Safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy from a first-in-human study of volrustomig, a novel PD-1/CTLA-4 bispecific antibody

  • Clin Cancer Res. 2026 Feb 17. doi: 10.1158/1078-0432.CCR-25-3447.
Ben Tran  1 ,  Mark Voskoboynik  2 ,  Sang-We Kim  3 ,  Charlotte Lemech  4 ,  Enric Carcereny  5 ,  Sun Young Rha  6 ,  Myung-Ju Ahn  7 ,  Enriqueta Felip  8 ,  Ki Hyeong Lee  9 ,  Eduardo Castañón Álvarez  10 ,  James Chih-Hsin Yang  11 ,  Paolo Antonio Ascierto  12 ,  Mariano Provencio Pulla  13 ,  Shunsuke Kondo  14 ,  Yasutoshi Kuboki  15 ,  Daniel Freeman  16 ,  Xuyang Song  17 ,  Jorge Blando  17 ,  Steven Eck  18 ,  Florian J Song  19 ,  Zoey Tang  18 ,  Michael Kuziora  18 ,  Shelby D Gainer  16 ,  Patrick Mitchell  20 ,  Julie Asare  16 ,  Amal Ayyoub  16 ,  Ikbel Achour  16 ,  Deepa S Subramaniam  21 ,  Seock-Ah Im  22
Affiliations
  • 1. Peter MacCallum Cancer Centre Melbourne Australia.
  • 2. The Alfred Hospital Melbourne Australia.
  • 3. Asan Medical Center, University of Ulsan College of Medicine Seoul Korea (South), Republic of.
  • 4. Scientia Clinical Research Ltd Sydney, NSW Australia.
  • 5. institute of Catalan Oncology Badalona Badalona Spain.
  • 6. Yonsei University College of Medicine Seoul Korea (South), Republic of.
  • 7. Samsung Medical Center Seoul Korea (South), Republic of.
  • 8. Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology Barcelona Spain.
  • 9. Chungbuk National University Hospital Cheongju Korea (South), Republic of.
  • 10. Clinica Universidad de Navarra Madrid Spain.
  • 11. National Taiwan University Hospital Taiwan.
  • 12. Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale" Napoli Italy.
  • 13. Hospital Universitario Puerta de Hierro Majadahonda Majadahonda, Madrid Spain.
  • 14. Tokyo Women's Medical University Tokyo Japan.
  • 15. National Cancer Center Hospital East Kashiwa, Chiba Japan.
  • 16. AstraZeneca (United States) Gaithersburg United States.
  • 17. AstraZeneca (United States) Gaithersburg, Maryland United States.
  • 18. AstraZeneca (United States) Gaithersburg, MD United States.
  • 19. AstraZeneca Munich Germany.
  • 20. AstraZeneca (United States) Waltham, MA United States.
  • 21. AstraZeneca (United States) United States.
  • 22. Seoul National University Hospital Seoul Korea (South), Republic of.
PMID: 41701940 DOI: 10.1158/1078-0432.CCR-25-3447
Abstract

Purpose: Volrustomig is an IgG1 monovalent bispecific antibody engineered to preferentially target CTLA-4 on PD-1-positive T cells while providing adequate and durable PD-1 inhibition. The aim of this phase I, first-in-human study (NCT03530397) is to evaluate the safety, tolerability, pharmacokinetics, immunogenicity, pharmacodynamics, and antitumor activity of volrustomig. This manuscript reports findings for the dose-exploration and immunotherapy-naïve expansion cohorts.

Patients and methods: Patients aged ≥18 years who had histologically or cytologically confirmed advanced Cancer, measurable disease, performance status of 0-1, and adequate organ and marrow function received volrustomig 2.25-2500 mg intravenously every 3 weeks until confirmed disease progression, initiation of alternative Cancer therapy, unacceptable toxicity, or consent withdrawal. The primary objective in the dose-exploration phase was to evaluate the safety and tolerability, describe dose-limiting toxicities, and determine the maximum tolerated dose. Secondary objectives included assessment of preliminary antitumor activity and volrustomig pharmacokinetics.

Results: 86 patients received volrustomig treatment in the dose-exploration and immunotherapy-naïve expansion cohorts; 78 (90.7%) patients were immunotherapy-naïve. Common treatment-related adverse events (TRAEs) were pruritus (30.2%), Hypothyroidism (26.7%), Hyperthyroidism (24.4%), and rash (24.4%). TRAEs led to treatment discontinuation in 33.7% of patients and one death. At doses ≥500 mg, volrustomig demonstrated robust peripheral and intra-tumoral T cell activation and proliferation at levels greater than those seen with approved PD-1/CTLA-4 regimens. Seventeen (19.8%) patients had objective responses, including 2 (2.3%) complete responses; median response duration was 17.5 months.

Conclusions: These results support further development of volrustomig as monotherapy and in combination regimens, with phase 3 trials ongoing.

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