Interleukin-21 (Il-21) Activity In Patients (Pts) With Metastatic Melanoma (Mm)

8507 Background: IL-21 is a T-cell derived cytokine with antitumor activity shown to be dependent on NK cells or CD8+ T cells through induction of central and effector memory cells. Two previous phase I studies suggested activity in MM. Methods: We conducted a phase II study of IL-21 evaluating the response rate (ORR) by RECIST, toxicity, progression free survival (PFS) and biomarker profile. Pts with no prior systemic therapy for MM were treated with IL-21 using 3 different dosing regimens. The initial cohort received 50 μ g/kg/day by outpatient intravenous bolus injection daily × 5, weeks 1, 3, 5 q 8 wks. Cohort 2 received 30 μ g/kg/day in the same schedule and Cohort 3 received 50 μ g/kg/day daily × 5, weeks 1, 3 q 6 wks. Results: 40 pts were enrolled: 3 in cohort 1, 30 in cohort 2, 7 in cohort 3. Two pts in cohort 1 had dose limiting toxicity (DLTs) and 4 in cohort 3, thus all other pts were treated with the 30 ug/kg/day dose. The most common adverse events were fatigue, rash, diarrhea and myalgia. 37 pts are evaluable for response: 9 had a PR (ORR = 24.3%; median duration 5 mo), 16 had stable disease (median 5.1 mo) and 12 had PD. ORR was not dependent on dose, IL-21 receptor expression or BRAF mutation status (3 of the PRs were BRAF positive, 5 were BRAF negative, 1 was BRAF inconclusive). The median PFS is 5.19 mo (95% C.I. [2.17, 5.95]). The encouraging PFS result was examined further by comparing the outcome of this study to historical NCIC CTG phase II melanoma trials in those patients who matched the IL-21 trial entry criteria (n = 68). The PFS in the historical group was 1.58 mo (95% C.I. [1.22, 1.87]). A multivariate analysis comparing PFS of IL-21 treated patients to the historical group to adjust for prognostic factors (age, gender, perf status, liver mets, number of metastatic sites) revealed that age (HR = 0.97, p = 0.0008), performance status (1 vs. 0: HR = 1.497 and 2 vs. 0: HR = 8.091, p = 0.0026) and treatment with IL-21 (HR = 0.584, p = 0.0198) were significant predictors of PFS. Conclusions: The ORR to IL-21 is 24% for first line MM and warrants further investigation. A median PFS of 5.19 months is superior to that observed in historical NCIC CTG data even when adjusted for prognostic variables. We plan a randomized phase II study of IL-21 to confirm and extend these observations. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ZymoGentics ZymoGentics ZymoGenetics