CHICAGO – The novel cytokine interleukin-21 has shown itself to be biologically active with an overall response rate of 22% in first-line metastatic melanoma patients.
Median progression-free survival reached 4.32 months in the phase II, multicenter IND 189 trial involving 40 patients, Dr. Teresa Petrella reported on behalf of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG).
This finding held up well when it was benchmarked against the widely cited Korn meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma (J. Clin. Oncol. 2008;26:527-34) and 68 historical NCIC CTG melanoma patients who matched the IND 189 study entry criteria. Median progression-free survival was 1.31 months in the Korn analysis and 1.58 months for the NCIC CTG patients, said Dr. Petrella of the Odette Cancer Centre in Toronto.
Age, performance status, and interleukin-21 (IL-21) treatment were significant predictors of progression-free survival in a multivariate analysis among IL-21–treated patients and historical controls that adjusted for prognostic factors.
Based on the findings, study sponsor ZymoGenetics Inc. is planning a phase IIB randomized trial with the NCIC CTG to validate the results, Dr. Petrella said.
Invited discussant Dr. Antoni Ribas of the University of California, Los Angeles, said the response rate was very respectable for a single-agent cytokine in previously untreated metastatic melanoma. The caveat is that the responses seem to be of limited duration.
Nine patients had a partial response by RECIST (Response Evaluation Criteria in Solid Tumors) and CT for the objective response rate of 22.5% and median duration of 5.0 months. In all, 16 patients (40%) had stable disease for a median duration of 5.3 months.
“Two patients had a tail of 1.5 years of progression-free survival, but there was no clear evidence that most of the responses were durable, which questions if this is a memory T-cell response or maybe more of an innate response,” said Dr. Ribas. “I hope that further clinical investigation will address this question.”
IL-21 is a novel cytokine that has multiple immunomodulatory effects including beneficial effects on B cells, natural killer cells, and T cells, in particular CD4 and CD8 T cells. In two phase I, dose-escalation studies of IL-21 in metastatic melanoma, there was evidence of tumor response and immune activation with an eightfold increase in soluble CD25, reflecting lymphocyte activation (J. Clin. Oncol. 2008;26:2034-9; Clin. Cancer Res. 2007;13:3630-6).
The majority of patients in the IND 189 trial received IL-21 30 mcg/kg per day for 5 days on the first, third, and fifth weeks of an 8-week schedule, after dose-limiting toxicities were observed at higher, more frequent dosing.
Overall, IL-21 was well tolerated, with most adverse events being grade 1/2, Dr. Petrella said. The most common of these were fatigue, rash, fever, myalgia, anorexia, chills, and nausea, which were very similar to what was seen in the phase I studies. Seven patients experienced grade 3 rash.
Nine serious adverse events were reported, of which four were possibly, probably, or definitely treatment related. They included one infection with grade 4 neutropenia, two grade 4 liver enzyme elevations, and one second malignancy (acute myeloid leukemia) that occurred 11 months after the patient received only 5 days of interleukin-21 and thus was most likely not related to the treatment, she said.
Most patients had an Eastern Cooperative Oncology Group performance status of 0, 17 had received prior adjuvant immunotherapy with interferon, and 32 had metastases to the lung. Their median age was 56 years. Responses were seen in all sites of disease, and patients continue to be followed.
ZymoGenetics Inc. provided research funds and employs one of the researchers. Dr. Ribas reports honoraria from Amgen Inc. and Roche.