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Predictive Biomarkers for Outcomes of Immune Checkpoint Inhibitors (ICIs) in Melanoma: A Systematic Review.

ABSTRACT: Immune checkpoint inhibitors (ICIs) have strongly improved the survival of melanoma patients. However, as durable response to ICIs are only seen in a minority, there is an unmet need to identify biomarkers that predict response. Therefore, we provide a systematic review that evaluates all biomarkers studied in association with outcomes of melanoma patients receiving ICIs. We searched Pubmed, COCHRANE Library, Embase, Emcare, and Web of Science for relevant articles that were published before June 2020 and studied blood, tumor, or fecal biomarkers that predicted response or survival in melanoma patients treated with ICIs. Of the 2536 identified reports, 177 were included in our review. Risk of bias was high in 40%, moderate in 50% and low in 10% of all studies. Biomarkers that correlated with response were myeloid-derived suppressor cells (MDSCs), circulating tumor cells (CTCs), CD8+ memory T-cells, T-cell receptor (TCR) diversity, tumor-infiltrating lymphocytes (TILs), gene expression profiling (GEP), and a favorable gut microbiome. This review shows that biomarkers for ICIs in melanoma patients are widely studied, but heterogeneity between studies is high, average sample sizes are low, and validation is often lacking. Future studies are needed to further investigate the predictive utility of some promising candidate biomarkers.

SUBMITTER: Baltussen JC

PROVIDER: S-EPMC8699321 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Predictive Biomarkers for Outcomes of Immune Checkpoint Inhibitors (ICIs) in Melanoma: A Systematic Review.

Baltussen Joosje C JC Welters Marij J P MJP Verdegaal Elizabeth M E EME Kapiteijn Ellen E Schrader Anne M R AMR Slingerland Marije M Liefers Gerrit-Jan GJ van der Burg Sjoerd H SH Portielje Johanneke E A JEA de Glas Nienke A NA

Cancers 20211218 24

Immune checkpoint inhibitors (ICIs) have strongly improved the survival of melanoma patients. However, as durable response to ICIs are only seen in a minority, there is an unmet need to identify biomarkers that predict response. Therefore, we provide a systematic review that evaluates all biomarkers studied in association with outcomes of melanoma patients receiving ICIs. We searched Pubmed, COCHRANE Library, Embase, Emcare, and Web of Science for relevant articles that were published before Jun ...[more]

PMID: 34944986

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Project description:BACKGROUND:Immune checkpoint inhibitors (ICIs), targeting CTLA-4 or PD-1 molecules, have shown impressive therapeutic results. However, only 20-40% of advanced melanoma patients have durable responses to ICI, and these positive effects must be balanced against severe off-target immune toxicity and high costs. This urges the development of predictive biomarkers for ICI response to select patients with likely clinical benefit from treatment. Although many candidate biomarkers exist, a systematic overview of biomarkers and their usefulness is lacking. OBJECTIVES:Here, we systematically review the current literature of clinical data of ICI treatment to provide an overview of candidate predictive biomarkers for ICI in melanoma patients. METHODS:To identify studies on biomarkers for clinical response or survival to ICI therapy in melanoma patients, we performed a systematic search in OVID MEDLINE and retrieved 429 publications, of which 67 met the eligibility criteria. RESULTS:Blood and genomic biomarkers were mainly studied for CTLA-4 ICI, while tumor tissue markers were analyzed for both CTLA-4 and PD-1 ICI. Blood cytology and soluble factors correlated more frequently to overall survival (OS) than to response, indicating their prognostic rather than predictive nature. Systemic T-cell response and regulation markers correlated to response, but progression-free survival or OS were not analyzed. Tumor tissue analyses revealed response correlations with mutational load, neoantigen load, immune-related gene expression, and CD8+ T-cell infiltration at the invasive margin. The predictive value of PD-L1 varied, possibly due to the influence of T-cell infiltration on tumor PD-L1 expression. Genomic biomarker studies addressed CTLA-4 and other immune-related genes. CONCLUSION:This review outlines all published biomarkers for ICI therapy and highlights potential candidate markers for future research. To date, PD-L1 is the best studied biomarker for PD-1 ICI response. The most promising candidate predictive biomarkers for ICI response have not yet been identified. Variations in outcome parameters, statistical power, and analyses hampered summary of the results. Further investigation of biomarkers in larger patient cohorts using standardized objectives and outcome measures is recommended.

