Pembrolizumab已获得FDA批准，在肿瘤突变负荷（TMB）≥10个突变/兆碱基（mut/Mb）的肿瘤中使用。然而，免疫检查点抑制剂（ICI）的反应在不同的肿瘤组织学之间存在显著差异。我们描述了移位突变（FSs）的分布情况，并评估了它们作为ICI预测生物标志物的作用，该评估是在临床患者队列中进行的。对至少324个基因进行了广泛的基因组分析。该临床队列包括接受ICI单药治疗并进行肿瘤测序的转移性固体恶性肿瘤患者。对比了组间的无进展生存期（PFS）、总生存期和客观反应率（ORR）。对包括246,252个基因组稳定（MSS）样本和4561个微卫星不稳定样本的固体肿瘤进行了分析。根据TMB和FS将组织学分为不同的组别。MSS分布：TMB-L (<10个mut/Mb)/FS-A（无FS）（N=111,065，45%），TMB-H（≥10个mut/Mb）/FS-A（N=15,313，6%），TMB-L/FS-P（p≥1个FS）（N=98,389，40%），TMB-H/FS-P（N=21,485，9%）。FS主要在p53通路中被鉴定出来。在临床队列中，共有212名患者。组别：TMB-L/FS-A（N=80，38%），TMB-H/FS-A（N=36，17%），TMB-L/FS-P（N=57，27%），TMB-H/FS-P（N=39，18%）。与ICI相比，FS与更高的ORR相关，分别为23.8% vs 12.8%（p=0.02）。TMB-L/FS-P组的中位PFS（5.1个月）优于TMB-L/FS-A组（3.6个月，p<0.01）。TMB-L/FS-P组的12个月PFS概率为34%，而TMB-L/FS-A组为17.1%。FS在MSS/TMB-L固体肿瘤的患者中发现率为47%。FS可能在预测免疫疗法反应方面补充TMB的作用，尤其适用于TMB较低的肿瘤。 © 作者（或其雇主）2023。在CC BY-NC许可下允许再次使用。不允许商业再使用。详见权利和许可。由BMJ出版。

Pembrolizumab is FDA approved for tumors with tumor mutational burden (TMB) of ≥10 mutations/megabase (mut/Mb). However, the response to immune checkpoint inhibitors (ICI) varies significantly among cancer histologies. We describe the landscape of frameshift mutations (FSs) and evaluated their role as a predictive biomarker to ICI in a clinical cohort of patients.Comprehensive genomic profiling was performed on a cohort of solid tumor samples examining at least 324 genes. The clinical cohort included patients with metastatic solid malignancies who received ICI monotherapy and had tumor sequencing. Progression-free survival (PFS), overall survival, and objective response rates (ORR) were compared between the groups.We analyzed 246,252 microsatellite stable (MSS) and 4561 samples with microsatellite instability across solid tumors. Histologies were divided into groups according to TMB and FS. MSS distribution: TMB-L (<10 mut/Mb)/FS-A (absent FS) (N=111,065, 45%), TMB-H (≥10 mut/Mb)/FS-A (N=15,313, 6%), TMB-L/FS-P (present ≥1 FS) (N=98,389, 40%) and TMB-H/FS-P (N=21,485, 9%). FSs were predominantly identified in the p53 pathway. In the clinical cohort, 212 patients were included. Groups: TMB-L/FS-A (N=80, 38%), TMB-H/FS-A (N=36, 17%), TMB-L/FS-P (N=57, 27%), TMB-H/FS-P (N=39, 18%). FSs were associated with a higher ORR to ICI, 23.8% vs 12.8% (p=0.02). TMB-L/FS-P had superior median PFS (5.1 months) vs TMB-L/FS-A (3.6 months, p<0.01). The 12-month PFS probability was 34% for TMB-L/FS-P vs 17.1% for TMB-L/FS-A.FSs are found in 47% of patients with MSS/TMB-L solid tumors in a pan-cancer cohort. FS may complement TMB in predicting immunotherapy responses, particularly for tumors with low TMB.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.