Abstract 1770P
Background
Tebe, an investigational TCR–anti-CD3 bispecific fusion protein that targets gp100 and activates T cells, has shown survival benefit in mUM. In a phase 2 trial enrolling patients (pts) with mUM, we explored genomic correlates of clinical outcomes.
Methods
127 HLA-A*02:01+ pts with advanced UM were treated weekly with 68mcg tebentafusp after intra-patient dose escalation (NCT02570308). RECISTv1.1 was evaluated by IRC. Whole exome sequencing and RNAseq was performed on frozen tumor biopsies collected at baseline (N=63 and N=70, respectively) and after the third dose of tebe (RNAseq, N=up to 35). 100 mRNA signatures cut at the median were tested for association with tumor shrinkage (TS) and overall survival (OS).
Results
Tumor mutations in GNAQ, GNA11, SF3B1 were not associated with TS or OS. Consistent with TCGA, tumor mutation burden was low (0.3-2.4 muts/Mb) and was not associated with TS or OS; however, novel somatic missense mutations in 7 genes (N=32/63) including UCP1 and NOTCH4 were identified and as a group associated with better OS (hazard ratio [HR] 0.2, 95% CI 0.1-0.47). In the tumor and/or microenvironment, high baseline mRNA levels of the type 1 IFN inducible and ISGylation gene UBA7 were associated with greater TS (odds ratio OR 0.2, 0.04-0.53) and OS (HR 0.3, 0.14-0.57). High expression of the type 2 IFN inducible GTPase binding gene, GBP1, was associated with better TS (OR 0.3, 0.08-0.93) and OS (HR 0.4, 0.19-0.73). In contrast, high GBP1 expression was associated with worse OS in TCGA UM (HR 4.3, 1.67,11.14). Expression of these and other type 1&2 IFN genes was significantly induced by tebentafusp (2-4-fold). High baseline levels of JAK2/STAT4, but not other JAK/STATs, were associated with increased TS (OR 0.3, 0.07-0.85) and OS (HR 0.4, 0.18-0.72), implicating IL12-induced type 2 IFN expression. Among the checkpoints, only high baseline levels of CTLA4 mRNA, which were further induced 1.7-fold by tebe, were associated with TS (OR 0.3, 0.08-0.94) and OS (HR 0.3, 0.16-0.62). PD-1-PDL1 axis was not associated with TS or OS.
Conclusions
Genomic analysis provides new insight into the potential role of ISGylation in UM and highlights the importance of type 1&2 IFN pathway genes in the anti-tumor immune response on tebe.
Clinical trial identification
NCT02570308.
Editorial acknowledgement
Legal entity responsible for the study
Immunocore Ltd.
Funding
Immunocore Ltd.
Disclosure
L. de la Cruz Merino: Other, Personal, Advisory Board: MSD-Merck; Other, Personal, Advisory Board: Roche Farma; Other, Personal, Advisory Board: Bristol-Myers-Squibb; Other, Personal, Advisory Board: Pierre-Fabré; Other, Personal, Advisory Board: Amgen; Other, Personal, Advisory Board: Novartis; Financial Interests, Personal, Funding: MSD-Merck; Financial Interests, Personal, Funding: Roche Farma; Financial Interests, Personal, Funding: Celgene. Z. Eroglu: Other, Personal, Advisory Board: Array Biopharma; Other, Personal, Advisory Board: OncoSec; Other, Personal, Advisory Board: Regeneron; Other, Personal, Advisory Board: Genentech; Other, Personal, Advisory Board: Novartis; Other, Personal, Advisory Board: SunPharma; Other, Personal, Advisory Board: Natera; Other, Personal, Funding: Novartis; Other, Personal, Funding: Pfizer. L. Collins: Financial Interests, Personal, Full or part-time Employment: Immunocore Ltd. A. Greenshields-Watson: Financial Interests, Personal, Full or part-time Employment: Immunocore Ltd. S. Stanhope: Financial Interests, Personal, Full or part-time Employment: Immunocore Ltd. S. Abdullah: Financial Interests, Personal, Full or part-time Employment: Immunocore Ltd. K. Ranade: Financial Interests, Personal, Full or part-time Employment: Immunocore Ltd. J. Sacco: Other, Personal, Advisory Board: Immunocore,; Other, Personal, Advisory Board: Delcath; Other, Personal, Advisory Board: BMS; Other, Personal, Advisory Board: MSD; Financial Interests, Institutional, Funding: Immunocore; Financial Interests, Institutional, Funding: BMS; Financial Interests, Institutional, Funding: AZ; Financial Interests, Institutional, Funding: Replimmune; Financial Interests, Institutional, Funding: MSD; Financial Interests, Institutional, Funding: Amgen.