Rationale for Immune Checkpoint Inhibitors Plus Targeted Therapy in Metastatic Melanoma

Dummer, Reinhard; Ascierto, Paolo A.; Nathan, Paul; Robert, Caroline; Schadendorf, Dirk

doi:10.1001/jamaoncol.2020.4401

Cited by 54 publications

(56 citation statements)

References 70 publications

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“…Melanoma is a tumor with strong immunogenicity. Pathological studies have reported that there is a high number of immune cell infiltration in melanoma tissues and, immunotherapy can directly inhibit tumor progression or even cure tumors [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Gene expression and immune infiltration in melanoma patients with different mutation burden

Wang

et al. 2021

BMC Cancer

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Background Immunotherapy is a vital component in cancer treatment. However, due to the complex genetic bases of cancer, a clear prediction index for efficacy has not been established. Tumor mutation burden (TMB) is one of the essential factors that affect immunotherapeutic efficacies, but it has not been determined whether the mutation is associated with the survival of Skin Cutaneous Melanoma (SKCM) patients. This study aimed at evaluating the correlation between TMB and immune infiltration. Methods Somatic mutation profiles (n = 467), transcriptome data (n = 471), and their clinical information (n = 447) of all SKCM samples were downloaded from The Cancer Genome Atlas (TCGA) database. For each sample, TMB was calculated as the number of variants per megabase. Based on K-M survival analysis, they were allocated into the high-TMB and low-TMB groups (the optimal cutoff was determined by the ‘surv_cutpoint’ algorithm of survival R package). Then, Gene ontology (GO) and Gene Set Enrichment Analyses (GSEA) were performed, with immune-associated biological pathways found to be significantly enriched in the low-TMB group. Therefore, immune genes that were differentially expressed between the two groups were evaluated in Cox regression to determine their prognostic values, and a four-gene TMB immune prognostic model (TMB-IP) was constructed. Results Elevated TMB levels were associated with better survival outcomes in SKCM patients. Based on the cutoff value in OS analysis, they were divided into high-TMB and low-TMB groups. GSEA revealed that the low-TMB group was associated with immunity while intersection analysis revealed that there were 38 differentially expressed immune-related genes between the two groups. Four TMB-associated immune genes were used to construct a TMB-IP model. The AUC of the ROC curve of this model reached a maximum of 0.75 (95%CI, 0.66–0.85) for OS outcomes. Validation in each clinical subgroup confirmed the efficacy of the model to distinguish between high and low TMB-IP score patients. Conclusions In SKCM patients, low TMB was associated with worse survival outcomes and enriched immune-associated pathways. The four TMB-associated immune genes model can effectively distinguish between high and low-risk patients.

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Section: Introductionmentioning

confidence: 99%

Gene expression and immune infiltration in melanoma patients with different mutation burden

Wang

et al. 2021

BMC Cancer

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“…To this end, the concurrent use of BRAF-MEK inhibitors and ICB or the sequenced use could favor a higher response with improved survival and is currently under investigation. Of importance, it has been suggested that when using an approach utilizing targeted therapy followed by ICB, waiting until progression while on BRAF-MEK inhibitors prior to starting immunotherapy could lead to an immunosuppressive environment and downregulation of effector T cells, which could negatively impact the efficacy of ICB [ 24 ]. This further supports our approach of switching BRAF-MEK inhibitors to ICB prior to an evidence of progressive disease in our patient.…”

Section: Discussionmentioning

confidence: 99%

BRAF-MEK Inhibitors as Steroid-Sparing Bridge Prior to Checkpoint Blockade Therapy in Symptomatic Intracranial Melanoma

2021

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The introduction of immune checkpoint blockade (ICB) and BRAF-MEK inhibitors has substantially improved outcomes in patients with metastatic melanoma. However, several challenging factors may hinder the efficacy of ICB in patients with symptomatic intracranial metastatic melanoma who are immunosuppressed due to the use of steroids prior to the administration of ICB. This has resulted in the exclusion of patients treated with high dose steroid at baseline from the majority of ICB clinical trials. In addition, despite the high efficacy of BRAF-MEK inhibitors in BRAF-mutant intracranial metastatic melanoma, most tumors will eventually progress. This demonstrates a gap in addressing the best management in such patients. Here, we present a case demonstrating our approach in this patient population.

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“…Despite the conflicting data from these retrospective cases, the success of this combination in pre-clinical studies led to the initiation of several clinical trials designed to prospectively assess the efficacy of combined MAPK/ERK targeted therapy and ICB (reviewed in [128][129][130]. Early phase safety trials of MAPK/ERK inhibitors co-administered with anti-CTLA-4 therapy demonstrated significant toxicities (131)(132)(133).…”

Section: Combining Mapk/erk-targeted Therapy With Immune Checkpoint Blockadementioning

confidence: 99%

Immunomodulatory Effects of BRAF, MEK, and CDK4/6 Inhibitors: Implications for Combining Targeted Therapy and Immune Checkpoint Blockade for the Treatment of Melanoma

et al. 2021

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The recent advent of targeted and immune-based therapies has revolutionized the treatment of melanoma and transformed outcomes for patients with metastatic disease. The majority of patients develop resistance to the current standard-of-care targeted therapy, dual BRAF and MEK inhibition, prompting evaluation of a new combination incorporating a CDK4/6 inhibitor. Based on promising preclinical data, combined BRAF, MEK and CDK4/6 inhibition has recently entered clinical trials for the treatment of BRAFV600 melanoma. Interestingly, while BRAF- and MEK-targeted therapy was initially developed on the basis of potent tumor-intrinsic effects, it was later discovered to have significant immune-potentiating activity. Recent studies have also identified immune-related impacts of CDK4/6 inhibition, though these are less well defined and can be both immune-potentiating and immune-inhibitory. BRAFV600 melanoma patients are also eligible to receive immunotherapy, specifically checkpoint inhibitors against PD-1 and CTLA-4. The immunomodulatory activity of BRAF/MEK-targeted therapies has prompted interest in combination therapies incorporating these with immune checkpoint inhibitors, however recent clinical trials investigating this approach have produced variable results. Here, we summarize the immunomodulatory effects of BRAF, MEK and CDK4/6 inhibitors, shedding light on the prospective utility of this combination alone and in conjunction with immune checkpoint blockade. Understanding the mechanisms that underpin the clinical efficacy of these available therapies is a critical step forward in optimizing novel combination and scheduling approaches to combat melanoma and improve patient outcomes.

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Rationale for Immune Checkpoint Inhibitors Plus Targeted Therapy in Metastatic Melanoma

Cited by 54 publications

References 70 publications

Gene expression and immune infiltration in melanoma patients with different mutation burden

Gene expression and immune infiltration in melanoma patients with different mutation burden

BRAF-MEK Inhibitors as Steroid-Sparing Bridge Prior to Checkpoint Blockade Therapy in Symptomatic Intracranial Melanoma

Immunomodulatory Effects of BRAF, MEK, and CDK4/6 Inhibitors: Implications for Combining Targeted Therapy and Immune Checkpoint Blockade for the Treatment of Melanoma

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