Predictive Efficacy of Blood-Based Tumor Mutation Burden Assay for Immune Checkpoint Inhibitors Therapy in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

In non-small cell lung cancer (NSCLC) patients treated by immune checkpoint inhibitors (ICIs), tumor mutation burden (TMB) has been found to have predictive potential for survival. When compared to TMB detection in tissue (tTMB), detecting TMB in the blood (bTMB) has practical advantages; yet, the results of various studies are conflicting. The question of whether bTMB can be utilized as a predictive biomarker is becoming increasingly contentious. To confirm the predictive efficacy of bTMB, researchers did a systematic review and meta-analysis to look into the relationship between ICIs and bTMB. From the inception to March 2021, Cochrane Library, PubMed, EMBASE and other databases were systematically searched. The predictive value of bTMB in ICIs, or the efficacy of ICIs against chemotherapy, was studied. The results were presented as pooled ratio rate (RR) and hazard ratio (HR) with 95% confidence intervals for the Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Subgroup analysis, heterogeneity analyses, and sensitivity analysis were also performed. A total of 2,610 NSCLC patients were studied in seven trials. There were no significant differences in OS (HR = 1.09; 95% CI: 0.62-1.91, P = 0.774) or PFS (HR = 0.73; 95% CI: 0.20-2.65, P = 0.629) between high and low bTMB groups in the ICIs cohort. When ICIs were compared to chemotherapy, ICIs were found to enhance OS (HR = 0.74; 95% CI: 0.59-0.92, P = 0.006), but the improvement in PFS and ORR was only a numerical trend (PFS: HR = 0.83; 95% CI: 0.63-1.09, P = 0.173; ORR: RR = 0.92, 95% CI: 0.77-1.10, P = 0.372). NSCLC patients treated with ICIs in the high bTMB group had better survival benefits than chemotherapy patients in terms of OS (HR = 0.63; 95% CI: 0.51-0.76, P <0.001), PFS (HR = 0.63; 95% CI: 0.52-0.76, P <0.001), and ORR (RR = 1.86; 95% CI: 1.32-2.62, P <0.001), while in the low TMB group, the results were no different or even reversed (OS: HR = 0.89; 95% CI: 0.64-1.24, P = 0.485; PFS: HR = 1.21, 95% CI: 0.93-1.58, P = 0.154; ORR: RR = 0.68, 95% CI: 0.54-0.85, P = 0.001). TMB could predict the enhanced survival benefit of NSCLC patients treated with ICIs; however the role of bTMB is limited at this stage. For NSCLC patients with high TMB, ICIc may be a better option than chemotherapy.

Zhang N ，Zhang J ，Wang G ，He X ，Mi Y ，Cao Y ，Yu X ... -  《Frontiers in Oncology》

The relationship between blood-based tumor mutation burden level and efficacy of PD-1/PD-L1 inhibitors in advanced non-small cell lung cancer: a systematic review and meta-analysis.

