Treatment sequence with tebentafusp and immune checkpoint inhibitors in patients with metastatic uveal melanoma and metastatic GNA11/GNAQ mutant melanocytic tumors

Florentia Dimitriou¹, Marlana M Orloff², Erica C Koch Hein³, Phil F Cheng⁴, Isaac F Hughes⁵, Ester Simeone⁶, Kamaneh Montazeri⁷, Piyush Grover⁸, Inderjit Mehmi⁹, Camille L Gerard¹⁰, Caroline Gaudy-Marqueste¹¹, Jean-Jacques Grob¹¹, Olivier Michielin⁴, Omid Hamid⁹, Georgina V Long¹², Ryan Sullivan⁷, Ellen Kapiteijn¹³, Douglas B Johnson¹⁴, Paolo A Ascierto⁶, Anthony M Joshua¹⁵, Richard D Carvajal⁵, Marcus O Butler¹⁶, Jessica C Hassel¹⁷, Reinhard Dummer¹⁸

Affiliations

¹ Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland; Faculty of Medicine, University of Zurich, Zurich, Switzerland. Electronic address: florentia.dimitriou@usz.ch.
² Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
³ Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada; Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Departments of Medicine and Immunology, University of Toronto, Toronto, Canada; Department of Hematology and Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
⁴ Department of Oncology, Geneva University Hospital, Geneva, Switzerland.
⁵ Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.
⁶ Istituto Nazionale Tumori IRCCS Fondazione G Pascale, Napoli, Italy.
⁷ Massachusetts General Hospital, Harvard Medical School, Boston, USA.
⁸ 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.
⁹ The Angeles Clinic and Research Institute, a Cedars Sinai Affiliate, Los Angeles, CA, USA.
¹⁰ Precision Oncology Center, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
¹¹ Dermatology and Skin Cancer Department, Aix-Marseille University, Marseille, France.
¹² 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; Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, NSW, Australia; Charles Perkins Centre, The University of Sydney, Camperdown, Australia.
¹³ Department of Medical Oncology, Leiden University Medical Centre, Leiden, the Netherlands.
¹⁴ Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
¹⁵ Department of Medical Oncology, Kinghorn Cancer Centre, St Vincent's Hospital Sydney and Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
¹⁶ Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada; Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Departments of Medicine and Immunology, University of Toronto, Toronto, Canada.
¹⁷ Heidelberg University, Medical Faculty Heidelberg, Department of Dermatology and National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and University Hospital Heidelberg, Heidelberg, Germany.
¹⁸ Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland; Faculty of Medicine, University of Zurich, Zurich, Switzerland.

PMID: 39647344
DOI: 10.1016/j.ejca.2024.115161

Free article

Treatment sequence with tebentafusp and immune checkpoint inhibitors in patients with metastatic uveal melanoma and metastatic GNA11/GNAQ mutant melanocytic tumors

Florentia Dimitriou et al. Eur J Cancer. 2025 Jan.

Free article

. 2025 Jan:214:115161.

doi: 10.1016/j.ejca.2024.115161. Epub 2024 Nov 30.

Authors

Affiliations

¹ Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland; Faculty of Medicine, University of Zurich, Zurich, Switzerland. Electronic address: florentia.dimitriou@usz.ch.
² Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
³ Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada; Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Departments of Medicine and Immunology, University of Toronto, Toronto, Canada; Department of Hematology and Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
⁴ Department of Oncology, Geneva University Hospital, Geneva, Switzerland.
⁵ Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.
⁶ Istituto Nazionale Tumori IRCCS Fondazione G Pascale, Napoli, Italy.
⁷ Massachusetts General Hospital, Harvard Medical School, Boston, USA.
⁸ 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.
⁹ The Angeles Clinic and Research Institute, a Cedars Sinai Affiliate, Los Angeles, CA, USA.
¹⁰ Precision Oncology Center, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
¹¹ Dermatology and Skin Cancer Department, Aix-Marseille University, Marseille, France.
¹² 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; Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, NSW, Australia; Charles Perkins Centre, The University of Sydney, Camperdown, Australia.
¹³ Department of Medical Oncology, Leiden University Medical Centre, Leiden, the Netherlands.
¹⁴ Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
¹⁵ Department of Medical Oncology, Kinghorn Cancer Centre, St Vincent's Hospital Sydney and Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
¹⁶ Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada; Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Departments of Medicine and Immunology, University of Toronto, Toronto, Canada.
¹⁷ Heidelberg University, Medical Faculty Heidelberg, Department of Dermatology and National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and University Hospital Heidelberg, Heidelberg, Germany.
¹⁸ Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland; Faculty of Medicine, University of Zurich, Zurich, Switzerland.

