BACKGROUND: Despite the positive impact of targeted therapies on metastatic renal cell carcinoma (mRCC), durable responses are infrequent and an unmet need exists for novel therapies with distinct mechanisms of action.
We investigated the combination of recombinant Interleukin 21 (IL-21), a cytokine with unique immunostimulatory properties, plus sorafenib, a VEGFR tyrosine kinase inhibitor.
METHODS: In this phase 1/2 study, 52 mRCC patients received outpatient treatment with oral sorafenib 400 mg twice daily plus intravenous IL-21 (10-50 mcg/kg) on days 1-5 and 15-19 of each 7-week treatment course. The safety, antitumor activity, pharmacokinetic and pharmacodynamic effects of the combination were evaluated.
RESULTS: In phase 1 (n = 19), the maximum tolerated dose for IL-21 with the standard dose of sorafenib was determined to be 30 mcg/kg/day; grade 3 skin rash was the only dose-limiting toxicity. In phase 2, 33 previously-treated patients tolerated the combination therapy well with appropriate dose reductions; toxicities were mostly grade 1 or 2. The objective response rate was 21% and disease control rate was 82%. Two patients have durable responses that are ongoing, despite cessation of both IL-21 and sorafenib, at 41+ and 30+ months, respectively. The median progression-free survival in phase 2 was 5.6 months. The pharmacokinetic and pharmacodynamic properties of IL-21 appeared to be preserved in the presence of sorafenib.
CONCLUSION: IL-21 plus sorafenib has antitumor activity and acceptable safety in previously treated mRCC patients. IL-21 may represent a suitable immunotherapy in further exploration of combination strategies in mRCC.
Written by:
Bhatia S, Curti B, Ernstoff MS, Gordon M, Heath EI, Miller WH Jr, Puzanov I, Quinn DI, Flaig TW, VanVeldhuizen P, Byrnes-Blake K, Freeman JA, Bittner R, Hunder N, Souza S, Thompson JA. Are you the author?
University of Washington, Seattle, WA, USA; Division of Medical Oncology, Department of Medicine, University of Washington, Seattle Cancer Care Alliance, 825 Eastlake Ave East, Mailstop G4-830, Seattle, WA 98109-1023, USA; Providence Portland Medical Center, Portland, OR, USA; Norris Cotton Cancer Center, Dartmouth Hitchcock Medical Center, Lebanon, NH, USA; Pinnacle Oncology Hematology, Scottsdale, AZ, USA; Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA; Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, Quebec; Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA; University of Colorado Cancer Center, Aurora, CO, USA; University of Kansas Medical Center, Westwood, KS, USA; Formerly of ZymoGenetics (Bristol-Myers Squibb), Seattle, WA, USA; ZymoGenetics (Bristol-Myers Squibb), Seattle, WA, USA.
Reference: J Immunother Cancer. 2014 Jan 27;2:2.
doi: 10.1186/2051-1426-2-2.
PubMed Abstract
PMID: 24829759
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