There is no standard active treatment for metastatic uveal melanoma. Precision medicine with high-throughput genomics could improve the outcome of patients suffering of “hard-to-treat” cancer.
Metastatic uveal melanoma included in the prospective TREAT20Plus study had fresh tumor biopsies that were subjected to a complete genomic analysis program (WGS, whole exome seq, RNAseq, Methylome, Proteome and cell culture). Integrative data analysis was performed and generated a comprehensive molecular tumor analysis (CMTA). An interdisciplinary molecular tumour board interpreted the data and provided treatment recommendations.
Thirteen patients (6 F, 7 M) were biopsied. Age: 68 (33-81). Site of biopsy: soft tissue: 5, liver: 4, lung: 2, pleura: 1, lymph node: 1. Pre-treatment number: 2 (0-4) and type: iv chemotherapy: 10, checkpoint Inh:6, intra-hepatic: 8. Genomic results were available in the first 10 patients within 34 days (31-40). The number of mutations was low: median 25 (16-44.). Mutations were found in GNAQ: 11, GNA11: 6, BAP1; 3, SF3B1: 4. We detected one gene-fusion: ZNF704-PKIA. The most frequent gene overexpression affected the following genes: MYC: 7, MET: 5, BCL2: 4, CCND2: 1, ERBB3: 1. There was a loss of expression of: CDKN2A: 2, PTEN: 1, EFS: 1. A slightly up-regulated expression of ALK was detected in one patient and confirmed as an oncogenic ALKATI isoform that originates from an alternative internal transcription start site in intron 19. At time of recurrence a second biopsy showed a complete loss of CDKN2A expression through a bi-allelic loss of chromosome 9. Treatment recommendations were the following: inhibitor of MEK: 10, of MET: 5, of CDK4/6: 3, of ALK: 1, of PI3K: 1. Treatment was initiated in 7 patients: 5 received Trametinib, one patient each received Palbociclib, Crizotinib or Cabozantinib, respectively. Among the 6 currently evaluable patients one showed minor response (15%), one a stable disease, one progressive disease, and 3 patients cannot yet be evaluated.
Genomic integrative analysis showed a net advantage over exome-only or panel sequencing. This strategy is clinically feasible and led to individualized treatment recommendations. Treatment outcome will be presented for the whole cohort.
Clinical trial identification
Legal entity responsible for the study
Charité Comprehensive Cancer Center
German Federal Ministry of Research and Education (BMBF) grant Nr. 031A512 Max Planck Society
M. Schuette, C. Wierling, B. Lange: Employees of Alacris Theranostics. T. Kessler: Employee of Alacris Theranostics GmbH. F. Kiecker: Advisory Boards: Novartis, Bristol-Myers Squibb, MSD, Roche, Amegen, Merck Serono. H. Lehrach: Board of direction of Alacris Theranostics. U. Keilholz: Speaker honoraria and advisory board roles are with AstraZeneca, Bristol-Myers Squibb, Merck, MSD, Pfizer, Novartis, Innate Corporate-sponsored research is with AstraZeneca and Merck. All other authors have declared no conflicts of interest.