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


Scott A. Tomlins, Strata Oncology, Ann Arbor, MI, USA.
Nickolay A. Khazanov, Strata Oncology, Ann Arbor, MI, USA.
Benjamin J. Bulen, Strata Oncology, Ann Arbor, MI, USA.
Daniel H. Hovelson, Strata Oncology, Ann Arbor, MI, USA.
Melissa J. Shreve, Strata Oncology, Ann Arbor, MI, USA.
Laura E. Lamb, Strata Oncology, Ann Arbor, MI, USA.
Marc R. Matrana, Ochsner Cancer Institute, New Orleans, LA, USA.
Mark E. Burkard, University of Wisconsin Carbone Cancer Center, Madison, WI, USA.Follow
Eddy Shih-Hsin Yang, O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA.
William Jeffery Edenfield, Prisma Health Greenville Memorial Hospital, Greenville, SC, USA.
E Claire Dees, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.Follow
Adedayo A. Onitilo, Cancer Care and Research Center, Marshfield Clinic Research Institute, Marshfield, WI, USA.
Michael Thompson, Advocate Aurora HealthFollow
Gary L. Buchschacher, Kaiser Permanente Southern California, Los Angeles, CA, USA.
Alan M. Miller, SCL Health-CO, Broomfield, CO, USA.
Alexander Menter, Kaiser Permanente Colorado, Lone Tree, CO, USA.
Benjamin Parsons, Gundersen Health System, La Crosse, WI, USA.
Timothy Wassenaar, UW Health Cancer Center at ProHealth Care, Waukesha, WI, USA.
Leon C. Hwang, Kaiser Permanente of the Mid-Atlantic States, Rockville, MD, USA.
J Marie Suga, Kaiser Permanente Northern California, Vallejo, CA, USA.
Robert Siegel, Bon Secours St. Francis Cancer Center, Greenville, SC, USA.
William Irvin, Bon Secours Cancer Institute, Midlothian, VA, USA.
Suresh Nair, Lehigh Valley Topper Cancer Institute, Allentown, PA, USA.
Jennifer N. Slim, MultiCare Regional Cancer Center, Tacoma, WA, USA.
Jamal Misleh, The US Oncology Network, Newark, DE, USA.
Jamil Khatri, ChristianaCare Oncology Hematology, Newark, DE, USA.
Gregory Masters, Medical Oncology Hematology Consultants, Helen F Graham Cancer Center and Research Institute,, Newark, DE, USA.
Sachdev Thomas, Kaiser Permanente - Northern California, Oakland, CA, USA.
Malek Safa, Kettering Health, Kettering, OH, USA.
Daniel M. Anderson, Metro-Minnesota Community Oncology Research Consortium, St. Louis Park, MN, USA.Follow
Kat Kwiatkowski, Strata Oncology, Ann Arbor, MI, USA.


Aurora Cancer Care


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.



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