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Abstract
Background Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel engineered cytokine designed to selectively bind the intermediate-affinity interleukin-2 receptor, preferentially expanding antitumor CD8+ T and natural killer (NK) cells with minimal effect on immunosuppressive regulatory T cells (Tregs).1 In ARTISTRY-1, intravenous (IV) nemvaleukin on days 1–5 (QD×5) in 21-day cycles showed antitumor activity across multiple tumor types as monotherapy at the recommended phase 2 dose of 6 μg/kg/day and in combination with pembrolizumab at doses of 3 and 6 μg/kg/day.2 Expansion of circulating CD8+ T and NK cells was observed, with minimal effect on Tregs.2 Pharmacodynamic data from ARTISTRY-1 were used in quantitative systems pharmacology modeling studies to predict less-frequent IV dosing regimens that mimic expansion of CD8+ T and NK cells observed with 3 μg/kg/day and 6 μg/kg/day QD×5.3 We report preliminary results from ARTISTRY-3, an ongoing phase 1/2, open-label study evaluating less-frequent IV nemvaleukin dosing in advanced solid tumors.
Methods Eligible patients with select solid tumors must have exhausted standard-of-care therapies. Escalating doses of nemvaleukin (10–40 μg/kg/day) were evaluated across 3 schedules in 3-week cycles (Q3W)—day 1 (D1), days 1 and 8 (D1+D8), and days 1 and 4 (D1+D4)—allowing a maximum sample size of 30 patients per schedule. The primary endpoint was incidence of DLTs from the first dose through the end of the DLT observation period. Secondary endpoints included objective response, pharmacokinetics, and severity of adverse events (AEs). Dose-escalation decisions were based on predefined safety parameters of dose-limiting toxicity (DLT) criteria evaluated during cycle 1. Pharmacodynamic assessments included absolute counts of CD8+ T, NK, and Treg cells (cells/μL) by flow cytometry at baseline and in the first 2 cycles.
Results As of June 1, 2023, no DLTs have been observed. Preliminary data indicate expansion of NK and CD8+ T cells at all schedules, with slightly better expansion at D1+D8 and D1+D4 Q3W schedules (figure 1). Minimal to no expansion of Tregs has been observed. The most frequent treatment-related AEs (>20%) include cytokine release syndrome and nausea; most events were grade 1–2 (Safety cutoff: April 21, 2023). There have been no grade ≥3 treatment-related AEs. Maximum serum concentration (Cmax) and exposure (AUC) increased with escalating doses (table 1).
Conclusions This preliminary analysis demonstrates immunologic activity with all 3 nemvaleukin dosing schedules. Nemvaleukin was tolerable at all doses tested. Dose escalation is ongoing and expected to complete by the end of the year.
Acknowledgements The authors would like to thank all the patients who are participating in this study and their families. We thank Corrine Elliott for her contributions to the analysis. The study is sponsored by Alkermes, Inc. Medical writing and editorial support was provided by Parexel International and funded by Alkermes, Inc.
Trial Registration www.clinicaltrials.gov NCT04592653
References
Lopes JE, Fisher JL, Flick HL, et al. ALKS 4230: a novel engineered IL-2 fusion protein with an improved cellular selectivity profile for cancer immunotherapy. J Immunother Cancer. 2020;8(1):e000673.
Vaishampayan U, Tomczak P, Muzaffar J, et al. Nemvaleukin alfa monotherapy and in combination with pembrolizumab in patients (pts) with advanced solid tumors: ARTISTRY-1. J Clin Oncol. 2022;40(16_suppl). Abstract #2500.
Sun L, Matsuura T, Pichardo-Almarza C, et al. Use of quantitative system pharmacology (QSP) modeling to optimize dosing frequency and interval for nemvaleukin alfa (nemvaleukin), an investigational cancer immunotherapy. Poster presented at the Quantitative Systems Pharmacology Conference, 20–22 April 2022, Leiden, The Netherlands.
Ethics Approval The study protocol and its amendments, patient informed consent form, and all relevant documents were approved by an institutional review board or local ethics committee. This study is being conducted according to Declaration of Helsinki and all applicable guidelines from the International Council on Harmonisation (ICH) E6 Good Clinical Practice, US Code of Federal Conduct, and state, local and federal laws. All patients are required to provide written informed consent to participate.
Pharmacodynamic responses: NK and CD8+ T cell expansion (data cutoff: 30 May 2023)a
Pharmacokinetic parameters following increasing doses of nemvaleukin in ARTISTRY-3 (data cutoff: March 2023)
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