PMID: 39647344
DOI: 10.1016/j.ejca.2024.115161

Abstract

Background: Metastatic uveal melanoma (mUM) is rare. Immune checkpoint inhibitors (ICIs) have shown modest efficacy in mUM. Tebentafusp prolonged overall survival (OS) in a phase 3 study. We aimed to investigate the efficacy and safety of the sequence of tebentafusp and ICIs.

Methods: Patients with HLA-A * 02:01 positive mUM, or metastatic GNA11/GNAQ mutant melanocytic tumors treated with tebentafusp followed by ICIs (group 1) or the inverse sequence (group 2) at any treatment line were retrospectively identified. The primary objective was OS rate at 2 years.

Results: 131 patients were included; 51 in group 1 and 80 in group 2. 30 % in group 1 % and 40 % in group 2 had normal baseline lactate dehydrogenase (LDH, p = 0.05). 94 % in group 1 % and 77 % in group 2 had multilobular liver disease (p = 0.02). Median OS was 22.4 months (95 % CI 19-24.8) in group 1 and 33.6 months (95 % CI 28.9-43) in group 2 (p = 0.004). Total median PFS was 12 months (95 % CI 10.7-18.8) in group 1 and 20.3 months (95 % CI 17.2-27.3) in group 2 (p = 0.04). The frequency of cytokine release syndrome was higher in group 2 (15 % vs 27 %). Other clinical factors were associated with short total PFS in the multivariable analysis.

Conclusions: Both treatment sequences are clinically feasible. A clinical benefit was noted in the sequential combination of ICIs followed by tebentafusp. This observation is limited by the retrospective nature of the study and merits further investigation in prospective clinical trials.

Keywords: GNA11; GNAQ; Immune checkpoint inhibitors; Tebentafusp; Uveal melanoma.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: FD receives/received honoraria and travel support from Merck Sharp & Dohme, Bristol Myers Squibb, Pierre Fabre and Sun Pharma. EKH reports: advisory role; Novartis, MSD; speaker´s Bureau: Novartis, MSD; research Funding: funding paid to Dr. Koch Hein Institution for support of a melanoma registry in Chile; travel, accommodations, expenses: Pfizer, Novartis, Roche Pharma AG. CGM receives/received honoraria for lectures/advisory board and travel support from Pierre Fabre, BMS, MSD. GVL is consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Bayer, BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., IOBiotech, Immunocore, Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, PHMR Ltd, Pierre Fabre, Regeneron, Scancell, SkylineDX B.V. O.M. has consulting/advisory roles for Bristol Myers Squibb, MSD, Roche, Novartis, Amgen, Pierre Fabre, and Neracare; has received research grants from Bristol Myers Squibb, MSD, and Amgen; is a consultant advisor or a paid speaker for Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Amgen, and Nektar; has received research funding from Bristol Myers Squibb and Pierre Fabre; and is the cofounder of a cell therapy company called Cellula. DBJ has served on advisory boards or as a consultant for BMS, Catalyst Biopharma, Iovance, The Jackson Laboratory, Mallinckrodt, Merck, Mosaic ImmunoEngineering, Novartis, Oncosec, Pfizer, Targovax, and Teiko, and has received research funding from BMS and Incyte. EK has consultancy/advisory relationships with Bristol Myers Squibb, Novartis, Pierre Fabre, Immunocore and Lilly, and received research grants from Bristol Myers Squibb, Delcath, Novartis and Pierre-Fabre. Not related to current work and paid to institute. AMJ has received research funding (institution) from Immunocore, Merck Sharp and Dohme, Bristol Myers Squibb. RD declares financial interests from Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA, Pfizer, Simcere and touchIME. All other authors have declared no conflicts of interest.

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Treatment sequence with tebentafusp and immune checkpoint inhibitors in patients with metastatic uveal melanoma and metastatic GNA11/GNAQ mutant melanocytic tumors

Affiliations

Treatment sequence with tebentafusp and immune checkpoint inhibitors in patients with metastatic uveal melanoma and metastatic GNA11/GNAQ mutant melanocytic tumors

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

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LinkOut - more resources

Full Text Sources

Medical

Research Materials