross A McKinnon, Andrew Rowland, Ashley M Hopkins

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Abstract

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.

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非小细胞肺癌的肿瘤突变负担和免疫检查点抑制剂反应：连续建模方法。

背景：肿瘤突变负担（TMB）是免疫检查点抑制剂（ICIs）治疗患者的既定生物标志物。最佳TMB截止值是不确定的。随着TMB的增加，临床结果是否有一个急剧的TMB阈值或更渐进的变化也不确定。目的：我们旨在通过非小细胞肺癌患者的替代统计方法确定TMB和ICI治疗结果之间的关系。方法：肿瘤突变负担作为晚期非小细胞肺癌的预后和预测性生物标志物进行评估，利用来自两个真实世界的ICI使用队列（n = 968）和三个评估ICI的随机对照试验（n = 1588）的数据。使用不需要指定TMB截止值的统计方法评估持续TMB与反应/生存/疗效结果之间的非线性关系。结果：所有队列的TMB中位数为7个突变/兆基，但MYSTIC组除外，其中位数为13个突变/兆基。在Memorial Sloan - Kettering-Integrated Mutation Profiling of Actionable Cancer Targets [MSK-IMPACT]中，渐进式较高的TMB与渐进式较高的客观缓解率和ci治疗患者的无进展生存率显著相关（客观缓解率：p）。结论：使用单一截止值分析连续生物标志物可能隐藏重要信息。为TMB与预后之间的潜在关系提供更多细微差别的方法，使读者能够自行判断TMB截断值在临床实践中的价值和局限性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Targeted Oncology 医学-肿瘤学

CiteScore

8.40

自引率

3.70%

发文量

审稿时长

>12 weeks

期刊介绍： Targeted Oncology addresses physicians and scientists committed to oncology and cancer research by providing a programme of articles on molecularly targeted pharmacotherapy in oncology. The journal includes: Original Research Articles on all aspects of molecularly targeted agents for the treatment of cancer, including immune checkpoint inhibitors and related approaches. Comprehensive narrative Review Articles and shorter Leading Articles discussing relevant clinically established as well as emerging agents and pathways. Current Opinion articles that place interesting areas in perspective. Therapy in Practice articles that provide a guide to the optimum management of a condition and highlight practical, clinically relevant considerations and recommendations. Systematic Reviews that use explicit, systematic methods as outlined by the PRISMA statement. Adis Drug Reviews of the properties and place in therapy of both newer and established targeted drugs in oncology.