CNTO328 (Anti-IL-6 mAb) Treatment Is Associated with An Increase in Hemoglobin (Hb) and Decrease in Hepcidin Levels in Renal Cell Carcinoma (RCC).
Authors: Schipperus Martin , Rijnbeek Britte , Reddy Manjula , Qin Xiang , Cornfeld Mark J. 
Published: October 2019

Abstract
Abstract 4045
Poster Board III-980

Introduction
CNTO328 is a chimeric monoclonal antibody against the inflammatory cytokine, IL-6, which is currently being studied in hematologic and solid malignancies. IL-6 is reported to play a key role in the etiology and symptoms of Anemia of Cancer (AOC). Increased IL-6 during cancer associated inflammation up-regulates the hepatic production of hepcidin, which is the iron-regulatory hormone that may be responsible for most of the features of this disorder. CNTO328 treatment has previously been shown to be associated with Hb increases in Castleman's Disease (a disorder caused by deregulated IL-6 production) and Renal Cell Carcinoma (RCC). We retrospectively undertook this assessment in the RCC patients, to assess whether there was an associated decrease in hepcidin.

Patients and Methods
Serum Hb, IL-6 and CRP (a surrogate for IL-6 activity) levels were prospectively studied in RCC patients selected from two 6 mg/kg CNTO328 treatment cohorts (IV Q2W or Q3W) in a phase 1/2 study. Free and total IL-6 could not be measured due to interference of the drug with assay performance which prevents accurate measurement. Serum hepcidin levels were retrospectively measured using a hepcidin C-ELISA. The change from baseline in Hb, hepcidin and CRP levels was calculated at multiple time points. The association between Hb response (defined as max Hb increase of ≥1 g/dL) and change in hepcidin and CRP levels was evaluated by Pearson Correlation Coefficient (r).

Results
38 RCC patients with a median baseline Hb of 13.2 g/dL (10.1-17.1) were studied. All patients had normal renal function throughout the study. Two patients were excluded from analysis because of blood transfusions at baseline. None of the patients studied received ESAs or blood transfusions during screening or treatment. Treatment with CNTO328 resulted in an Hb increase during study in 35 (92%) of the 38 patients starting on Day 8, with 25 (66%) achieving a max Hb increase of 31 g/dL (median 2.0; range 1.0-3.5). Hb responses were not due to tumor response, were independent of dosing schedule (Q2W vs Q3W) and were even seen in 6 (86%) out of 7 patients with a baseline Hb <12 g/dL. As expected, a marked reduction in day 8 hepcidin was noted (median decrease of 61.1%, range -90%-53.9%). A moderate correlation was found between Hb response and the Day 8 percent change in hepcidin (r = -0.56, n=19) but not between baseline hepcidin and Hb response (r = 0.056, n=21). A sustained suppression of serum CRP levels from baseline was evident in all patients and Hb responses were moderately correlated with the Day 8 absolute change in CRP (r = -0.41, n=24) and less well correlated with baseline CRP (r = 0.31, n=25) levels. Max Hb levels (median 14.9 g/dl, range 11.1-17.7) did not exceed the upper limit of normal for any patient, and no thromboembolic events were observed.

Conclusion
CNTO328 was associated with normalization of Hb in this moderately anemic RCC population, presumably due to reduction of hepcidin via IL-6 blockade. This mechanism may provide a physiologic alternative to transfusions in AOC and warrants further evaluation with prospective mechanistic studies in more anemic patients. A possible Hb response correlation with hepcidin and CRP levels is of particular interest and will be actively pursued in prospective trials.

Disclosures:
Rijnbeek: Johnson & Johnson: Employment. Reddy:Johnson & Johnson: Employment. Qin:Johnson & Johnson: Employment. Cornfeld:Johnson & Johnson: Employment, Equity Ownership.