Abstract
Background: Tumor mutational burden (TMB) is a genomic biomarker that can predict favorable responses to immune checkpoint inhibitors (ICIs). Although we have better understanding of TMB in cancer immunity and cancer immunotherapy, the relationship between TMB and the clinical efficacy of ICIs remains unknown in the treatment of melanoma patients. Here, we conduct a systematic review and meta-analysis to evaluate the predictive value of TMB on the efficacy of ICIs in patients with melanoma. Methods: We systematically collected data from PubMed, Embase, Cochrane Library, CNKI, China Biomedical Database (CBM), and Wanfang Database. The end date was set to 26 June 2021. We included retrospective studies or clinical trials of ICIs that reported hazard ratios (HRs) for overall survival and/or progression-free survival according to TMB. Data for 1,493 patients from 15 studies were included. In addition, pooled effect size, heterogeneity analysis, sensitivity analysis, publication bias detection, and subgroup analysis were performed based on the included data. Results: Patients with high TMB showed significantly improved OS (HR = 0.49, 95% CI: 0.33, 0.73; p = 0.001) and PFS (HR = 0.47, 95% CI: 0.33, 0.68; p < 0.001) compared with patients with low TMB. This association was very good in patients treated with monotherapy, that is, anti-CTLA-4 or anti-PD-(L)-1 inhibitors, but not for the patients treated with a combination of the two drugs. The subgroup analysis results showed that heterogeneity was substantial in the targeted next-generation sequencing (NGS) group. Publication bias was detected, and the results were visualized using the funnel chart. And sensitivity analysis and trim-and-fill method analysis showed that our results were stable and reliable. Conclusion: High TMB is associated with improved OS and PFS in melanoma patients treated with mono-drug ICIs. TMB determined by NGS should be standardized to eliminate heterogeneity. Therefore, the role of TMB in identifying melanoma patients who may benefit from ICI should be further determined in more randomized controlled trials in the future.
Highlights
As a highly aggressive type of skin cancer, melanoma is the leading cause of skin cancer-related deaths, causing nearly 60,000 deaths worldwide each year (Karimkhani et al, 2017)
The primary target of this meta-analysis was to assess the association between Tumor mutational burden (TMB) and OS or PFS in melanoma patients treated with immune checkpoint inhibitors (ICIs)
Our pooled analysis integrated the data of 1,493 melanoma patients, and results showed that compared with the low-TMB group, the risk of death in the high-TMB group was reduced by 51%, and the risk of disease progression was reduced by 53%
Summary
As a highly aggressive type of skin cancer, melanoma is the leading cause of skin cancer-related deaths, causing nearly 60,000 deaths worldwide each year (Karimkhani et al, 2017). With the deepening of research, the emergence of immune checkpoint inhibitors (ICIs) has completely changed the treatment prospects for patients with stage III/IV melanoma. A variety of ICIs have been proven to have a good effect on patients with unresectable or metastatic melanoma. These drugs, whether used as a monotherapy or in combination, produce lasting improvement in survival rates and potential cure rates for patients with advanced-stage III and IV melanomas (Eggermont et al, 2016; Schachter et al, 2017; Larkin et al, 2019). We have better understanding of TMB in cancer immunity and cancer immunotherapy, the relationship between TMB and the clinical efficacy of ICIs remains unknown in the treatment of melanoma patients. We conduct a systematic review and meta-analysis to evaluate the predictive value of TMB on the efficacy of ICIs in patients with melanoma
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