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Phase II Trial of Interleukin-21 and Nexavar
Shailender Bhatia from the University of Washington presented the results, in a poster session, of a Phase II trial of the combination of Interleukin-21 (IL-21) and sorafenib (Nexavar) as a second-line therapy in kidney cancer. IL-21, like IL-2, is an immunotherapy that activates the body's T-cells and natural killer cells to attack and destroy foreign substances like tumors. Unlike IL-2, IL-21 does not activate T-reg cells, which have an inhibiting effect on the immune system. The object of this study is to combine low dosage IL-21 with the normal dosage, 400 mg twice a day, of Nexavar, to gauge the effect of combining an immunotherapy and a targeted therapy (in this case, a tyrosine kinase inhibitor) in the fight against kidney cancer. This being a second-line trial, 79% of patients had one prior therapy while 21% had two priors. The most prevalent prior therapies were Sutent (58%) and IL-2 (33%).
33 patients were enrolled in the trial, but seven (21%) withdrew due to adverse events, a fairly high number. The most common grade 3/4 adverse events (AEs) were rash (9 patients) and hand-foot syndrome (8 patients) although 70% and 61% of patients suffered from all grades of fatigue and fever, respectively. A dose reduction was required in Nexavar in 70% of patients and in IL-21 in 9% of patients.
The response rate to the treatment was as follows. The progression-free survival was 5.7 months, and, by independent review, 21% of patients had a partial response, 55% had stable disease, 12% had progressive disease, with the rest being unconfirmed.
As a point of reference, we should compare these results against the Target Trial reported two years ago by Bernard Escudier where Nexavar was tested against a placebo in a second-line setting in a similar patient mix. There were 451 patients on the Nexavar arm of the trial. Treatment discontinuation due to adverse event was 9%, the most significant grade 3/4 AE was hand-foot syndrome at 5%, and dose reduction or interruption was required in 78% of the patients. The overall response was: progression-free survival (pfs) 5.6 mos. and 2% partial response, 78% stable disease, 9% progressive disease, with the rest missing data. An Expanded Access Trial of 2,500 metastatic kidney cancer patients who were treated with Nexavar in a free distribution program by Bayer/Onyx while the companies were awaiting FDA approval for the drug yielded similar results. 50% of these patients had had prior therapy, mostly cytokine (IL-2 or Interferon). The grade 3/4 AEs were hand-foot syndrome (8%), fatigue (6%), rash (5%), hypertension (5%). The overall response was 4% partial response and 80% stable disease.
The results of these trials are not directly comparable with the combination trial since the patient mix is not the same but we can look at the trend. The IL-21/Nexavar combo trial seems to have higher adverse events, which is understandable since you are adding a second toxic medicine to the same dosage of a toxic monotherapy. The combination therapy also had a higher partial response rate than the Nexavar alone. Nexavar adherents claim that the stable disease category implies that although the tumor doesn't shrink, it becomes necrotic as proved by a reduction in vascularization as seen in scans.
At any rate, the results of the IL-21/Nexavar trial are interesting enough to warrant a Phase III trial testing the combination against Nexavar alone. I asked a ZymoGenetics (producer of IL-21) rep about that and was told that the company plans to partner with another company to raise funds before proceeding with a Phase III trial, which would occur in melanoma not in kidney cancer since the latter field is already "too crowded". That would be disappointing, but is an example of why we cannot be dependent on drug companies alone to fund research in kidney cancer!