1218PD - Precision medicine for the treatment of metastatic uveal melanoma: a pilot study.

Date 11 September 2017
Event ESMO 2017 Congress
Session Melanoma and other skin tumours
Topics Cancer in Adolescents
Melanoma and other Skin Tumours
Presenter Serge Leyvraz
Citation Annals of Oncology (2017) 28 (suppl_5): v428-v448. 10.1093/annonc/mdx377
Authors S. Leyvraz1, M. Schuette2, D.T. Rieke1, T. Kessler2, S. Ochsenreither1, V. Amstislavskiy3, T. Risch3, C. Wierling2, K. Joehrens4, C.A. Peuker5, M. Lamping1, S. Burock1, G. Poch6, F. Kiecker6, R. Schaefer1, B. Lange2, H. Lehrach3, A. Joussen7, U. Keilholz1, M. Yaspo8
  • 1Charite Comprehensive Cancer Center, Charité University Hospital, 10117 - Berlin/DE
  • 2Alacris Theranostics Gmbh, Alacris Theranostics GmbH, 14195 - Berlin/DE
  • 3Otto Warburg Laboratory Gene Regulation And Systems Biology Of Cancer, Max Planck Institute for Molecular Genetics, 14195 - Berlin/DE
  • 4Institut Of Pathologie, Charité University Hospital, 10117 - Berlin/DE
  • 5Department Of Hematology And Medical Oncology, Charite, Campus Benjamin Franklin, 12200 - Berlin/DE
  • 6Clinic Of Dermatology, Charité University Hospital, 10117 - Berlin/DE
  • 7Department Of Ophtalmology, Charité University Hospital, 13353 - Berlin/DE
  • 8Department Of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 - Berlin/DE

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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

Funding

German Federal Ministry of Research and Education (BMBF) grant Nr. 031A512 Max Planck Society

Disclosure

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.