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

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<sup>+</sup> and CD3<sup>+</sup> 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 .

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Journal
Nature Medicine
Published
2025-09-24
DOI
https://doi.org/10.1038/s41591-025-03967-2
Citations
3
Primary Topic
CAR-T cell therapy research
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article
Field-Weighted Citation Impact
3.14
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article

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

Giuseppe Curigliano, Uri Bader, Mario Mandalà, Ahmad A. Tarhini et al.
3 citations
Nature Medicine
CAR-T cell therapy research
3.14
article

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

Giuseppe Curigliano, Uri Bader, Mario Mandalà, Ahmad A. Tarhini, Alexander Maxwell Menzies, Célèste Lebbé, Omid Hamid, Rodabe Navroze Amaria, Paolo A. Ascierto, Sabine Wilson, Daniel Marbach, Caroline Gaudy‐Marqueste, Denise Cotting, Nikki Jessop, Christoph Markert, Nicolas Städler, Eva Muñoz‐Couselo, Nitya Nair, Maurizio Perdicchio, Georgina Venetia Long, Volker Teichgräber, Merlind Muecke, Richard A. Scolyer, Christian U. Blank, Caroline Robert, Cécile Pagès
article en
3 citations

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<sup>+</sup> and CD3<sup>+</sup> 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 .

Nature MedicineVol. 31(11)
Roche (Switzerland) (CH), Centre National de la Recherche Scientifique (FR), The University of Sydney (AU), The University of Texas MD Anderson Cancer Center (US), Inserm (FR), University of Milan (IT), Université Paris Cité (FR), Aix-Marseille Université (FR), University of Perugia (IT), Université Paris-Saclay (FR), Royal Prince Alfred Hospital (AU), Leiden University Medical Center (NL), Royal North Shore Hospital (AU), Institut Gustave Roussy (FR), The Netherlands Cancer Institute (NL), Moffitt Cancer Center (US), University Hospital Regensburg (DE), Sorbonne Paris Cité (FR), Roche Pharma AG (Germany) (DE), Assistance Publique – Hôpitaux de Paris (FR), Angeles Clinic and Research Institute (US), Roche (United Kingdom) (GB), Melanoma Institute Australia (AU), Vall d'Hebron Hospital Universitari (ES), Institut Claudius Regaud (FR), Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale" (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Hôpital de la Timone (FR), Vall d'Hebron Institute of Oncology (ES), University of Regensburg (DE), European Institute of Oncology (IT)
Openalex Percentile: Top 7%
CAR-T cell therapy research
3.14
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