C-reactive protein as a response biomarker to immune checkpoint blockade: A meta-analysis.

person Alexander B Karol Department of Medicine, Icahn School of Medicine at Mount Sinai, Mount Sinai Hospital, New York, NY info_outline Alexander B Karol, Yu Fujiwara, Tyler J D'Ovidio, Elena Baldwin, Himanshu Joshi, Deborah Blythe Doroshow, Matt D. Galsky

Authors person Alexander B Karol Department of Medicine, Icahn School of Medicine at Mount Sinai, Mount Sinai Hospital, New York, NY info_outline Alexander B Karol, Yu Fujiwara, Tyler J D'Ovidio, Elena Baldwin, Himanshu Joshi, Deborah Blythe Doroshow, Matt D. Galsky Organizations Department of Medicine, Icahn School of Medicine at Mount Sinai, Mount Sinai Hospital, New York, NY, Icahn School of Medicine at Mount Sinai, Mount Sinai Beth Israel, New York, NY, Icahn School of Medicine at Mount Sinai, New York, NY, Division of Hematology and Medical Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, New York, NY Abstract Disclosures Research Funding No funding received None. Background: Tumor-promoting inflammation is a hallmark of cancer pathogenesis and is associated with poor outcomes and treatment resistance. C-reactive protein (CRP) is a routinely measured acute phase reactant whose synthesis is stimulated by cytokines and may thereby represent a surrogate for tumor promoting inflammation. Pre-treatment CRP has been associated with resistance to immune checkpoint blockade (ICB) in several studies. However, whether post-treatment changes in CRP correlate with ICB outcomes has not been systematically examined. Methods: We performed a systematic review to identify cohort studies or clinical trials in solid tumor patients receiving ICB therapy with CRP response comparator pairs (high/low) available. We included studies that had hazard ratio (HR) of overall survival (OS), progression-free survival (PFS), or odds ratio (OR) of objective response rate (ORR) available. We performed a meta-analysis using a random-effect model to evaluate if post-treatment changes in CRP are associated with ORR, PFS, or OS. Subgroup analysis for primary cancer type was performed. Heterogeneity was assessed using the I-squared statistic. Results: We screened 691 eligible studies; 19 met inclusion criteria and 2,101 patients were included. Patients experiencing post-ICB declines in CRP had improved ORR HR=4.67 [95% CI] [2.81-7.78] (p<0.0001, I 2 =42%), PFS HR=2.47 [1.98-3.09] (p<0.0001, I 2 =18%), and OS HR=2.28 [1.68-3.08] (p<0.0001, I 2 =56%). Heterogeneity among subgroups was low in ORR (I 2 =14.6%) and PFS analysis ( I 2 =0%), and moderate in OS analysis (I 2 =64.2%). Conclusions: In patients receiving ICB therapy, post-treatment declines in CRP were associated with improved ORR, PFS, and OS across multiple histologies. These findings support the integration of on-treatment CRP decline as a clinically relevant response biomarker for novel therapies directed at modulating tumor-promoting inflammation. A meta-regression analysis will help determine optimal post-treatment CRP cutpoints. Pooled OR of ORR [95%CI] and HR [95%CI] of PFS and OS with subgroup analysis results and heterogeneity assessment. Primary malignancy Overall Subgroup Non-small cell lung cancer Renal cell carcinoma Melanoma Urothelial carcinoma Varied Subgroup differences ORR 4.67 [2.81,7.78] 7.97 [3.54- 17.94] 3.85 [2.11-7.00] 7.14 [2.31-22.13] I 2 =14.6% (P=0.31) PFS 2.47 [1.98-3.09] 2.53 [1.79- 3.59] 2.55 [1.87- 3.46] I 2 =0% (P=0.99) OS 2.28 [1.68-3.08] 1.64 [1.16-2.31] 3.90 [2.02-7.54] 1.46 [1.03-2.07] 3.17 [1.59-6.34] 2.28 [1.68-3.08] I 2 =64.2% (P=0.02)