Recombinant interleukin-21 plus sorafenib for metastatic renal cell carcinoma: a phase 1/2 study.
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.


CONCLUSIONS
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.


BACKGROUND
ClinicalTrials.gov Identifier: NCT00389285.
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.
Shailender
S
Bhatia
Providence Portland Medical Center, Portland, OR, USA.
Brendan
B
Curti
Norris Cotton Cancer Center, Dartmouth Hitchcock Medical Center, Lebanon, NH, USA.
Marc S
MS
Ernstoff
Pinnacle Oncology Hematology, Scottsdale, AZ, USA.
Michael
M
Gordon
Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
Elisabeth I
EI
Heath
Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, Quebec.
Wilson H
WH
Miller
Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA.
Igor
I
Puzanov
Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
David I
DI
Quinn
University of Colorado Cancer Center, Aurora, CO, USA.
Thomas W
TW
Flaig
University of Kansas Medical Center, Westwood, KS, USA.
Peter
P
VanVeldhuizen
Formerly of ZymoGenetics (Bristol-Myers Squibb), Seattle, WA, USA.
Kelly
K
Byrnes-Blake
Formerly of ZymoGenetics (Bristol-Myers Squibb), Seattle, WA, USA.
Jeremy A
JA
Freeman
ZymoGenetics (Bristol-Myers Squibb), Seattle, WA, USA.
Rachel
R
Bittner
Formerly of ZymoGenetics (Bristol-Myers Squibb), Seattle, WA, USA.
Naomi
N
Hunder
Formerly of ZymoGenetics (Bristol-Myers Squibb), Seattle, WA, USA.
Sonia
S
Souza
University of Washington, Seattle, WA, USA.
John A
JA
Thompson
Cytokine; Durable response; Immunotherapy; Interleukin-21; Renal cell carcinoma (RCC); Sorafenib; Targeted therapy; Tyrosine kinase inhibitors (TKI); VEGF