Molecular profiling and matched targeted therapy for patients with advanced melanoma: Results from part I of the MatchMEL study

BackgroundWhile the molecular landscape of melanoma (Mel) has been defined, the clinicopathological associations of pts with BRAF/NRAS wild-type (WT) Mel and immune-checkpoint inhibitors (ICIs) treatment outcomes are less well understood. The MatchMEL study investigated the mutational profile of WT Mel and examined whether targeted treatments could be matched to specific molecular alterations with clinical efficacy.MethodsIn Part 1, consecutive pts with newly diagnosed advanced Mel presenting to two centres in Australia were enrolled. WT pts underwent FoundationOneCDx® (CDx) sequencing. Clinicopathologic features and ICI outcomes were examined. A molecular tumor board analysed CDx results to match targeted therapy to molecular alterations. Part 2 assessed outcomes for patients treated with targeted therapies.Results167 pts were enrolled from Nov '21 to Nov '23, 119 pts were treatment-naïve and 36 received prior neo/adjuvant treatment. A total of 51 (33%) pts had BRAFV600 and 36 (23%) NRAS mutations. Among 68 (44%) WT pts (Table), TMB was possible in 61, with a median 27 Muts/Mb. Pts with mucosal Mel had the lowest TMB (3.5), while the highest TMB was observed in pts with primary Mel of sun-exposed skin (53) and in pts with an NF1 mutation (55). The main mutations were identified in NF1 (37%), BRAF (non-V600; 19%), MEK1 (8%), KIT or PDGFRa (12%), CDKN2a or CDK4 (48%). In 16%, NF1 and CDKN2a/CDK4 mutations overlapped. Aftrer a median 11.6 (2.5-29) months follow-up, the ORR to first-line ICI in treatment-naïve pts was numerically higher in the NF1 population followed by the NRAS and BRAFV600 (75%, 64% and 51%, respectively, p>0.05); among WT pts, lower TMB was seen in neo/adjuvant ICIs progressors compared to treatment-naïve pts (11 vs. 37, p=0.016). Table: 1088P BRAF/NRAS wild-type population (n=68) Primary melanoma type Cutaneous, No. (%) 48 (71) Sun-exposed, No. (%) 27 (56) Non sun-exposed, No. (%) 21 (44) Acral, No. (%) 4 (6) Mucosal, No. (%) 4 (6) Unknown, No. (%) 12 (17) CDx results n=63 TMB, median NF1, No. (%) 23 (37) ∗ 55 (10-264) BRAF non-V600, No. (%) 12 (19), class 2 (n=8), class 3 (n=3) 21.5 (4-135) KIT or PDGFRa, No. (%) 8 (12) 62 (0-140) CDKN2A/B or CDK4, No. (%) 30 (48) ∗ 24 (0-140) MEK1, No. (%) 5 (8) 33 (5-72) NRAS 1 8 ∗n=10 overlapping NF1 and CDKN2A/B or CDK4 ConclusionsPreliminary results of the MatchMel study revealed a variety of molecular mutations in WT melanoma pts. NF1 alterations appeared to be linked with Hi-TMB, which was associated with response to immunotherapy.Clinical trial identificationNCT02645149.Legal entity responsible for the studyMelanoma Institute Australia.FundingRoche, Novartis.DisclosureM.S. Carlino: Financial Interests, Personal, Advisory Board, Consultant Advisor: MSD, BMS, Novartis, Amgen, Oncosec, Merck, Sanofi, Ideaya, Pierre Fabre, Eisai, Nektar, Regeneron. I. Pires da Silva: Financial Interests, Personal, Invited Speaker: BMS, MSD, Roche, Novartis; Financial Interests, Personal, Other, Travel Support: BMS, Roche; Financial Interests, Personal, Advisory Board: MSD. G.V. Long: Financial Interests, Personal, Other, Consultant Advisor: Agenus Inc, Amgen Inc, Array Biopharma Inc, AstraZeneca UK Limited, Bayer Healthcare Pharmaceuticals, BioNTech SE, Boehringer Ingelheim Ingelheim International GmbH, Bristol Myers Squibb, Evaxion Biotech A/S, Hexal AG, Highlight Therapeutics S.L, IOBiotech, Immunocore Ireland Limited, Innovent Bioilogics USA Inc, Merck Sharp & Dohme, Novartis Pharma AG, PHMR Limited, Pierre Fabre, Regeneron Pharmaceuticals Inc, Scancell Limited, SkylineDX B.V; Non-Financial Interests, Principal Investigator, GL is PI on over 30 clinical trials: GL is PI on over 30 clinical trials. A.M. Menzies: Financial Interests, Personal, Advisory Board, advisory board: BMS, MSD, Novartis, Roche, Pierre Fabre, QBiotics. All other authors have declared no conflicts of interest.