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

Florentia Dimitriou; Marlana M Orloff; Erica C Koch Hein; Phil F Cheng; Isaac F Hughes; Ester Simeone; Kamaneh Montazeri; Piyush Grover; Inderjit Mehmi; Camille L Gerard; Caroline Gaudy-Marqueste; Jean-Jacques Grob; Olivier Michielin; Omid Hamid; Georgina V Long; Ryan Sullivan; Ellen Kapiteijn; Douglas B Johnson; Paolo A Ascierto; Anthony M Joshua; Richard D Carvajal; Marcus O Butler; Jessica C Hassel; Reinhard Dummer

doi:10.1016/j.ejca.2024.115161

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

Eur J Cancer. 2025 Jan:214:115161. doi: 10.1016/j.ejca.2024.115161. Epub 2024 Nov 30.

Authors

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: [email protected].
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.

MeSH terms

Adult
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols / therapeutic use
Female
GTP-Binding Protein alpha Subunits* / genetics
GTP-Binding Protein alpha Subunits, Gq-G11* / genetics
Humans
Immune Checkpoint Inhibitors* / therapeutic use
Male
Melanoma* / drug therapy
Melanoma* / genetics
Melanoma* / mortality
Melanoma* / pathology
Melanoma* / secondary
Middle Aged
Mutation*
Retrospective Studies
Uveal Neoplasms* / drug therapy
Uveal Neoplasms* / genetics
Uveal Neoplasms* / mortality
Uveal Neoplasms* / pathology

Substances

Immune Checkpoint Inhibitors
GNAQ protein, human
GTP-Binding Protein alpha Subunits, Gq-G11
GNA11 protein, human
GTP-Binding Protein alpha Subunits

Supplementary concepts

Uveal melanoma