1. Genomic heterogeneity and ploidy identify patients with intrinsic resistance to PD-1 blockade in metastatic melanoma.
- Author
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Tarantino G, Ricker CA, Wang A, Ge W, Aprati TJ, Huang AY, Madha S, Chen J, Shi Y, Glettig M, Feng CH, Frederick DT, Freeman S, Holovatska MM, Manos MP, Zimmer L, Rösch A, Zaremba A, Livingstone E, Jameson JC, Saghafian S, Lee A, Zhao K, Morris LGT, Reardon B, Park J, Elmarakeby HA, Schilling B, Giobbie-Hurder A, Vokes NI, Buchbinder EI, Flaherty KT, Haq R, Wu CJ, Boland GM, Hodi FS, Van Allen EM, Schadendorf D, and Liu D
- Subjects
- Humans, Genetic Heterogeneity, Female, Exome Sequencing, Neoplasm Metastasis, Genomics methods, Male, Biomarkers, Tumor genetics, Middle Aged, Melanoma drug therapy, Melanoma genetics, Melanoma pathology, Melanoma mortality, Drug Resistance, Neoplasm genetics, Immune Checkpoint Inhibitors therapeutic use, Immune Checkpoint Inhibitors pharmacology, Ploidies, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor genetics
- Abstract
The introduction of immune checkpoint blockade (ICB) has markedly improved outcomes for advanced melanoma. However, many patients develop resistance through unknown mechanisms. While combination ICB has improved response rate and progression-free survival, it substantially increases toxicity. Biomarkers to distinguish patients who would benefit from combination therapy versus aPD-1 remain elusive. We analyzed whole-exome sequencing of pretreatment tumors from four cohorts ( n = 140) of ICB-naïve patients treated with aPD-1. High genomic heterogeneity and low ploidy robustly identified patients intrinsically resistant to aPD-1. To establish clinically actionable predictions, we optimized and validated a predictive model using ploidy and heterogeneity to confidently identify (90% PPV) patients with intrinsic resistance to and worse survival on aPD-1. We further observed that three of seven (43%) patients predicted to be intrinsically resistant to single-agent PD-1 ICB responded to combination ICB, suggesting that these patients may benefit disproportionately from combination ICB. These findings highlight the importance of heterogeneity and ploidy, nominating an approach toward clinical actionability.
- Published
- 2024
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