Molecular Profiling and Matched Targeted Therapy for Patients With Advanced Melanoma: Results From Part 1 of the MatchMEL Study.

Abstract

Although the clinicopathologic features of <i>BRAF/NRAS</i>-mutant melanoma are well defined, the molecular landscape, clinicopathologic features, and treatment outcomes of <i>BRAF/NRAS</i> wild-type (WT) patients on immune checkpoint inhibitors (ICIs) remain less clear. The MatchMEL study investigated the mutational profile of WT melanoma (Part 1) and examined whether targeted treatments could be matched to specific molecular alterations with clinical activity (Part 2). We report findings from Part 1 only, focusing on the genomic landscape and clinicopathologic correlates in ICI-treated patients. In Part 1, consecutive patients with advanced melanoma at two Australian centers were enrolled. <i>BRAF</i>/<i>NRAS</i> WT patients underwent FoundationOneCDx (F1CDx) sequencing. Clinical, pathologic, and treatment data were collected. Patients were stratified by mutational status (<i>BRAF</i>, <i>NRAS</i>, <i>NF1</i>, triple WT), and associations between tumor mutational burden (TMB), overall response rates (ORR), and survival outcomes (progression-free survival [PFS]) were analyzed using logistic regression and Kaplan-Meier methods. A molecular tumor board analyzed F1CDx results to match targeted therapy to molecular alterations. Part 2 assessed outcomes for patients treated with matched targeted therapies. From 2021 to 2023, 210 patients were enrolled. Fifty-seven (27%) had <i>BRAF</i> V600 mutation, 53 (25%) had <i>NRAS</i> mutation, and 100 (48%) were <i>BRAF/NRAS</i> WT. Of these, 86 underwent profiling; <i>NF1</i> mutations were detected in 37 (43%) and were associated with the highest median TMB (53 mut/Mb). NF1-mutant melanoma had a numerically longer median PFS (26.8 months [95% CI, 20.2 to not reached]; <i>P</i> = .58) and higher ORR (63%; <i>P</i> = .67) to first-line ICIs than other subtypes. Our findings suggest significant clinical, pathologic, and molecular correlations in an Australian cohort of advanced melanoma treated with ICIs. Patients with <i>NF1</i> mutation exhibited higher TMB, which was associated with improved response to ICIs.