Targeted DNA Sequencing of Cutaneous Melanoma Identifies Prognostic and Predictive Alterations.

BACKGROUND: Cutaneous melanoma (CM) can be molecularly classified into four groups: BRAF mutant, NRAS mutant, NF1 mutant and triple wild-type (TWT) tumors lacking any of these three alterations. In the era of immune checkpoint inhibition (ICI) and targeted molecular therapy, the clinical significance of these groups remains unclear. Here, we integrate targeted DNA sequencing with comprehensive clinical follow-up in CM patients. METHODS: This was a retrospective cohort study that assessed clinical and molecular features from patients with localized or metastatic CM who underwent targeted next-generation sequencing as part of routine clinical care. A total of 254 patients with CM who had a CLIA-certified targeted sequencing assay performed on their tumor tissue were included. RESULTS: Of the 254 patients with cutaneous melanoma, 77 were BRAF mutant (30.3%), 77 were NRAS mutant (30.3%), 47 were NF1 mutant (18.5%), 33 were TWT (13.0%) and the remaining 20 (7.9%) carried mutations in multiple driver genes (BRAF/NRAS/NF1 co-mutated). The majority of this co-mutation group carried mutations in NF1 (n = 19 or 90%) with co-occurring mutations in BRAF or NRAS, often with a weaker oncogenic variant. Consistently, NF1 mutant tumors harbored numerous significantly co-altered genes compared to BRAF or NRAS mutant tumors. The majority of TWT tumors (n = 29, 87.9%) harbor a pathogenic mutation within a known Ras/MAPK signaling pathway component. Of the 154 cases with available TMB data, the median TMB was 20 (range 0.7-266 mutations/Mb). A total of 14 cases (9.1%) were classified as having a low TMB (≤5 mutations/Mb), 64 of 154 (41.6%) had an intermediate TMB (>5 and ≤20 mutations/Mb), 40 of 154 (26.0%) had a high TMB (>20 and ≤50 mutations/Mb) and 36 of 154 (23.4%) were classified as having a very high TMB (>50 mutations/Mb). NRAS mutant melanoma demonstrated significantly decreased overall survival on multivariable analysis (HR for death 2.95, 95% CI 1.13-7.69, p = 0.027, log-rank test) compared with other TCGA molecular subgroups. Of the 116 patients in our cohort with available treatment data, 36 received a combination of dual ICI with anti-CTLA4 and anti-PD1 inhibition as first-line therapy. Elevated TMB was associated with significantly longer progression-free survival following dual-agent ICI (HR 0.26, 95% CI 0.07-0.90, p = 0.033, log-rank test). CONCLUSIONS: NRAS mutation in CMs correlated with significantly worse overall survival. Elevated TMB was associated with increased progression-free survival for patients treated with a combination of dual ICI, supporting the potential utility of TMB as a predictive biomarker for ICI response in melanoma.

Current Role and Status for Intratumoral Injection Therapies in Metastatic Melanoma.

ABSTRACT: Intratumoral therapies represent a unique avenue for drug development in melanoma as patients often have accessible lesions that are particularly amenable to these approaches. In addition, a majority of intratumoral therapies have focused on stimulating antitumor immune responses, making them a particularly attractive option for use in melanoma. In this review, we describe applications for talimogene laherparepvec, a US Food and Drug Administration-approved intratumoral therapy in melanoma, as well as several classes of intratumoral therapies in development including novel oncolytic viruses, mRNA-based intratumoral injections, and cytokines and other signaling molecules.

Therapeutic Strategies in BRAF V600 Wild-Type Cutaneous Melanoma.

There have been many recent advances in melanoma therapy. While 50% of melanomas have a BRAF mutation and are a target for BRAF inhibitors, the remaining 50% are BRAF wild-type. Immune checkpoint inhibitors targeting PD-1, cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and lymphocyte activated gene-3 (Lag-3) are all approved for the treatment of patients with advanced BRAF wild-type melanoma; however, treatment of this patient population following initial immune checkpoint blockade is a current therapeutic challenge given the lack of other efficacious options. Here, we briefly review available US FDA-approved therapies for BRAF wild-type melanoma and focus on developing treatment avenues for this heterogeneous group of patients. We review the basics of genomic features of both BRAF mutant and BRAF wild-type melanoma as well as efforts underway to develop new targeted therapies involving the mitogen-activated protein kinase (MAPK) pathway for patients with BRAF wild-type tumors. We then focus on novel immunotherapies, including developing checkpoint inhibitors and agonists, cytokine therapies, oncolytic viruses and tumor-infiltrating lymphocytes, all of which represent potential therapeutic avenues for patients with BRAF wild-type melanoma who progress on currently approved immune checkpoint inhibitors.