ORCID

Abstract

BACKGROUND: Despite improved outcomes with immune checkpoint inhibitors (ICIs) and their combinations in advanced solid tumors, a subset of patients remains unresponsive or progresses, highlighting an unmet need for novel treatments with durable benefit. Nemvaleukin alfa (nemvaleukin, ALKS 4230) demonstrated manageable safety and antitumor activity, alone and in combination with pembrolizumab, across heavily pretreated advanced solid tumors in the ARTISTRY-1 study. We report in-depth antitumor activity, safety, pharmacokinetics, and pharmacodynamics of nemvaleukin monotherapy at the recommended phase 2 dose (RP2D) in advanced melanoma and renal cell carcinoma (RCC) cohorts from ARTISTRY-1.

METHODS: ARTISTRY-1 was a three-part (A, B, and C), multicenter, open-label, phase 1/2 study. Adult patients who had received prior treatment, including ICIs, and had advanced melanoma or RCC were enrolled in Part B. Patients received intravenous nemvaleukin once daily on days 1-5 (21-day cycle) at 6 µg/kg/day (RP2D determined from Part A). Primary endpoints for Part B were overall response rate (ORR) and safety. Secondary endpoints included pharmacokinetic and pharmacodynamic measures.

RESULTS: From July 2016 to March 2023, 74 patients in Part B received nemvaleukin monotherapy (melanoma, n=47; RCC, n=27). ORR in melanoma and RCC cohorts was 9% (95% CI, 2% to 21%; n=4) and 14% (95% CI, 3% to 35%; n=3), respectively; disease control rate was 50% (95% CI, 35% to 65%; n=23) and 50% (95% CI, 28% to 72%, n=11), respectively, with stable disease ≥6 months observed in 3 (7%) and 2 (9%) patients, respectively. The most common nemvaleukin-related treatment-emergent adverse event of grade 3-4 was neutropenia (melanoma, n=27 (57%); RCC, n=9 (33%)). No patients in either cohort experienced grade ≥3 treatment-emergent adverse events (TEAEs) of cytokine release syndrome or infusion-related reaction. There were no reported capillary leak syndrome TEAEs. Pharmacokinetic parameters for extent and duration of nemvaleukin exposure were similar between the two cohorts. Increases in peripheral CD8+ T-cell and natural killer cell populations from baseline were similar between the two cohorts, with minimal changes in regulatory T cells observed.

CONCLUSIONS: Nemvaleukin demonstrated pharmacodynamic proof of mechanism, with single-agent antitumor activity and manageable safety in patients with advanced melanoma and RCC.

TRIAL REGISTRATION NUMBER: NCT02799095.

