Nemvaleukin alfa, a modified interleukin-2 cytokine, as monotherapy and with pembrolizumab in patients with advanced solid tumors (ARTISTRY-1)

Background Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel, engineered cytokine that selectively binds to the intermediate-affinity interleukin-2 receptor, preferentially activating CD8+ T cells and natural killer cells, with minimal expansion of regulatory T cells, thereby mitigating the risk of toxicities associated with high-affinity interleukin-2 receptor activation. Clinical outcomes with nemvaleukin are unknown. ARTISTRY-1 investigated the safety, recommended phase 2 dose (RP2D), and antitumor activity of nemvaleukin in patients with advanced solid tumors.Methods This was a three-part, open-label, phase 1/2 study: part A, dose-escalation monotherapy, part B, dose-expansion monotherapy, and part C, combination therapy with pembrolizumab. The study was conducted at 32 sites in 7 countries. Adult patients with advanced solid tumors were enrolled and received intravenous nemvaleukin once daily on days 1-5 (21-day cycle) at 0.1-10 mu g/kg/day (part A), or at the RP2D (part B), or with pembrolizumab (part C). Primary endpoints were RP2D selection and dose-limiting toxicities (part A), and overall response rate (ORR) and safety (parts B and C).Results From July 2016 to March 2023, 243 patients were enrolled and treated (46, 74, and 166 in parts A, B, and C, respectively). The maximum tolerated dose was not reached. RP2D was determined as 6 mu g/kg/day. ORR with nemvaleukin monotherapy was 10% (7/68; 95% CI 4 to 20), with seven partial responses (melanoma, n=4; renal cell carcinoma, n=3). Robust CD8+ T and natural killer cell expansion, and minimal regulatory T cell expansion were observed following nemvaleukin treatment. ORR with nemvaleukin plus pembrolizumab was 13% (19/144; 95% CI 8 to 20), with 5 complete and 14 partial responses; 6 responses were in PD-(L)1 inhibitor-approved and five in PD-(L)1 inhibitor-unapproved tumor types. Three responses were in patients with platinum-resistant ovarian cancer. The most common grade 3-4 treatment-related adverse events (TRAEs) in parts B and C, respectively, were neutropenia (49%, 21%) and anemia (10%, 11%); 4% of patients in each part discontinued due to TRAEs.Conclusions Nemvaleukin was well tolerated and demonstrated promising antitumor activity across heavily pretreated advanced solid tumors. Phase 2/3 studies of nemvaleukin are ongoing.Trial registration number NCT02799095.