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608 Predicting primary resistance and exploring mechanisms in patients with advanced melanoma treated with immune checkpoint inhibitors (ICIs)
  1. Georgina Long AO1,
  2. Tracy Tang2,
  3. Abraham Apfel2,
  4. David Paulucci2,
  5. Scott Chasalow2,
  6. Daniel Tenney2,
  7. Gina Fusaro2,
  8. Dirk Schadendorf3,
  9. Hussein Tawbi4,
  10. F Stephen Hodi5,
  11. Pratik Thakkar2,
  12. James Larkin6,
  13. Jedd Wolchok7,
  14. Megan Wind-Rotolo2,
  15. Shu-Pang Huang2,
  16. Peter Mohr8,
  17. Caroline Robert9,
  18. Christoph Hoeller10,
  19. Jean-Jacque Grob11,
  20. Helen Gogas12,
  21. Jeffrey Weber13,
  22. Han Chang2 and
  23. Rebecca Moss2
  1. 1Melanoma Institute Australia, The University of Sydney; Royal North Shore Hospital; Mater Hospital, Wollstonecraft, Australia
  2. 2Bristol Myers Squibb, Princeton, NJ, United States
  3. 3University Hospital Essen, Essen, Germany
  4. 4University of Texas MD Anderson Cancer Center, Houston, United States
  5. 5Dana-Farber Cancer Institute, Boston, MA, United States
  6. 6Royal Marsden Hospital, London, UK
  7. 7Memorial Sloan Kettering Cancer Center; Weill Cornell Medicine; Parker Institute for Cancer Immunotherapy, New York, NY, United States
  8. 8Elbekliniken Buxtehude, Buxtehude, Germany
  9. 9Institut Gustave-Roussy, Villejuif-Paris, France
  10. 10Medical University of Vienna, Vienna, Austria
  11. 11APHM and Aix-Marseille University, Marseille, France
  12. 12National and Kapodistrian University of Athens, Athens, Greece
  13. 13NYU Langone Health, New York, NY, United States


Background Despite significant improvements in treatment outcomes with ICIs, deeper understanding is needed to improve outcomes for patients with melanoma who experience no clinical benefit from ICI therapy and exhibit early disease progression (primary resistance).1 We analyzed clinical and translational factors using data from 9 BMS-sponsored clinical trials of nivolumab (NIVO), ipilimumab (IPI) and their combination in patients with advanced cutaneous melanoma (CheckMate 003, 037, 038, 064, 066, 067, 069, 511, 742) to predict resistance to ICIs and explore underlying mechanisms.

Methods Analyses of pre-treatment clinical covariates and biomarkers (determined by tumor immunohistochemistry, whole exome DNA sequencing, RNA sequencing, and serum cytokine analysis) were performed in patients with melanoma who received NIVO, IPI or NIVO+IPI and were evaluable for resistance. Several methods were used to develop and test models predicting ICI primary resistance, defined as death due to disease or best overall response of progressive disease (excluding pseudoprogression) before the first radiographic scan (≤13 weeks of treatment). Model performance was assessed using cross-validated area under the receiver operating characteristic curve (AUROC) and bootstrap bias-adjusted calibration metrics. Additionally, we evaluated individual biomarker associations with primary resistance.

Results Across 1803 patients from 9 clinical trials, 1638 were evaluable for cutaneous melanoma primary resistance and 585 (36%) met the criteria. A multivariable logistic regression model for predicting primary resistance yielded an AUROC of 0.78 (R2=0.29) and included 17 commonly available clinical factors and PD-L1 (table 1). External validation using data from an independent study yielded an AUROC of 0.70 (R2=0.17). Higher levels of acute phase cytokines and expression of genes associated with suppressive tumor microenvironment or stromal factors, including epithelial-mesenchymal transition, cancer-associated fibroblasts, transforming growth factor beta, and angiogenesis, were associated with increased risk of primary resistance. In contrast, higher levels of tumor mutational burden, PD-L1, CD8, mutations in MAPK-pathway genes, and immune gene signature scores were associated with decreased risk (figure 1, table 2).

Conclusions This exploratory analysis of clinical and translational factors in patients with advanced cutaneous melanoma identified associations with primary resistance to NIVO, IPI, or NIVO+IPI, with the best model yielding an AUROC of 0.78. Factors associated with primary resistance included higher levels of prognostic cytokines, gene expression indicating an immune suppressive tumor microenvironment, lower levels of anti-tumor immunity, and lack of MAPK-pathway mutations. These findings are supportive of future clinical trial stratification of patients and mechanistic studies targeting the biology of primary resistance to ICI therapy.

Acknowledgements We would like to thank Jasmine Rizzo, John Loffredo, Darin Dobler, Amanda Scoffield, James Winters, Corey Ritchings, and Kenzie MacIsaac for supporting efforts. Editorial support was provided by Sandra Page, PhD, of Spark Medica Inc.


  1. Hodi FS, et al. TMB and inflammatory gene expression associated with clinical outcomes following immunotherapy in advanced melanoma. Cancer Immunol Res. 2021;9:1202–1213.

Ethics Approval The trial protocols were approved by site institutional review boards or independent ethics committees and conducted according to Good Clinical Practice guidelines, per the International Conference on Harmonisation. Patients provided written informed consent based on Declaration of Helsinki principles.

Abstract 608 Table 1

Ranking of variable importance, as assessed by Wald tests of overall effects, for the factors included in the multivariable logistic regression model predicting primary resistance.

Abstract 608 Figure 1

Common translational biomarkers were negatively associated with primary resistance to ICIs in patients with advanced cutaneous melanoma.

Abstract 608 Table 2

Additional translational factors associated with primary resistance to ICIs in patients with advanced or metastatic melanoma.

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