Preliminary phase I trial data suggest that the combination of recombinant IL-21 and sorafenib (Nexavar) is well tolerated in patients with metastatic renal cell carcinoma and has promising anti-tumor activity, lead investigator John A. Thompson, MD, and his colleagues reported
SAN FRANCISCOPreliminary phase I trial data suggest that the combination of recombinant IL-21 and sorafenib (Nexavar) is well tolerated in patients with metastatic renal cell carcinoma and has promising anti-tumor activity, lead investigator John A. Thompson, MD, and his colleagues reported at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics (abstract A60).
Thirteen patients have been enrolled; all had prior nephrectomy, and six had received prior treatment for metastatic disease. Of these 13 patients, 11 have gone on to have two or more rounds of combination treatment, Dr. Thompson said.
Of the 10 patients with measurable disease, all have experienced tumor shrinkage, and 4 of these patients have had a partial response (30% or greater reduction in tumor size as measured by the investigators). At the time of the presentation, only 2 patients had progressive disease.
"These preliminary data are encouraging, as treatment with sorafenib alone was associated with a confirmed overall response rate of only 10% in the phase III trial that led to regulatory approval," said Dr. Thompson, of the University of Washington, and Fred Hutchinson Cancer Research Center.
The study is testing three different dose levels of IL-21: 10, 30, and 50 μg/kg/d. Treatment consists of IL-21 administered IV on days 1-5 and 15-19 of a 6-week treatment course in combination with sorafenib given at the recommended dose of 400 mg twice daily. Patients with stable disease or better are eligible to receive repeat treatment.
Overall, the majority of adverse events and laboratory abnormalities have been mild to moderate, and consistent with the known safety profiles of IL-21 and sorafenib. Dose-limiting toxicities consisting of skin-related events have occurred in two patients, including one in the 10 μg/kg cohort (hand-foot syndrome) and one in the 50 μg/kg cohort (rash). Repeat treatment has not been associated with increased toxicity.
"We were very pleased to see that the combination of IL-21 and Nexavar can be safely administered for repeated courses," said Nicole Onetto, MD, chief medical officer of ZymoGenetics, which is headquartered in Seattle. The company, which is developing recombinant IL-21, is funding the ongoing study.
Because tyrosine kinase inhibitors such as sorafenib and sunitinib (Sutent) inhibit tumor cell growth, and IL-21 activates the immune system to target killing of tumor cells, the two therapies may provide additive or synergistic effects.
"Although sorafenib does not typically cause a large shrinkage of the tumor, it can prevent the tumor from growing further, and has been shown to delay the progression of kidney cancer," Dr. Thompson said.
He also pointed out that immune therapies have been shown to work in kidney cancer in the past, "but those previously available were very toxic and poorly tolerated by most patients. Recombinant IL-21 is well tolerated by most patients."
The researchers theorized that treatment with a TKI may make cancer cells more sensitive to natural killer or T-cell mediated killing after activation with IL-21. Preclinical research conducted by ZymoGenetics found that IL-21 had additive anti-tumor effects when combined with a TKI in a renal cell cancer model.
"At this point, the number of patients treated is still small, and it is too early to draw a definite conclusion concerning the efficacy of IL-21 in combination with sorafenib, compared to sorafenib alone," Dr. Thompson said. "We're looking forward to the phase II portion of the study to better evaluate the overall safety profile and anti-tumor activity."