Phase 1 study evaluating the safety, preliminary efficacy, and pharmacodynamics of recombinant interleukin-15 in combination with nivolumab and ipilimumab in patients with refractory cancers.

PURPOSE: Combinations of immune checkpoint inhibitors and cytokine therapies have shown promise in cancer immunotherapy. We aimed to evaluate the safety, tolerability, and preliminary efficacy of recombinant human interleukin-15 (rhIL-15) in combination with nivolumab and ipilimumab in patients with advanced, refractory cancers. METHODS: This open-label, non-randomized study employed a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD) of rhIL-15 combined with fixed doses of nivolumab and ipilimumab. Safety and tolerability were assessed according to Common Terminology Criteria for Adverse Events (CTCAE) criteria, and preliminary efficacy was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) and immune-related RECIST (iRECIST) criteria. Pharmacodynamic studies evaluated changes in immune cell populations in peripheral blood and paired baseline and on-treatment tumor biopsies. RESULTS: Thirty-one patients were enrolled, with a median age of 56 years (range: 24-81 years). Five patients received rhIL-15 with either nivolumab or ipilimumab in safety run-in cohorts, 26 patients received rhIL-15 with nivolumab plus ipilimumab. The most common cancer types were gastrointestinal (n=7) or gynecologic (n=5). The MTD was 1 µg/kg/day rhIL-15, 240 mg nivolumab, and 1 mg/kg ipilimumab. The triplet combination showed a manageable safety profile; the most common treatment-related adverse events (trAEs) were chills (20/26, 77%), fever (18/26, 69%), injection site reaction (15/26, 58%), anemia (14/26, 54%), and fatigue (14/26, 54%). Lymphopenia (4/26, 15%) was the most common grade 3/4 trAE. Pharmacodynamic analysis of tumor biopsies revealed increases in CD8+, CD8+CD3ζpY142+ (ie, activated CD8+T cells), PD-1+CD3+, and CD45RO+CD3+ (ie, memory T cells) in some patients. Tumor infiltration of natural killer (NK) and γδ T cells was also observed. NK cell populations in peripheral blood were modulated by rhIL-15. 11 of 26 patients (42%) had stable disease as a best response on the triplet regimen. A partial response was measured after cycle 1 in one patient (4%) with cholangiocarcinoma and confirmed after cycle 2; this patient completed 16 cycles. CONCLUSIONS: The combination of rhIL-15 with nivolumab and ipilimumab was safe and induced changes in immune cell populations in some patients. However, preliminary signs of efficacy were limited. Pharmacodynamic findings may support further clinical development of this combination with alternative dosing regimens or combinations of rhIL-15 with other therapeutic modalities.