A PD-1 /PD-L1 proximity assay as a theranostic marker for PD-1 blockade in patients with metastatic melanoma.

PURPOSE Less than 50% of patients with melanoma respond to anti-PD1, and this treatment can induce severe toxicity. Predictive markers are thus needed to improve the benefit/risk ratio of immune checkpoint inhibitors (ICI). Baseline tumor parameters such as PD-L1 expression, CD8+ T cell infiltration, mutational burden and various transcriptomic signatures are associated with response to ICI but their predictive values are not sufficient. Interaction between PD1 and its main ligand, PDL1 appears a valuable target of anti-PD1 therapy. Thus, instead of looking at PD-L1 expression only, we evaluated the predictive value of the proximity between PD1 and its neighboring PD-L1 molecules in terms of response to anti-PD1 therapy. EXPERIMENTAL DESIGN PD1/PD-L1 proximity was assessed by proximity ligation assay (PLA) on 137 samples from two cohorts (exploratory n=66 and validation n=71) of samples from melanoma patients treated with anti-PD1+/-anti CTLA4. Additional predictive biomarkers such as PD-L1 expression (MELscore), CD8+ cells density and nanostring RNA signature were also evaluated. RESULTS A PD1/PD-L1 PLA model was developed to predict tumor response in an exploratory cohort and further evaluated in an independent validation cohort. This score showed higher predictive ability (AUC=0.85 and 0.79, in the two cohorts respectively) for PD1/PD-L1 PLA as compared to other parameters (AUC from 0.71 to 0.77). Progression free and overall survival were significantly longer in patients with high PLA values (p=0.00019 and p<0.0001 respectively). CONCLUSION The proximity between PD-1 and PD-L1, easily assessed by this PLA on one FFPE section, appears as a new biomarker of anti-PD1 efficacy.