The predictive role of blood-based tumor mutation burden (bTMB) for selecting advanced nonsmall cell lung cancer (NSCLC) patients who might benefit from immune checkpoint inhibitors (ICIs) is still under debate. Therefore, the purpose of this meta-analysis was to evaluate the efficacy of programmed cell death 1 (PD-1) /programmed cell death ligand 1 (PD-L1) inhibitors versus that of standard-of-care therapy in patients with NSCLC who were bTMB high and bTMB low. PubMed, Embase, Cochrane, the Web of Science, and ClinicalTrials.gov were searched systematically from inception to February 2021 for studies of PD-1/PD-L1 inhibitors (durvalumab OR atezolizumab OR avelumab OR pembrolizumab OR Nivolumab) that provided hazard ratios (HRs) for overall survival (OS) or progression-free survival (PFS), or odds ratios (ORs) for objective response rate (ORR) in both bTMB high and bTMB low groups. A total of 2338 patients with advanced or metastatic NSCLC from six randomized controlled trials, which all used chemotherapy (CT) as a control, were included in this study. Compared with CT, PD-1/PD-L1 inhibitor therapy improved OS (HR 0.62, 95% CI 0.52-0.75, P < 0.01), PFS (HR 0.57, 95% CI 0.48-0.67, P < 0.01), and ORR (OR 2.69, 95% CI 1.84-3.93, P < 0.01) in bTMB-high NSCLC patients but not in bTMB-low patients (OS HR 0.86, 95% CI 0.69-1.07, P = 0.17; PFS HR 1.00, 95% CI 0.78-1.27, P = 0.98; ORR OR 0.63, 95% CI 0.49-0.80, P = 0.03). Subgroup analyses showed that these results were consistent across all subgroups (line of therapy, therapy regimen, type of NGS panel, PD-L1 expression, and cutoff value). Meta-regression analysis showed that the proportion of patients with squamous cell histology had no statistical effect on clinical outcomes. Sensitivity analyses illustrated that all results were stable. The efficacy of PD-1/PD-L1 inhibitor therapy in advanced NSCLC patients may be dependent on bTMB level. Patients with high bTMB tend to obtain significantly better OS, PFS, and ORR from PD-1/PD-L1 inhibitor therapy than from CT. However, because of multiple limitations, including those related to reproducibility, the results are exploratory and should be interpreted with caution.

Ba H ，Liu L ，Peng Q ，Chen J ，Zhu YD ... -  《BMC CANCER》

The Predictive Efficacy of Tumor Mutation Burden (TMB) on Nonsmall Cell Lung Cancer Treated by Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis.

Nonsmall cell lung cancer (NSCLC) is the most common type of lung cancer, and the majority of NSCLC patients are diagnosed at the advanced stage. Chemotherapy is still the main treatment at present, and the overall prognosis is poor. In recent years, immunotherapy has developed rapidly. Immune checkpoint inhibitors (ICIs) as the representative have been extensively applied for treating various types of cancers. Tumor mutation burden (TMB) as a potential biomarker is used to screen appropriate patients for treatment of ICIs. To verify the predictive efficacy of TMB, a systematic review and meta-analysis were conducted to explore the association between TMB and ICIs. PubMed, EMBASE, Cochrane Library, and son on were systematically searched from inception to April 2020. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were estimated. A total of 11 studies consisting of 1525 nonsmall cell lung cancer (NSCLC) patients were included. Comparison of high and low TMB: pooled HRs for OS, 0.57 (95% CI 0.32 to 0.99; P = 0.046); PFS, 0.48 (95% CI 0.33 to 0.69; P < 0.001); ORR, 3.15 (95% CI 2.29 to 4.33; P < 0.001). Subgroup analysis values: pooled HRs for OS, 0.75 (95% CI 0.29 to 1.92, P = 0.548) for blood TMB (bTMB), 0.44 (95% CI 0.26 to 0.75, P = 0.003) for tissue TMB (tTMB); for PFS, 0.54 (95% CI 0.29 to 0.98, P = 0.044) and 0.43 (95% CI 0.26 to 0.71, P = 0.001), respectively. These findings imply that NSCLC patients with high TMB possess significant clinical benefits from ICIs compared to those with low TMB. As opposed to bTMB, tTMB was thought more appropriate for stratifying NSCLC patients for ICI treatment.

Nan Z ，Guoqing W ，Xiaoxu Y ，Yin M ，Xin H ，Xue L ，Rong W ... -  《-》

The Predictive Value of Tumor Mutation Burden on Efficacy of Immune Checkpoint Inhibitors in Cancers: A Systematic Review and Meta-Analysis.

