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Development and validation of an integrative pan-solid tumor predictor of PD-1/PD-L1 blockade benefit
Journal article   Open access   Peer reviewed

Development and validation of an integrative pan-solid tumor predictor of PD-1/PD-L1 blockade benefit

Scott A. Tomlins, Nickolay A. Khazanov, Benjamin J. Bulen, Daniel H. Hovelson, Melissa J. Shreve, Laura E. Lamb, Marc R. Matrana, Mark E. Burkard, Eddy Shih-Hsin Yang, William Jeffery Edenfield, …
Communications medicine, Vol.3(1), pp.14-14
02/07/2023
DOI: 10.1038/s43856-023-00243-7
PMCID: PMC9905474
PMID: 36750617
url
https://doi.org/10.1038/s43856-023-00243-7View
Published (Version of record) Open Access

Abstract

Background Anti-PD-1 and PD-L1 (collectively PD-[L]1) therapies are approved for many advanced solid tumors. Biomarkers beyond PD-L1 immunohistochemistry, microsatellite instability, and tumor mutation burden (TMB) may improve benefit prediction. Methods Using treatment data and genomic and transcriptomic tumor tissue profiling from an observational trial (NCT03061305), we developed Immunotherapy Response Score (IRS), a pan-tumor predictive model of PD-(L)1 benefit. IRS real-world progression free survival (rwPFS) and overall survival (OS) prediction was validated in an independent cohort of trial patients. Results Here, by Cox modeling, we develop IRS-which combines TMB with CD274, PDCD1, ADAM12 and TOP2A quantitative expression-to predict pembrolizumab rwPFS (648 patients; 26 tumor types; IRS-High or -Low groups). In the 248 patient validation cohort (248 patients; 24 tumor types; non-pembrolizumab PD-[L]1 monotherapy treatment), median rwPFS and OS are significantly longer in IRS-High vs. IRS-Low patients (rwPFS adjusted hazard ratio [aHR] 0.52, p = 0.003; OS aHR 0.49, p = 0.005); TMB alone does not significantly predict PD-(L)1 rwPFS nor OS. In 146 patients treated with systemic therapy prior to pembrolizumab monotherapy, pembrolizumab rwPFS is only significantly longer than immediately preceding therapy rwPFS in IRS-High patients (interaction test p = 0.001). In propensity matched lung cancer patients treated with first-line pembrolizumab monotherapy or pembrolizumab+chemotherapy, monotherapy rwPFS is significantly shorter in IRS-Low patients, but is not significantly different in IRS-High patients. Across 24,463 molecularly-evaluable trial patients, 7.6% of patients outside of monotherapy PD-(L)1 approved tumor types are IRS-High/TMB-Low. Conclusions The validated, predictive, pan-tumor IRS model can expand PD-(L)1 monotherapy benefit outside currently approved indications.
 Life Sciences & Biomedicine Medicine, Research & Experimental Research & Experimental Medicine Science & Technology

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