5-methylthioadenosine phosphorylase (MTAP) loss in clinically advanced uveal melanoma (CAUM): A comprehensive genomic profiling (CGP) study

BackgroundUveal melanoma is the most prevalent intra-ocular tumor among adults, with nearly half of the patients developing metastatic disease. Treatment options are limited to Tebentafusp in patients with HLA-A*02:01 mutation with immunotherapy and chemotherapy yielding poor results. 5-Methylthioadenosine phosphorylase (MTAP), a key enzyme in the methionine salvage pathway, has emerged as a biomarker for synthetic lethality-based trials featuring Protein Arginine Methyltransferase 5 (PRMT5). In a recent phase I trial of a PRMT5 inhibitor, PRT811, clinical activity was described in cases of CAUM.Methods676 CAUM and 9666 CASM patients underwent hybrid capture based CGP to evaluate genomic alterations (GA). Microsatellite instability high status (MSIH), tumor mutation burden (TMB), homologous recombination defect (HRD) score, genomic ancestry and genomic signature were determined from the sequencing data. PD-L1 was determined by immunohistochemistry (Dako 22C3).ResultsCAUM patients when compared to clinically advanced skin melanoma (CASM) patients were more often female (53.7% vs 36.7%), and younger (median age 64 vs 66). CAUM had lower frequency of UV-light exposure signature (2.5% vs 55.9%), GA/tumor frequency (3 vs 6), and TMB>10mutations/Mb (4.1% vs 58%). CAUM had lower frequency of BRAF GA (13.3% vs 44.4%), MTAP loss associated with 9p chromosomal loss and CDKN2A/B (4% vs 15.5%). CAUM associated GA in GNA11 (44.1%) and GNAQ (46.2%) were rarely identified in CASM (1.0% or less). GA more frequent in CAUM included BAP1 (53.1% vs 1.7%), MYC (33.6% vs 4.0%), while in CASM included KIT (5.4% vs 0.7%), NF1 (21.0% vs 2.1%), and TERT (24.6% vs 4.0%). These differences were statistically significant (p<0.0001). Any level of PD-L1 expression was higher in CASM (43.8% vs 26.1%; p=0.0007). Both groups were noted to have 93% European ancestry and neither group had MSIH cases.ConclusionsAlthough MTAP loss is less frequent in CAUM than in CASM, the recent evidence that this genomic alteration predicts responsiveness to PRMT5 inhibition is noteworthy. This highlights the importance of further investigating this biomarker for patients with this rare and clinically aggressive type of cancer.Legal entity responsible for the studySUNY Upstate Medical University.FundingHas not received any funding.DisclosureD.C. Pavlick: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine, Inc; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche AG. J.S. Ross: Financial Interests, Personal, Full or part-time Employment, Medical Director: Foundation Medicine; Financial Interests, Personal, Stocks/Shares: Roche Holdings, Tango Therapeutics, Celsius Therapeutics. All other authors have declared no conflicts of interest.