Genomic, clinical data, and scripts for PD-1 blockade resistance in metastatic melanoma

We analyzed whole-exome-sequencing (WES) of pre-treatment tumor and
matched normals from four cohorts (n=140) of previously ICB-naïve aPD-1
ICB treated patients. We found high intratumoral genomic heterogeneity and
low ploidy robustly identified patients with intrinsic resistance to aPD-1
ICB. Utilizing a melanoma cohort from a period prior to targeted- and
ICB-therapy (“untreated” cohort), we found that genomic heterogeneity was
predictive while ploidy was prognostic. To establish clinically actionable
predictions, we optimized a predictive model using ploidy and
heterogeneity to identify, with high confidence (90% PPV), a subset of
patients with intrinsic resistance to and worse survival on aPD1 ICB. We
validated this model with independent cohorts, and further showed that a
significant proportion of patients predicted to have intrinsic resistance
to single agent aPD-1 ICB responded to combination ICB, suggesting these
patients may benefit disproportionately from combination ICB.