Publication Date

2025-08-04

Publication Title

Journal for ImmunoTherapy of Cancer

Volume

13

Issue

8

ISSN

2051-1426

Acceptance Date

2025-07-01

Deposit Date

2025-11-03

Funding

This study was supported by Mural Oncology (part of Alkermes, Inc. at the time of study design and conduct). We thank the patients and their families who made this study possible, and the investigators and the clinical study teams for study support. Professional medical writing and editorial assistance were provided by Mandakini Singh, PhD, of Parexel International and funded by Mural Oncology. Results reported in this manuscript were previously presented in part at the American Society of Clinical Oncology (ASCO) congress (June 3–7, 2022) as an oral presentation (abstract # 2500). The study was sponsored by Mural Oncology (part of Alkermes, Inc. at the time of study design and conduct). EC declares leadership at BeiGene, EORTC, Merus NV, Novartis, PharmaMar, Sanofi, and START; stock and other ownership interests in Oncoart Associated and START; honoraria fee from HM Hospitales group; consulting fee from or advisory role for Adcendo, Amunix, Anaveon, AstraZeneca/MedImmune, Bristol Myers Squibb, Chugai Pharma, Diaccurate Elevation Oncology, Ellipses Pharma, Genmab, Janssen-Cilag, MonTa, MSD Oncology, Nanobiotix, Nouscom, Novartis, OncoDNA, PharmaMar, Roche/Genentech, Servier, Syneos Health, TargImmune Therapeutics, and T-Knife; research funding from START; and other relationship as president and founder of Foundation INTHEOS (Investigational Therapeutics in Oncological Sciences), the not-for-profit Foundation PharmaMar, and the not-for-profit CRIS Cancer Foundation. VB declares employment and leadership at NEXT Madrid, University Hospital Quirónsalud Pozuelo; stock ownership in 1TRIALSP; consultant or advisory role at Puma Biotechnology, Ideaya Biosciences, Loxo Therapeutics, CytomX Therapeutics, Guidepoint, Oncoart, Lilly, Janssen, EMD Serono, and IDMC Nanobiotix NANORAY-312/Novartis; steering committee membership for CytomX Therapeutics; honoraria (speaking) fee from Eli Lilly, MSD, SOLTI, TACTICS, GETTHI, and GEDEFO; travel, inscription, and accommodation fees from Bayer (ESMO GI); institutional financial support for clinical trials from AbbVie, ACEO, Adaptaimmune, Affimed, Amcure, Amgen, Amunix, Astellas, AstraZeneca, BeiGene, Bicycle, BMS, Boehringer Ingelheim, Boston Therapeutics, Carrick therapeutics, Constellation Pharmaceutical, CytomX; Crescendo Biologics, Cullinan, Daiichi, DebioPharm, Dynavax, Ellipses Pharma, Exelixis, Famawav, GSK, Genentech/Roche, Genmab, Gilead, Incyte, Ipsen, Ideaya Biosciences, Invox Pharma, iOMX Therapeutics, Janssen, Kura, Kronos Bio, Lilly, Loxo Oncology, Macrogenics, Menarini, Merck, Merus, Mersana, Millennium, Moderna, MSD, Navire Pharma, Nektar, Nanobiotix, Novartis, ORCA, Pfizer, PharmaMar; Principia, PsiOxus, PUMA, Regeneron, Ryvu Therapeutics, Ribbon, Sanofi, Salubris Biotherapeutics, Scorpion Therapeutics, Seagen, Seattle Genetics, Spectrum, Stemline Therapeutics, Synthon, Taiho, Tesaro, Transgene, Takeda, Tolrelmo Therapeutics, Totus Medicine, Tyra Biosciences, Vividion Therapeutics, Urogen, Xencor, Zai Biopharmaceutical, and Zenith. OD declares no competing interests. SJS declares no competing interests. SR declares stock ownership in Amgen, Johnson & Johnson, and Pfizer. AC declares stock ownership in Novartis; and speakers’ bureau membership at Pharmacyclics. PRD declares grants (to institution) from Pfizer; consulting fees for participation on advisory boards from Astellas Pharma, Bristol Myers Squibb, Ipsen, MSD, and Pfizer; honoraria for lectures from Bayer; travel support from Janssen; (substitute) board membership for the Clinical Trials College, Federal Public Service, Kingdom of Belgium; and stock ownership in Alkermes, Mural Oncology PLC, and Biocartis Group NV. XH declares employment at Mural Oncology. UV declares research support from Bristol Myers Squibb and Merck; consulting fees from Alkermes, Aveo, Bayer, Bristol Myers Squibb, Exelixis, Gilead, Novartis, Pfizer, and Seattle Genetics; and speaker honoraria fees from Exelixis, Bayer, and Pfizer. DFM declares consulting/honoraria fee from BMS, Pfizer, Merck, Eisai, Xilio, Aveo, Genentech, Cullinan, and Exelixis; and research support from Alkermes Bristol Myers Squibb, Exelixis, Genentech, Merck, Pfizer, and X4 Pharma.

Keywords

Humans, Carcinoma, Renal Cell/drug therapy, Female, Male, Middle Aged, Melanoma/drug therapy, Aged, Kidney Neoplasms/drug therapy, Adult, Aged, 80 and over

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