Background: Despite an increasing understanding about tumor mutation burden (TMB) in cancer immunity and cancer immunotherapy, the comprehensive cognition between TMB and efficiency of immune checkpoint inhibitors (ICIs) is still lacking. A systematic review and meta-analysis was conducted to evaluate the predictive value of TMB on efficacy of ICIs. Methods: Systematic literature search was conducted on PubMed, EMBASE, Web of Science and Cochrane Library up to June 16, 2019. Pooled odds ratio (OR) of objective response rate (ORR), hazard ratio (HR) of progression-free survival (PFS) and overall survival (OS) were estimated by inverse variance weighted fixed-effects model (I 2 ≤ 50%) or DerSimonian-Laird random-effects model (I 2 > 50%). In addition, heterogeneity analysis, sensitivity analysis, publication bias and subgroup analysis were conducted. Moreover, fractional polynomial regression was conducted to investigate the dose-response relationship between TMB cutoffs and efficacy of ICIs. Furthermore, we assessed ORR by TMB and programmed cell death ligand 1 (PD-L1) expression after layering each other in studies which the two could be both acquired. Results: Three thousand six hundred fifty-seven records were retrieved through database searching, and 29 studies with 4,431 patients were finally included in the meta-analysis. TMB high group had significantly improved ORR (pooled OR 3.31, 95% CI 2.61, 4.19, P < 0.001), PFS (pooled HR 0.59, 95% CI 0.49, 0.71, P < 0.001) and OS (pooled HR 0.68, 95% CI 0.53, 0.89, P = 0.004). Sensitivity analyses illustrated the results were stable, and publication bias was identified in ORR. Subgroup analyses showed the predictive value of TMB was significant in non-small-cell lung cancer (except for the OS) and melanoma. In addition, heterogeneity was substantial in targeted next generation sequencing group but tiny in whole exome sequencing group. Furthermore, TMB and PD-L1 expression were capable to predict improved ORR of ICIs after stratification of each other, with tiny heterogeneity. Conclusions: High tumor mutation burden predicted improved efficacy of immune checkpoint inhibitors in cancers, and targeted next generation sequencing for estimating tumor mutation burden in clinic should be standardized to eliminate heterogeneity in the future. Moreover, tumor mutation burden and programmed cell death ligand 1 expression were independent factors on predicting efficacy of immune checkpoint inhibitors.

Wu Y ，Xu J ，Du C ，Wu Y ，Xia D ，Lv W ，Hu J ... -  《Frontiers in Oncology》

Blood tumor mutation burden can predict the clinical response to immune checkpoint inhibitors in advanced non-small cell lung cancer patients.

Tissue tumor mutation burden (tTMB) assessed by whole-exome sequencing (WES), which has been regarded as the gold standard method of tTMB measurement, can predict the clinical benefits of immune checkpoint inhibitors (ICIs). Multiple studies have investigated the feasibility of utilizing large panels to evaluate TMB but have obtained conflicting results. Furthermore, whether blood TMB (bTMB) can also be a predictive biomarker in NSCLC has not been determined. Fifty-six advanced NSCLC patients treated with ICIs were enrolled, including an exploratory cohort (n = 42) and a small independent validation cohort (n = 14). Next-generation sequencing was performed on tumor and plasma samples collected prior to ICI treatment using a panel consisting of 520 cancer-related genes (OncoScreen) to evaluate tTMB/bTMB. WES was also performed on tumor samples to serve as references. A positive correlation between tTMB derived from WES and OncoScreen was observed. OncoScreen-derived tTMB showed a positive correlation with OncoScreen-derived bTMB. Patients with OncoScreen-derived tTMB [Formula: see text] 7 mutations/Mb (p = 0.003) or bTMB [Formula: see text] 11 mutations/Mb (p = 0.0029) had superior progression-free survival (PFS). In the small validation cohort, patients with OncoScreen-derived bTMB [Formula: see text] 11 mutations/Mb exhibited longer PFS (p = 0.192) with a nonsignificant difference. In all 42 patients who had available bTMB and PFS, patients with bTMB [Formula: see text] 11 mutations/Mb had significantly longer PFS (p = 0.011) than those with bTMB [Formula: see text] 11 mutations/Mb. Our study confirmed the feasibility of using large panels to estimate TMB. We also demonstrated that bTMB can serve as a potential biomarker for predicting the efficacy of ICIs in NSCLC.

Chen X ，Fang L ，Zhu Y ，Bao Z ，Wang Q ，Liu R ，Sun W ，Du H ，Lin J ，Yu B ，Chen S ，Zhou J ，Zhou J ... -  《-》