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BackgroundNemvaleukin 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.MethodsEligible 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.ResultsAs 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).ConclusionsThis 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.AcknowledgementsThe 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 Registrationwww.clinicaltrials.gov NCT04592653ReferencesLopes 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 ApprovalThe 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.Abstract 744 Figure 1Pharmacodynamic responses: NK and CD8+ T cell expansion (data cutoff: 30 May 2023)aAbstract 744 Table 1Pharmacokinetic parameters following increasing doses of nemvaleukin in ARTISTRY-3 (data cutoff: March 2023)

Journal for immunotherapy of cancer, 2023-11, Vol.11 (Suppl 1), p.A839-A840

744 Assessment of safety and immunologic activity of nemvaleukin alfa in patients with advanced solid tumors treated with less frequent intravenous dosing (ARTISTRY-3)

BackgroundNemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel, engineered cytokine that selectively binds to the intermediate-affinity interleukin-2 receptor to preferentially activate antitumor CD8+ T cells and natural killer cells, with minimal expansion of immunosuppressive regulatory T cells. The first-in-human study, ARTISTRY-1, demonstrated antitumor activity with intravenous (IV) nemvaleukin (6 µg/kg on days 1–5 per 21-day cycle) monotherapy and nemvaleukin + pembrolizumab, with manageable safety in heavily pretreated adults with advanced solid tumors.1 ARTISTRY-2 (NCT03861793) is a phase 1/2 study evaluating the safety, antitumor activity, and pharmacokinetics/pharmacodynamics of subcutaneous (SC) nemvaleukin + pembrolizumab in patients with advanced solid tumors.MethodsIn ARTISTRY-2, the recommended phase 2 dose (RP2D) of SC nemvaleukin was identified as 3 mg every 7 days (Q7D).2 In phase 2, SC nemvaleukin + pembrolizumab was administered in the following cohorts: non-small-cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), gastric and gastroesophageal junction cancer (G/GEJ), and ovarian cancer Cohorts 1 (OC1) and 2 (OC2). OC2 cohort included definition of platinum resistance, number of prior lines of therapy and requirement for prior treatment with bevacizumab, reflecting baseline characteristics associated with higher likelihood of clinical benefit. Investigator-assessed antitumor activity (RECIST v1.1) and safety are reported as of April 21, 2023.ResultsIn phase 2, 59 patients (11 NSCLC, 10 SCCHN, 13 G/GEJ, 17 OC1, 8 OC2) received SC nemvaleukin + pembrolizumab. Antitumor activity was observed, including 2 partial responses (PRs) in OC (ORR 15.4% [OC1, 2/13]) and 1 PR in NSCLC (ORR 10% [NSCLC, 1/10]); responders were checkpoint inhibitor-naive. The most frequent treatment-related adverse events (TRAEs) of any grade (>40%) included pyrexia (50.8%) and injection-site reactions (45.8%), and of grade 3/4 (>5%) were fatigue (6.8%), lymphocyte count decreased (6.8%), and lymphopenia (5.1%). A total of 7 patients (11.9%) discontinued the study due to TRAEs. There was 1 treatment-related grade 5 event of pneumonitis (NSCLC cohort). The safety profile of SC nemvaleukin + pembrolizumab was consistent with that reported for IV dosing, except for injection-site reactions.ConclusionsSC nemvaleukin 3 mg Q7D with pembrolizumab was generally well tolerated and demonstrated antitumor activity in patients with refractory solid tumors. Although antitumor activity was observed, the robustness of this activity was less than that observed with the daily ×5 IV dosing; therefore, a less frequent IV dosing schedule of nemvaleukin is being explored in ARTISTRY-3 (NCT04592653).AcknowledgementsThe authors would like to thank all the patients who are participating in this study and their families. The study is sponsored by Alkermes, Inc. Medical writing and editorial support was provided by Parexel International and funded by Alkermes, Inc.Trial RegistrationClinicaltrials.gov NCT03861793ReferencesVaishampayan 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.Hamid O, Liu SV, Boccia RV, et al. Selection of the recommended phase 2 dose (RP2D) for subcutaneous nemvaleukin alfa: ARTISTRY-2. J Clin Oncol. 2021;39(15_suppl). Abstract #2552.Ethics ApprovalThe 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.

Journal for immunotherapy of cancer, 2023-11, Vol.11 (Suppl 1), p.A819-A819

724 Subcutaneous nemvaleukin alfa in combination with pembrolizumab in patients with refractory solid tumors (ARTISTRY-2)

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744 Assessment of safety and immunologic activity of nemvaleukin alfa in patients with advanced solid tumors treated with less frequent intravenous dosing (ARTISTRY-3)

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724 Subcutaneous nemvaleukin alfa in combination with pembrolizumab in patients with refractory solid tumors (ARTISTRY-2)

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