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Publications

Journal Article Ahead of print

PubMed: 40993242 DOI: 10.1038/s41591-025-03967-2

Neoadjuvant PD-1 and LAG-3-targeting bispecific antibody and other immune checkpoint inhibitor combinations in resectable melanoma: the randomized phase 1b/2 Morpheus-Melanoma trial.

Nat Med

Authors: Georgina V Long, Nitya Nair, Daniel Marbach, Richard A Scolyer, Sabine Wilson, Denise Cotting, Nicolas Staedler, Rodabe N Amaria, Paolo Antonio Ascierto, Ahmad A Tarhini, Caroline Robert, Omid Hamid, Caroline Gaudy-Marqueste, Celeste Lebbe, Eva Munoz-Couselo, Alexander M Menzies, Cecile Pages, Giuseppe Curigliano, Mario Mandala, Nikki Jessop, Uwe Bader, Maurizio Perdicchio, Volker Teichgräber, Merlind Muecke, Christoph Markert, Christian Blank

Affiliations

  • Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.
  • Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
  • Royal North Shore Hospital and Mater Hospitals, Sydney, New South Wales, Australia.
  • Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, Ltd. Basel, Switzerland.
  • Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, Ltd. Basel, Switzerland.
  • Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.
  • Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
  • Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, New South Wales, Australia.
  • Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia.
  • Roche Pharma Research and Early Development, Roche Innovation Center Welwyn, Roche Products, Ltd. Welwyn Garden City, UK.
  • F. Hoffmann-La Roche, Ltd. Basel, Switzerland.
  • The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy.
  • H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
  • Gustave Roussy and Paris Saclay University, Villejuif, France.
  • The Angeles Clinic, Los Angeles, CA, USA.
  • Department of Dermatology and Skin Cancer, Aix-Marseille University, APHM, CEPCM, Hôpital Timone, Marseille, France.
  • Université Paris Cité, AP-HP Dermato-oncology and CIC, Cancer Institute APHP Nord Paris Cité, INSERM U1342 - Equipe 1 - CNRS EMR8000, Saint-Louis Hospital, Paris, France.
  • Vall d'Hebron Institute of Oncology, Barcelona, Spain.
  • Vall d'Hebron Hospital, Barcelona, Spain.
  • Royal North Shore Hospital and Mater Hospitals, Sydney, New South Wales, Australia.
  • Oncopole Claudius Regaud and Institut Universitaire du Cancer, Toulouse, France.
  • European Institute of Oncology, IRCCS, Milano, Italy.
  • Department of Oncology and Hemato-Oncology, University of Milano, Milano, Italy.
  • University of Perugia, Santa Maria Misericordia Hospital, Perugia, Italy.
  • Roche Pharma Research and Early Development, Roche Diagnostics GmbH, Penzberg, Germany.
  • Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands.
  • Leiden University Medical Center (LUMC), Leiden, The Netherlands.
  • University Clinic Regensburg (UKR), Regensburg, Germany.

Abstract

Patients with stage III melanoma are at high risk of relapse. The NADINA trial evaluating neoadjuvant nivolumab plus ipilimumab and the SWOG-1801 trial evaluating neoadjuvant pembrolizumab have demonstrated superior clinical outcomes with neoadjuvant versus adjuvant checkpoint inhibition. Morpheus-Melanoma was a phase 1b/2, randomized umbrella trial evaluating tobemstomig (anti-PD-1/anti-LAG-3 bispecific antibody; n = 40), tobemstomig plus tiragolumab (anti-TIGIT monoclonal antibody; n = 20) and atezolizumab (PD-L1-targeting monoclonal antibody) plus tiragolumab (n = 20) versus nivolumab (anti-PD-1 monoclonal antibody) plus ipilimumab (anti-CTLA-4 monoclonal antibody; n = 22) in stage III melanoma. The primary endpoint was pathological response by independent pathological review. Additional endpoints included safety and exploratory biomarkers. Here tobemstomig showed a similar pathological response rate (pRR) versus nivolumab plus ipilimumab (80.0% (32/40) versus 77.3% (17/22)); major pathological responses were less frequent with tobemstomig versus nivolumab plus ipilimumab treatment (62.5% (25/40) versus 72.7% (16/22)). Tobemstomig plus tiragolumab and atezolizumab plus tiragolumab showed a lower pRR versus nivolumab plus ipilimumab (60.0% (12/20) and 45.0% (9/20) versus 77.3% (17/22), respectively). Tobemstomig demonstrated improved safety versus nivolumab plus ipilimumab, with 2.5% (1/40) and 22.7% (5/22) of patients experiencing grade 3 or higher treatment-related adverse events (TRAEs), respectively, and 0% (0/40) and 13.6% (3/22) of patients discontinuing treatment due to TRAEs, respectively. Grade 3 or higher TRAEs were reported by 15% (3/20) of patients in the tobemstomig plus tiragolumab arm and by no patients in the atezolizumab plus tiragolumab arm. Baseline CD8 + and CD3 + tumor-infiltrating T cell density, IFNγ pathway and effector T cell gene expression, tumor mutational burden and pre-surgery circulating tumor DNA correlated with pathological response across treatments. In conclusion, in the Morpheus-Melanoma study, tobemstomig demonstrated a similar pathological response and improved safety profile versus nivolumab plus ipilimumab in patients with resectable stage III melanoma. ClinicalTrials.gov identifier: NCT05116202 .

MeSH

Cells, Safety, Molecular Biology, Melanoma, Neoplasms, Immune Checkpoint Inhibitors, Nivolumab, Antibodies, Monoclonal, Therapeutics, Ipilimumab