Development and validation of an integrative pan-solid tumor predictor of PD-1/PD-L1 blockade benefit.
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.
Published In/Presented At
Tomlins, S. A., Khazanov, N. A., Bulen, B. J., Hovelson, D. H., Shreve, M. J., Lamb, L. E., Matrana, M. R., Burkard, M. E., Yang, E. S., Edenfield, W. J., Dees, E. C., Onitilo, A. A., Thompson, M., Buchschacher, G. L., Jr, Miller, A. M., Menter, A., Parsons, B., Wassenaar, T., Hwang, L. C., Suga, J. M., … Rhodes, D. R. (2023). Development and validation of an integrative pan-solid tumor predictor of PD-1/PD-L1 blockade benefit. Communications medicine, 3(1), 14. https://doi.org/10.1038/s43856-023-00243-7
Medicine and Health Sciences
Department of Medicine, Hematology-Medical Oncology Division