Phase 1 study of recombinant interleukin 15 in combination with nivolumab and ipilimumab in subjects with refractory cancers.

Abstract

2617 Background: Combining immune checkpoint inhibitors with cytokine therapies holds promise in cancer immunotherapy. Recombinant human interleukin-15 (rhIL-15) increases circulating CD8+ T cells and natural killer (NK) cells. This Phase 1 study evaluated the safety (NCI-CTCAE v5.0), tolerability, and preliminary efficacy (RECIST v1.1 and iRECIST) of rhIL-15 with nivolumab and ipilimumab. Safety data for rhIL-15/ipilimumab and rhIL-15/nivolumab doublets were reported earlier (O’Sullivan et al., AACR 2019). Here, we present updated triplet dose-escalation results and correlative analyses. Methods: This open-label, non-randomized Phase 1 trial employed a 3+3 dose-escalation design to determine the MTD/RP2D of rhIL-15 SQ (administered on days 1-8 and 22-29, cycles (C) 1-4 only) combined with fixed doses of nivolumab (240 mg IV on days 8, 22, 36) and ipilimumab (1 mg/kg IV on day 8) in 42-day cycles in patients with advanced, refractory cancers. Correlative analyses assessed effects on circulating T cell subsets, PD-1/PD-L1 expression, and immune cell activation in tumor tissue (using multiplex immunofluorescence, immunohistochemistry and flow cytometry). Results: Thirty-one patients (median age: 56 years, range: 24-81) were enrolled and evaluable for safety and response. The most prevalent cancer types were sarcoma, pancreatic, and colorectal cancers (n = 5 each). The MTD/RP2D was established at 1 µg/kg/day SQ rhIL-15, with a manageable safety profile. Common treatment-related adverse events (TRAE) included injection site reactions (74%), fever (65%), and chills (65%). Grade 3/4 lymphopenia was seen in 13% of patients (4 of 31). Confirmed partial response (cPR) was measured in 1/31 patients (3%); the patient had cholangiocarcinoma and was treated at dose level 1 (DL1, 0.5 µg/kg/day rhIL-15) and the response lasted through cycle 16. Stable disease (SD) occurred in 17/31 patients (55%, median: 2 cycles, range: 1-10), including durable SD (10 cycles at DL1) in salivary gland squamous cell carcinoma. Nine patients had progressive disease as a best response. Four patients did not have tumor measurements after C1 or did not complete C1, including 3 with clinical disease progression and one with grade 3 TRAE. NK cells and γδ-T cells increased in blood, but increases did not correlate with tumor infiltration measured on C1D42. CD8+ T cells increased modestly in blood and tumor without correlation to either clinical benefit, increased PD1+CD3+ lymphocytes, or PD-L1+ tumor cells on C1D42. Conclusions: These data suggest the addition of rhIL-15 to the combination of ipilimumab and nivolumab is safe, elicited a pharmacodynamic response from the immune system in blood but not tumor, and did not improve overall response rate. Clinical trial information: NCT03388632 .