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Published on: May 18, 2018
Molecular Profiling and Matched Targeted Therapy for Patients With Advanced Melanoma: Results From Part 1 of the
Andrea Boutros1,2, Matteo S Carlino1,3, Raja Chaganti3
1Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia.
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.
Insights
Advanced melanoma patients with NF1 mutations showed higher tumor mutational burden and better response to immune checkpoint inhibitors (ICIs). This finding highlights potential therapeutic targets in BRAF/NRAS wild-type melanoma.
Area of Science:
- Oncology
- Genomics
- Immunotherapy
Background:
- Clinicopathologic features of BRAF/NRAS-mutant melanoma are established.
- The molecular profile and treatment outcomes of BRAF/NRAS wild-type (WT) melanoma patients receiving immune checkpoint inhibitors (ICIs) require further elucidation.
- The MatchMEL study aimed to address these knowledge gaps.
Purpose of the Study:
- To investigate the genomic landscape of BRAF/NRAS WT advanced melanoma.
- To identify clinicopathologic features and molecular alterations in patients treated with ICIs.
- To correlate molecular findings with treatment response and survival outcomes.
Main Methods:
- Enrolled 210 patients with advanced melanoma across two Australian centers.
- Performed FoundationOneCDx (F1CDx) sequencing on BRAF/NRAS WT patients.
- Analyzed associations between tumor mutational burden (TMB), overall response rates (ORR), and progression-free survival (PFS) using logistic regression and Kaplan-Meier methods.
Main Results:
- Identified 100 (48%) BRAF/NRAS WT patients among the cohort.
- Detected NF1 mutations in 37 (43%) of profiled WT patients, associated with the highest median TMB (53 mut/Mb).
- NF1-mutant melanoma demonstrated a numerically longer median PFS (26.8 months) and higher ORR (63%) to first-line ICIs compared to other subtypes.
Conclusions:
- Significant clinical, pathologic, and molecular correlations exist in advanced melanoma patients treated with ICIs.
- NF1 mutations in melanoma are linked to increased TMB.
- Higher TMB associated with NF1 mutations correlates with improved response to ICIs.
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