1047O - Baseline tumor T cell receptor (TcR) sequencing analysis and neo antigen load is associated with benefit in melanoma patients receiving sequential...

Date 07 October 2016
Event ESMO 2016 Congress
Session Immunotherapy of cancer
Topics Cancer Immunology and Immunotherapy
Melanoma and other Skin Tumours
Translational Research
Presenter Jeffrey Weber
Citation Annals of Oncology (2016) 27 (6): 359-378. 10.1093/annonc/mdw378
Authors J. Weber1, C. Horak2, F..S. Hodi3, H. Chang2, D. Woods4, C. Sanders5, H. Robins6, E. Yusko5
  • 1Laura And Isaac Perlmutter Cancer Center, NYU Langone Medical Center, 10016 - New York/US
  • 2Biomarkers, BMS, Princeton/US
  • 3Oncology, Dana-Farber Cancer Institute, Boston/US
  • 4Cancer Center, Laura and Isaac Perlmutter Cancer Center, 10016 - New York, NY/US
  • 5Computational Biology, Adaptive Biotechnologies, Seattle/US
  • 6Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle/US

Abstract

Background

In a randomized phase II clinical trial of nivolumab (NIVO) then ipilimumab (IPI) with a planned switch at week 12 (arm A), versus the reciprocal combination of IPI then NIVO (arm B), followed by maintenance NIVO in both arms, in 140 patients with metastatic unresectable melanoma, best overall response rates and overall survival were superior for arm A versus B (Weber, J. et al Lancet Oncology, in press 2016), but grades 3-4 immune related side effects were similar.

Methods

In that trial, pre- and post-treatment tumors and peripheral blood samples were analyzed by DNA sequencing for TcR clonality and tumors were also analyzed for T cell infiltration. Whole exome sequencing was also performed to assess mutational and neo-epitope load in pre-treatment tumors.

Results

For 94 pre-treatment tumor samples, a combination of high T cell fraction and T cell clonality was associated with response to treatment in arm A (p = 0.019 using Fishers exact test, odds ratio =6.7), and with survival (p = 0.05) but not in arm B. In 22 paired samples, patients responding to treatment had an increase in the tumor T cell fraction and clonality post treatment at week 13 (p = 0.015 – signed ranked Wilcox test), but tumors from progressing patients had a decrease in T cell fraction compared to those responding to treatment (p = 0.004, U-test of pooled arms A and B). When changes in tumor T cell clonality and T cell fraction were assessed together at week 13, for both arms there was a strong correlation with response to treatment (p = 0.0023 with odds ratio of 30). Tumor mutational load was associated with response to NIVO then IPI in arm A (p = 0.03), but not with response to IPI then NIVO in arm B. In the peripheral blood, there were no differences in TcR clonality, or the abundance of the top TcR clone post-treatment compared to baseline. No peripheral blood pre-treatment TcR parameter was associated with response to treatment in either arm.

Conclusions

Baseline tumor micro-environment T cell infiltration and clonality are crucial determinants of response to treatment with the PD-1 blocking antibody nivolumab. Altering both parameters may impact on resistance to immunotherapy in melanoma.

Clinical trial identification

NCT01783938

Legal entity responsible for the study

BMS

Funding

BMS

Disclosure

J. Weber: Ad Boards for BMS, Merck, GSK, Amgen, Novartis, Celldex, CytoMx, Celyad Stock Ownership in Celldex, CytoMx, Altor. C. Horak: Employment and Stock Ownership in BMS. F.S. Hodi: Research funding and Advisory Board attendance for BMS. H. Chang: Employment by BMS. C. Sanders: Employed by Adaptive Biotechnology. E. Yusko: Employment by Adaptive Biotechnology. All other authors have declared no conflicts of interest.