Multiple trials are ongoing to evaluate combinations of immune checkpoint inhibitors (ICIs) across a variety of tumor types. Most of these studies utilize programmed death-1(PD-1) or programmed death-ligand 1 (PD-L1) inhibitors as a backbone. We interrogate the relationship of PD-L1 with other immune checkpoints to inform rational combination strategies.
We performed whole transcriptomic sequencing (RNA-Seq; ∼200x106 reads/tumor) across 1,467 unselected clinical cases (NantHealth; Culver City, CA). Cases reflected 38 distinct histologies; the most common histologies were breast (17.8%), colon (9.5%) and lung (7.9%). High and low PD-L1 was delineated as the top and bottom 15th percentile of expression values. Co-expression of checkpoint markers (TIGIT, FOXP3, LAG3, OX40, TIM3 and IDO) was analyzed within PD-L1-defined categories, along with putative markers of ICI resistance (e.g, VEGF-A/B/C). Tumor mutational burden (TMB; defined as exonic nonsynonymous mutations) was characterized across checkpoints.
High PD-L1 expression was strongly associated with high expression of TIGIT, FOXP3 and LAG3 (P < 0.001 for each). In contrast, there was no significant difference in expression of OX40, TIM3 and IDO in groups subdivided by high and low PD-L1 expression. High expression of PD-L1 was associated with elevated levels of VEGF-C, but there was no relationship with VEGF-A or VEGF-B expression. Very limited concordance was seen between elevated TMB (> 200 nonsynonymous mutations) and checkpoint expression.
Recent results of combination trials assessing IDO and PD-1 inhibitors may be attributable to a lack of concomitant expression of these markers, thereby limiting synergy. Combinations of PD-1/-L1-directed therapies with TIGIT and LAG3 inhibitors may therefore be of greater interest. Enrichment strategies using TMB for these combinations may be challenging, given the lack of association with checkpoint expression.
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S.K. Pal: Consultant: Pfizer, Inc., Novartis, Aveo Pharmaceuticals, Inc., Myriad Genetics, Genentech, Inc., Exelixis, Bristol-Myers Squibb Company, Astellas Pharma, Inc.; Research/grant support: Medivation, Inc,; Honorarium: Novartis, Medivation, Inc., and Astellas Pharma, Inc. C. Szeto, S. Reddy: Employee and stockholder: NantOmics LLC. O. Hamid: Consultant: Amgen, Novartis, Roche, BMS, Merck; Speaker: BMS, Genentech, Novartis, Amgen; Contracted research (for institution): AstraZeneca, BMS, Celldex, Genentech, Immunocore, Incyte, Merck, Merck-Serono, MedImmune, Novartis, Pfizer, Rinat, Roche. All other authors have declared no conflicts of interest.