The Prognostic Value of ctDNA and bTMB on Immune Checkpoint Inhibitors in Human Cancer.

Circulating tumor DNA (ctDNA) levels and blood tumor mutation burden (bTMB) have a significant impact on the prognosis of tumor patients. However, their prognostic role in immune checkpoint inhibitors (ICIs) in cancer patients is still unclear. We used the Review Manager software (version 5.3) to perform a meta-analysis based on the published literature to explore the prognostic value of ctDNA and bTMB in patients receiving immunotherapy. We extracted the hazard ratios (HRs) of progression-free survival (PFS) and overall survival (OS) for each included study and their respective 95% confidence intervals (CIs) and p-values for analysis. Thirteen studies were included in the meta-analysis. Higher ctDNA levels were significantly associated with shorter OS (HR = 3.35, 95%CI = 2.49-4.51, p < 0.00001) and PFS (HR = 3.28, 95%CI = 2.47-4.35, p < 0.00001). The results of ctDNA subgroup analysis showed that high posttreatment ctDNA levels significantly correlated with shorter OS in cancer patients receiving ICIs (HR = 5.09, 95%CI = 1.43-18.07, p = 0.01). Moreover, patients with ctDNA clearance had better OS (HR = 4.94, 95%CI = 2.96-8.26, p < 0.00001). Patients with high posttreatment ctDNA levels had shorter PFS (HR = 3.00, 95%CI = 2.02-4.46, p < 0.00001) and those with ctDNA clearance had longer PFS (HR = 4.61, 95%CI = 2.78-7.65, p < 0.00001). However, there was no statistically significant difference in the OS benefits between a high and a low bTMB after ICI therapy (HR = 0.68, 95%CI = 0.33-1.37, p = 0.28). The host immune system and tumor burden together determine whether cancer patients can benefit from ICI therapy. Our systematic review and meta-analysis revealed for the first time that the levels of pretreatment and posttreatment ctDNA and the clearance of ctDNA can independently be used as prognostic factors for antitumor immunotherapy, while bTMB cannot. In conclusion, ctDNA levels have great potential as an assistant tool for radiological assessments to make clinical therapeutic decisions. The prognostic utility of bTMB still requires further exploration.

Wei J ，Feng J ，Weng Y ，Xu Z ，Jin Y ，Wang P ，Cui X ，Ruan P ，Luo R ，Li N ，Peng M ... -  《Frontiers in Oncology》

Dynamic bTMB combined with residual ctDNA improves survival prediction in locally advanced NSCLC patients with chemoradiotherapy and consolidation immunotherapy.

Wang Y ，Wang W ，Zhang T ，Yang Y ，Wang J ，Li C ，Xu X ，Wu Y ，Jiang Y ，Duan J ，Wang L ，Bi N ... -  《JNCC-Journal of the National Cancer Center》

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》

ctDNA-adjusted bTMB as a predictive biomarker for patients with NSCLC treated with PD-(L)1 inhibitors.

In non-small cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICIs), higher blood tumor mutational burden (bTMB) was usually associated with better progression-free survival (PFS) and objective response rate (ORR). However, the association between bTMB and overall survival (OS) benefit remains undefined. It has been reported that patients harboring a high level of circulating tumor DNA (ctDNA) had poor survival. We hypothesized that ctDNA-adjusted bTMB might predict OS benefit in NSCLC patients receiving ICIs. Our study was retrospectively performed in three cohorts, including OAK and POPLAR cohort (n = 853), Shanghai and Wuhan (SH&WH) cohort (n = 44), and National Cancer Center (NCC) cohort (n = 47). Durable clinical benefit (DCB) was defined as PFS lasting ≥ 6 months. The cutoff value of ctDNA-adjusted bTMB for DCB prediction was calculated based on a receiver operating characteristic curve. Interaction between treatments and ctDNA-adjusted bTMB was assessed. The bTMB score was significantly associated with tumor burden, while no association was observed between ctDNA-adjusted bTMB with tumor burden. In the OAK and POPLAR cohort, significantly higher ORR (P = 0.020) and DCB (P < 0.001) were observed in patients with high ctDNA-adjusted bTMB than those with low ctDNA-adjusted bTMB. Importantly, the interactions between ctDNA-adjusted bTMB and treatments were significant for OS (interaction P = 0.019) and PFS (interaction P = 0.002). In the SH&WH cohort, the interactions between ctDNA-adjusted bTMB and treatment were marginally significant for OS (interaction P = 0.081) and PFS (interaction P = 0.062). Similar result was demonstrated in the NCC cohort. Our study indicated that ctDNA-adjusted bTMB might predict OS benefit in NSCLC patients receiving ICIs. The potential of ctDNA-adjusted bTMB as a noninvasive predictor for immunotherapy should be confirmed in future studies.

Nie W ，Wang ZJ ，Zhang K ，Li B ，Cai YR ，Wen FC ，Zhang D ，Bai YZ ，Zhang XY ，Wang SY ，Cheng L ，Zhong H ，Liu L ，Wang J ，Han BH ... -  《BMC Medicine》

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》