1090PD - Genetic determinants of ipilimumab outcomes for advanced melanoma

Date 29 September 2014
Event ESMO 2014
Session Melanoma and other skin tumours
Topics Cancer Immunology and Immunotherapy
Melanoma and other Skin Tumours
Translational Research
Presenter Tomas Kirchhoff
Citation Annals of Oncology (2014) 25 (suppl_4): iv374-iv393. 10.1093/annonc/mdu344
Authors T. Kirchhoff1, C. Adaniel2, J. Rendleman3, E. Kern4, N. Fleming4, D. Polsky1, R. Berman1, R. Shapiro5, Y. Shao6, A. Heguy7, I. Osman1, A. Pavlick8
  • 1Nyu Cancer Institute, New York University Langone Medical Center, 10016 - New York/US
  • 2Hematology And Oncology, NYU Medical Center, 10016 - New York/US
  • 3Cancer Institute, NYU Medical Center, 10016 - New York/US
  • 4Nyu Cancer Institute, New York University Langone Medical Center, New York/US
  • 5Dermatology, New York University Langone Medical Center, 10016 - New York/US
  • 6Division Of Biostatistics, NYU Medical Center, New York/US
  • 7Genome Technology Center, New York University Medical Center, New York/US
  • 8Hematology-oncology, New York University Langone Medical Center, New York/US

 

Abstract

Aim

Ipilimumab has substantially increased survival for patients with advanced melanoma, however, the benefit is only observed in a small portion of treated patients. Clearly there are yet unknown factors that affect response. Unlike host immunity and tumor microenvironment, the underlying genetic factors, as putative markers of response, have been sparsely studied. To date, the role of germline genetic variants in the modulation of immunotherapy response has been almost completely unexplored. To this end, we have performed whole-exome sequencing (WES) to discover novel germline determinants of response to ipilimumab therapy for metastatic melanoma.

Methods

Blood samples were collected from 80 metastatic melanoma patients treated with ipilimumab at the New York University Cancer Center. WES was performed on objective responders (OR) and non-responders (NR), defined by immune-related response criteria, using the Nextera platform (Illumina) at average 30x coverage. Patient and tumor characteristics were obtained from a well-annotated institutional database. A novel method for testing the association between OR and NR by variant and gene/molecular network enrichment was implemented. Gene-Set Enrichment Analysis and Pathway Studio were used to test the pathway associations.

Results

The preliminary analysis evaluating the first 30 OR and 30 NR identified significant associations with ipilimumab response for several loci including RPS6KB1 (p = 0.001) and LNX2 (0.001). In addition, the pathway analysis showed significant associations for SMAD 3 (p = 0.04) and interleukin 1 (p = 0.04) related pathways.

Conclusions

The preliminary findings on a subset of 60 patients provide promising evidence for the presence of germline genetic factors associated with response to ipilimumab therapy. While several novel genetic loci (RPS6KB1, LNX2) and molecular pathways (SMAD3, interleukin 1) have been identified in our preliminary scan, the study is currently undergoing a larger expansion involving >80 patients, anticipating the final analysis to be complete by September 2014. This expanded analysis will not only provide a validation of the current novel findings but, due to a substantial increase of power, will also have a greater ability to display the true effect of additional novel germline genetic factors modulating immunotherapy response.

Disclosure

All authors have declared no conflicts of interest.