AACR-NCI-EORTC: Immune Stimulation May Boost Kidney Cancer Response to Targeted Therapy

SAN FRANCISCO, Oct. 24 -- Early findings suggest that sorafenib (Nexavar) may be more effective against metastatic kidney cancer when given in combination with a novel immune-stimulating cytokine, researchers said.All 10 evaluable patients treated with recombinant interleukin-21 (IL-21) plus sorafenib had tumor regression in a small, phase I trial presented here at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.
Four patients also achieved a partial response with tumor shrinkage of at least 30%, reported John A. Thompson, M.D., of the University of Washington and the Fred Hutchinson Cancer Research Center in Seattle, and colleagues.
"We can't really make direct comparisons yet of this combination versus sorafenib alone," he said, although the findings are "encouraging."
"Tyrosine kinase inhibitors such as sunitinib [Sutent] and sorafenib have shown clinical benefit in patients with metastatic renal cell carcinoma," the researchers said. "However, durable responses continue to be elusive, except in a small subset of patients treated with high dose interleukin-2 (IL-2)."
IL-21 stimulates T-cell and natural killer cell function much as IL-2 does, he said. However, IL-21 is less toxic and can be used on an outpatient basis whereas IL-2 required administration in an intensive care unit, he added.
Dr. Thompson reported interim results from the dose escalation phase of a trial of first- or second-line treatment for metastatic renal cell carcinoma of predominantly clear cell histology among patients with ECOG performance status 0 or 1.
He and his colleagues treated 12 patients with the standard 400 mg dose of sorafenib twice a day during six-week cycles of recombinant IL-21. Treatment courses were repeated for patients with stable disease or better outcomes.
Six patients received IL-21 at a 10 μg/kg dose, three received a 30 μg/kg dose, and another three received a 50 μg/kg dose.
All 10 of the patients evaluable for tumor response had tumor shrinkage of at least 20% at some point during treatment.
Two patients in second-line treatment had tumor shrinkage of at least 30% after the first course of combination therapy. Another two patients in first-line treatment had a partial tumor response after the third course, although one went on to have progressive disease after the fourth course of combination therapy.
These findings were promising because in the phase III trial that led to approval of sorafenib for advanced kidney cancer, the drug was associated with only a 2% overall response rate, Dr. Thompson said.
Sorafenib works by blocking tumor growth and angiogenesis to delay progression rather than causing a large shrinkage of tumors by itself, he added.
The researchers reported no additive toxicity when sorafenib was used in combination with IL-21. Adverse events were similar to what would be expected. These included two cases of grade 3 hand-foot syndrome, one of grade 3 rash, one of grade 3 intermittent fever, and one of grade 3 fatigue.
Grade 3/4 laboratory abnormalities included seven cases of hypophosphatemia, two cases of hyponatremia and elevated amylase, three patients with elevated lipase, and thrombocytopenia and hyperuricemia in one patient each.
Toxicity did not appear to accumulate with repeat treatment.
The ongoing phase II study expanding on this cohort will assess the objective response rate and progression-free survival, the researchers said.
The study was funded by ZymoGenetics, which is developing recombinant IL-21. Two of the coauthors were employees of the company. Primary source: AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics
Source reference: Bhatia S, et al "Recombinant IL-21 (rIL-21) in Combination with Sorafenib: Preliminary Results from a Phase I/II Study in Patients with Metastatic Renal Cell Cancer (RCC)" AACR-NCI-EORTC meeting 2007; Abstract A60.