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

Abstract

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 µg/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 µg/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.

Keywords: Cytokine; Immunotherapy; Ovarian Cancer; Skin Cancer; Solid tumor.

Figure 1. Mechanism of action of nemvaleukin. Nemvaleukin is designed to selectively bind to the intermediate-affinity dimeric interleukin-2 receptor and is sterically occluded from binding to the high-affinity trimeric interleukin-2 receptor. Adapted from Lopes et al. under the CC BY-NC Attribution 4.0 International license. NK, natural killer; T_reg, regulatory T cell.

Figure 2. ARTISTRY-1 study profile.

Figure 3. Summary of most frequent nemvaleukin-related treatment-emergent adverse events. Nemvaleukin-related treatment-emergent adverse events (≥10% in either cohort) in patients with advanced treatment-refractory solid tumors receiving nemvaleukin as monotherapy (part B; n=74) or in combination with pembrolizumab (part C; n=166). Part B includes patients who received nemvaleukin 6 µg/kg intravenous. Part C includes patients who received nemvaleukin at 1, 3, or 6 µg/kg intravenous in combination with pembrolizumab 200 mg intravenous.

Figure 4. Summary of responses. (A) Duration of nemvaleukin plus pembrolizumab therapy (part C) for patients in PD-(L)1 inhibitor-unapproved cohort.* (B) Duration of nemvaleukin plus pembrolizumab therapy (part C) for patients in PD-(L)1 inhibitor-approved cohort.* *PD-(L)1 inhibitor-approved/unapproved indication based on US FDA prescribing information at the time of the study design and could have changed over time. Responses per investigator-assessed Response Evaluation Criteria in Solid Tumors V.1.1. Swimmer plots show both confirmed and unconfirmed responses. BEV, bevacizumab; BL, bladder cancer; BR, breast cancer; CBP, carboplatin; CDDP, cisplatin; CE, cervical cancer; CO, colorectal cancer; CR, complete response; DOC, docetaxel; EA, esophageal adenocarcinoma; ER, estrogen receptor; FDA, Food and Drug Administration; GEM, gemcitabine; HER, human epidermal growth factor; Mo, month; NIR, niraparib; NSCLC, non–small-cell lung cancer; PAC, paclitaxel; PCA, paclitaxel albumin; PD, progressive disease; PLD, pegylated liposomal doxorubicin hydrochloride; PR, partial response; SCC, squamous cell carcinoma; SCLC, small-cell lung cancer; SD, stable disease; TAM, tamoxifen; TOP, topotecan; uPR, unconfirmed partial response.