Project description:IntroductionAcral melanoma (AM) has different biological characteristics from cutaneous melanoma. Although systemic therapeutic strategies for advanced AM resemble those for advanced cutaneous melanoma, the evidence of the clinical use of immune checkpoint inhibitors (ICIs) for AM is still inadequate. We aimed to systematically analyze the therapeutic effects and safety profile of ICI treatments in advanced AM.MethodsThis systematic review was conducted in line with a previously registered protocol. Three electronic databases, conference abstracts, clinical trial registers, and reference lists of included articles were searched for eligible studies. The primary outcomes were therapeutic effects, and the secondary outcomes were the safety profiles.ResultsThis systematic review included six studies investigating anti-CTLA-4 immunotherapy, 12 studies investigating anti-PD-1 immunotherapy, one study investigating the combination therapy of anti-CTLA-4 and anti-PD-1, and one study investigating anti-PD-1 immunotherapy in combination with radiotherapy. In most studies investigating ipilimumab, the anti-CTLA-4 antibody, the objective response rate ranged from 11.4 to 25%, the median progression-free survival ranged from 2.1 to 6.7 months, and the median overall survival was more than 7.16 months. For studies discussing anti-PD-1 immunotherapy with nivolumab, pembrolizumab, or JS001, the objective response rate ranged from 14 to 42.9%, the median progression-free survival ranged from 3.2 to 9.2 months, and the median overall survival was more than 14 months. The combination therapy of anti-CTLA-4 and anti-PD-1 immunotherapy showed better efficacy with an objective response rate of 42.9% than single-agent therapy. The retrospective study investigating the combination therapy of anti-PD-1 immunotherapy and radiation showed no overall response. Few outcomes regarding safety were reported in the included studies.ConclusionsICIs, especially anti-CTLA-4 monoclonal antibodies combined with anti-PD-1 antibodies, are effective systematic treatments in advanced AM. However, there remains a lack of high-level evidence to verify their efficacy and safety and support their clinical application.

Project description:Advances in immunotherapy, including immune checkpoint inhibitors (ICIs), have transformed the standard of care for many types of cancer including melanoma. ICIs have improved the overall outcome of melanoma patients; however, a significant proportion of patients suffer from primary or secondary tumor resistance. Therefore, there is an urgent need to develop predictive biomarkers to better select patients for ICI therapy. Numerous biomarkers that predict the response of melanoma to ICIs have been investigated, including biomarker signatures based on genomics or transcriptomics. Most of these predictive biomarkers have not been systematically evaluated across different cohorts to determine the reproducibility of these signatures in metastatic melanoma. We evaluated 28 previously published predictive biomarkers of ICIs based on gene expression signatures in eight previously published studies with available RNA-sequencing data in public repositories. We found that signatures related to IFN-γ-responsive genes, T and B cell markers, and chemokines in the tumor immune microenvironment are generally predictive of response to ICIs in these patients. In addition, we identified that these predictive biomarkers have higher predictive values in on-treatment samples as compared to pretreatment samples in metastatic melanoma. The most frequently overlapping genes among the top 18 predictive signatures were CXCL10, CXCL9, PRF1, RANTES, IFNG, HLA-DRA, GZMB, and CD8A. From gene set enrichment analysis and cell type deconvolution, we estimated that the tumors of responders were enriched with infiltrating cytotoxic T-cells and other immune cells and the upregulation of genes related to interferon-γ signaling. Conversely, the tumors of non-responders were enriched with stromal-related cell types such as fibroblasts and myofibroblasts, as well as enrichment with T helper 17 cell types across all cohorts. In summary, our approach of validating and integrating multi-omics data can help guide future biomarker development in the field of ICIs and serve the quest for a more personalized therapeutic approach for melanoma patients.

Project description:BackgroundConventional cytotoxic chemotherapy offers minor benefit to patients with mucosal melanoma (MM). Although immune checkpoint inhibitors (ICIs) have become the preferred approach in patients with advanced or metastatic cutaneous melanoma, the evidence of their clinical use for MM is still limited. This systematic review aims to summarize the efficacy and safety of ICIs in advanced or metastatic MM.MethodsWe searched electronic databases, conference abstracts, clinical trial registers and reference lists for relevant studies. The primary outcomes included the overall response rate (ORR), median progression-free survival (PFS), median overall survival (OS), one-year PFS rate, and one-year OS rate.ResultsThis review identified 13 studies assessing anti-CTLA-4 monotherapy, 22 studies assessing anti-PD-1 monotherapy, two studies assessing anti-CTLA-4 and anti-PD-1 combination therapy, one study assessing anti-PD-1 antibodies combined with axitinib, and three studies assessing anti-PD-1 antibodies combined with radiotherapy. For most patients who received ipilimumab monotherapy, the ORR ranged from 0% to 17%, the median PFS was less than 5 months, and the median OS was less than 10 months. For patients who received nivolumab or pembrolizumab monotherapy, most studies showed an ORR of more than 15% and a median OS of more than 11 months. The combined administration of anti-CTLA-4 and anti-PD-1 agents showed benefits over single-agent therapy with an ORR of more than 33.3%. In a phase Ib trial of toripalimab in combination with axitinib, approximately half of patients had complete or partial responses. Three retrospective studies that investigated anti-PD-1 antibodies combined with radiotherapy showed an ORR of more than 50%, which was higher than each single modality treatment.ConclusionsImmune checkpoint inhibitors, especially anti-PD-1 monoclonal antibodies alone and in combination with anti-CTLA-4 monoclonal antibodies or other modalities, are promising treatment options for advanced or metastatic MM. However, high-level evidence is still needed to support the clinical application.

Dataset Information

Predictive Biomarkers for Outcomes of Immune Checkpoint Inhibitors (ICIs) in Melanoma: A Systematic Review.

Publications

Predictive Biomarkers for Outcomes of Immune Checkpoint Inhibitors (ICIs) in Melanoma: A Systematic Review.

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