Siltuximab Treatment Increases Hemoglobin (Hb) Levels: Preliminary Results From a Prospective Phase 1 Study In Refractory Solid Tumors
Authors: Kurzrock R. , Angévin E. , Cohen S. , Van Laethem J. , Rijnbeek B. , Vermeulen J. , Tromp B. , Li W. , Reddy M. , Cornfeld M. , Tabernero J. 
Published: October 2019

Abstract 5150

Introduction:

Siltuximab is a chimeric monoclonal antibody with high affinity for the inflammatory cytokine, IL-6, which is currently being studied in hematologic, solid malignancies and multicentric Castleman's disease (MCD). In addition to representing a therapeutic target, IL-6 is reported to play a key role in the etiology and symptoms of anemia of cancer. A possible mechanism is through up-regulation of hepatic production of hepcidin, the central iron-regulatory hormone. Siltuximab treatment has previously been shown to be associated with clinically significant Hb increases in MCD (a disorder caused by deregulated IL-6 production) and renal cell carcinoma. We have prospectively studied the Hb response in the context of a phase I study with siltuximab in patients with advanced solid tumors.

Patients and Methods

Siltuximab was administered intravenously to patients with any advanced solid tumor at increasing dose levels (2.8 or 5.5 mg/kg every 2 weeks, 11 or 15 mg/kg every 3 weeks). Hepcidin (C-ELISA), Hb, CRP (marker for inflammation) and iron status (serum iron, ferritin, transferrin saturation, total iron binding capacity) were measured at baseline and serially during treatment. IL-6 was not measured since interference of the drug with assay performance prevents accurate measurement of bioactive IL-6. The relationships between these biomarkers and Hb response (defined as a maximum Hb increase of ≥1 g/dL during treatment) were evaluated.

Results:

Forty-four pts (18 colorectal, 12 ovarian, 5 pancreatic, 9 other) received a median of 3 siltuximab cycles (range 1 – 25). Eight patients were excluded from analysis because they received blood transfusions or ESAs. There were no objective tumor responses (CR or PR). Baseline Hb ranged from 9.4–15.3 g/dL (median 12.2). All 36 evaluable patients had an increase in Hb (median 1.35 g/dL; range 0.1–3.2). Eleven (31%) patients had a maximum increase of ≥2 g/dL. Maximum Hb levels did not exceed the upper limit of normal. Baseline hepcidin (median 118.6 ng/mL; range 9.5–493.3) was positively correlated with baseline CRP (median 13.6 mg/L; range 0.42–152.0) (p<0.05) and ferritin (median 346 pmol/L; range 74.2–8543.1) (p<0.05) but not with baseline Hb or Hb response. For subjects with a Hb response of more than 2 g/dL an association was found with Day 8 hepcidin (p = 0.03) when controlled for baseline serum iron. Early hepcidin percentage change was not correlated with Hb response.

Conclusion:

Siltuximab treatment was associated with clinically meaningful Hb response in this moderately anemic refractory cancer population. The exact mechanism of action remains uncertain, however correlation with additional markers (e.g., soluble transferrin receptor, inflammatory markers such as IL-6) might also be important to identify patients most likely to respond to treatment and should be evaluated further in randomized trials.

Disclosures:

Kurzrock: Johnson & Johnson: Research Funding. Angévin:Johnson & Johnson: Research Funding. Cohen:Johnson & Johnson: Research Funding. Van Laethem:Johnson & Johnson: Research Funding. Rijnbeek:Johnson & Johnson: Employment. Vermeulen:Johnson & Johnson: Employment. Tromp:Johnson & Johnson: Employment. Li:Johnson & Johnson: Employment. Reddy:Johnson & Johnson: Employment. Cornfeld:Johnson & Johnson: Employment. Tabernero:Johnson & Johnson: Research Funding.