Abstract
e20648 Background: 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 a potent inducer of hepatic production of hepcidin, which is the key regulator of iron homeostasis and causes anemia by blocking iron export from enterocytes and macrophages. Hepcidin is an important factor in the pathogenesis of ‘anemia of chronic disease‘. CNTO328 treatment has previously been shown to produce profound Hb increases in Castleman's disease, a disorder caused by deregulated IL-6 production. We subsequently conducted this retrospective review to assess whether CNTO328 treatment is associated with an increase in Hb level in renal cell cancer patients (pts). Methods: All laboratory results for pts with metastatic renal cell carcinoma in this open label phase 2 study were reviewed. Pts were treated with CNTO328 (6 mg/kg) IV infusions Q2 weeks and were evaluated for tumor response and markers of pharmacodynamic effect. The difference in Hb levels from baseline to end of study was calculated. Results: Twenty pts (19 males) with a median age of 62 yrs (range 50–77) were studied. The median number of infusions was 6 (1–13). Of 18 pts evaluable for tumor response, 11 (61%) had SD and 7 (39%) had PD. The median baseline Hb was 13.6 g/dL (10.8–17.1). Nineteen pts were evaluable for Hb response. No pts received ESAs or transfusions. Treatment with CNTO328 resulted in a sustained Hb increase in 16 of the 19 pts (84%), with 13 (68%) achieving a max Hb increase of ≥ 1 g/dL (median 1.9; range 1.0–3.5). Hb responses were early (by day 8) and independent of tumor response. No Hb overshoot or thromboembolic events were observed. A trend toward decreased platelet and neutrophil counts was observed. Conclusions: Though pts were not anemic at baseline, our results suggest that CNTO328 leads to sustained increase in Hb levels, not correlated with tumor response. This increase in Hb is presumably due to the reduction of hepcidin via IL-6 blockade and targeting the hepcidin pathway may lead to new therapies for anemia of cancer. This hypothesis warrants further evaluation with prospective mechanistic studies. [Table: see text]
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