What question did this study set out to answer?

The aim is to investigate the molecular profile of BRAF/NRAS wild-type melanoma and its treatment outcomes with immune checkpoint inhibitors.

March 14, 2026

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

Key Points

The aim is to investigate the molecular profile of BRAF/NRAS wild-type melanoma and its treatment outcomes with immune checkpoint inhibitors.
Enrolled consecutive patients with advanced melanoma at two Australian centers.
Conducted FoundationOneCDx sequencing for BRAF/NRAS WT patients.
Collected clinical, pathologic, and treatment data; analyzed associations using logistic regression and Kaplan-Meier methods.
Stratified patients by mutational status including BRAF, NRAS, NF1, and triple wild-type.
Out of 210 patients, 48% were BRAF/NRAS wild-type.
37% of patients with NF1 mutations had the highest median tumor mutational burden.
NF1-mutant melanoma showed a median progression-free survival of 26.8 months, indicating positive treatment outcome.

Abstract

PURPOSE Although the clinicopathologic features of BRAF/NRAS -mutant melanoma are well defined, the molecular landscape, clinicopathologic features, and treatment outcomes of BRAF/NRAS 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. METHODS In Part 1, consecutive patients with advanced melanoma at two Australian centers were enrolled. BRAF / NRAS WT patients underwent FoundationOneCDx (F1CDx) sequencing. Clinical, pathologic, and treatment data were collected. Patients were stratified by mutational status ( BRAF , NRAS , NF1 , 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. RESULTS From 2021 to 2023, 210 patients were enrolled. Fifty-seven (27%) had BRAF V600 mutation, 53 (25%) had NRAS mutation, and 100 (48%) were BRAF/NRAS WT. Of these, 86 underwent profiling; NF1 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; P = .58) and higher ORR (63%; P = .67) to first-line ICIs than other subtypes. CONCLUSION Our findings suggest significant clinical, pathologic, and molecular correlations in an Australian cohort of advanced melanoma treated with ICIs. Patients with NF1 mutation exhibited higher TMB, which was associated with improved response to ICIs.

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Cite This Study

Boutros et al. (Sun,) studied this question.

synapsesocial.com/papers/69b4fbb1b39f7826a300c159 https://doi.org/https://doi.org/10.1200/po-25-00886

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