Clinical application of next-generation sequencing-based panel to BRAF wild-type advanced melanoma identifies key oncogenic alterations and therapeutic strategies

Molecular profiling with next-generation sequencing (NGS) has been applied in multiple solid cancers in order to discover potential therapeutic targets. Here, we describe the results of a clinical NGS panel in advanced melanoma patients. Thirty-six tumor tissues from BRAF wild-type melanoma patients at Seoul National University Hospital (SNUH) were collected and deep-sequenced using the SNUH FIRST-Cancer NGS panel to assess single nucleotide variants, small insertions/deletions, copy number variations, and structural variations to estimate tumor mutation burden (TMB). We discovered 106 oncogenic alterations and most of the patients (n = 33, 92 %) harbored at least one oncogenic alteration, including two patients who were initially diagnosed as BRAF V600E negative but were later confirmed to be positive. Altogether, 36 samples were classified into RAS/BRAF/NF1 mutant (n = 14, 39%) or triple wild-type (n = 22, 61%) melanoma subtypes. The estimated median TMB was 8.2 mutations per Mb, ranging from 0 to 146.67 mutations per Mb. Of the 36 patients, 25 (70%) had actionable alterations with currently developed drugs and 7 (19.4%) were enrolled in clinical trials with RAF inhibitor, multiple receptor tyrosine kinase inhibitor, and anti-programmed cell death-1 (PD-1) antibody. TMB tended to associate with progression-free survival (PFS) of treatment with anti-PD-1/programmed death ligand-1 antibody (hazard ratio 0.96, 95% confidence interval 0.92 - 1.00, p = 0.07). High-TMB (≥13) group was associated with longer PFS than the low-TMB group (Median 34.0 vs. 11.0 weeks, p = 0.04). Overall, the clinical use of NGS panel in advanced melanoma patients shows association with clinical outcomes and several therapeutic strategies.