Brain metastasis and survival outcomes after first-line therapy in metastatic melanoma: a multicenter DeCOG study on 1704 patients from the prospective skin cancer registry ADOREG
Background Despite the availability of effective systemic therapies, a significant number of advanced melanoma patients develops brain metastases. This study investigated differences in incidence and time to diagnosis of brain metastasis and survival outcomes dependent on the type of first-line ther...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2023-04-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/4/e005828.full |
| _version_ | 1797400948566392832 |
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| author | Dirk Schadendorf Lucie Heinzerling Jessica C Hassel Lisa Zimmer Ralf Gutzmer Alexander Kreuter Andrea Forschner Elisabeth Livingstone Bastian Schilling Selma Ugurel Peter Mohr Thilo Gambichler Patrick Terheyden Sebastian Haferkamp Friedegund Meier Claudia Pfoehler Dirk Debus Rudolf Herbst Carmen Loquai Frank Meiss Carsten Weishaupt Jochen Utikal Martin Kaatz Jens Ulrich Edgar Dippel Michael Weichenthal Maike Trommer Jürgen Christian Becker Ulrike Leiter Cindy Franklin Christoffer Gebhardt Katharina Kahler Leonie Bluhm Imke Grimmelmann Marlene Garzarolli Dorothee Nashan Michael Sachse Julia Welzel Gerhard Weyandt Susanne Horn Fabian Ziller Harald Löffler Stephan Grabbe Gaston Schley Georg Lodde Jan-Malte Placke Anca Sindrilaru |
| author_facet | Dirk Schadendorf Lucie Heinzerling Jessica C Hassel Lisa Zimmer Ralf Gutzmer Alexander Kreuter Andrea Forschner Elisabeth Livingstone Bastian Schilling Selma Ugurel Peter Mohr Thilo Gambichler Patrick Terheyden Sebastian Haferkamp Friedegund Meier Claudia Pfoehler Dirk Debus Rudolf Herbst Carmen Loquai Frank Meiss Carsten Weishaupt Jochen Utikal Martin Kaatz Jens Ulrich Edgar Dippel Michael Weichenthal Maike Trommer Jürgen Christian Becker Ulrike Leiter Cindy Franklin Christoffer Gebhardt Katharina Kahler Leonie Bluhm Imke Grimmelmann Marlene Garzarolli Dorothee Nashan Michael Sachse Julia Welzel Gerhard Weyandt Susanne Horn Fabian Ziller Harald Löffler Stephan Grabbe Gaston Schley Georg Lodde Jan-Malte Placke Anca Sindrilaru |
| author_sort | Dirk Schadendorf |
| collection | DOAJ |
| description | Background Despite the availability of effective systemic therapies, a significant number of advanced melanoma patients develops brain metastases. This study investigated differences in incidence and time to diagnosis of brain metastasis and survival outcomes dependent on the type of first-line therapy.Methods Patients with metastatic, non-resectable melanoma (AJCCv8 stage IIIC–V) without brain metastasis at start of first-line therapy (1L-therapy) were identified from the prospective multicenter real-world skin cancer registry ADOREG. Study endpoints were incidence of brain metastasis, brain metastasis-free survival (BMFS), progression-free survival (PFS), and overall survival (OS).Results Of 1704 patients, 916 were BRAF wild-type (BRAFwt) and 788 were BRAF V600 mutant (BRAFmut). Median follow-up time after start of 1L-therapy was 40.4 months. BRAFwt patients received 1L-therapy with immune checkpoint inhibitors (ICI) against CTLA-4+PD-1 (n=281) or PD-1 (n=544). In BRAFmut patients, 1L-therapy was ICI in 415 patients (CTLA-4+PD-1, n=108; PD-1, n=264), and BRAF+MEK targeted therapy (TT) in 373 patients. After 24 months, 1L-therapy with BRAF+MEK resulted in a higher incidence of brain metastasis compared with PD-1±CTLA-4 (BRAF+MEK, 30.3%; CTLA-4+PD-1, 22.2%; PD-1, 14.0%). In multivariate analysis, BRAFmut patients developed brain metastases earlier on 1L-therapy with BRAF+MEK than with PD-1±CTLA-4 (CTLA-4+PD-1: HR 0.560, 95% CI 0.332 to 0.945, p=0.030; PD-1: HR 0.575, 95% CI 0.372 to 0.888, p=0.013). Type of 1L-therapy, tumor stage, and age were independent prognostic factors for BMFS in BRAFmut patients. In BRAFwt patients, tumor stage was independently associated with longer BMFS; ECOG Performance status (ECOG-PS), lactate dehydrogenase (LDH), and tumor stage with OS. CTLA-4+PD-1 did not result in better BMFS, PFS, or OS than PD-1 in BRAFwt patients. For BRAFmut patients, multivariate Cox regression revealed ECOG-PS, type of 1L-therapy, tumor stage, and LDH as independent prognostic factors for PFS and OS. 1L-therapy with CTLA-4+PD-1 led to longer OS than PD-1 (HR 1.97, 95% CI 1.122 to 3.455, p=0.018) or BRAF+MEK (HR 2.41, 95% CI 1.432 to 4.054, p=0.001), without PD-1 being superior to BRAF+MEK.Conclusions In BRAFmut patients 1L-therapy with PD-1±CTLA-4 ICI resulted in a delayed and less frequent development of brain metastasis compared with BRAF+MEK TT. 1L-therapy with CTLA-4+PD-1 showed superior OS compared with PD-1 and BRAF+MEK. In BRAFwt patients, no differences in brain metastasis and survival outcomes were detected for CTLA-4+PD-1 compared with PD-1. |
| first_indexed | 2024-03-09T02:01:48Z |
| format | Article |
| id | doaj.art-78c357556a7d4fdbba1d2ae0e5644ffc |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-03-09T02:01:48Z |
| publishDate | 2023-04-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-78c357556a7d4fdbba1d2ae0e5644ffc2023-12-08T04:10:07ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-04-0111410.1136/jitc-2022-005828Brain metastasis and survival outcomes after first-line therapy in metastatic melanoma: a multicenter DeCOG study on 1704 patients from the prospective skin cancer registry ADOREGDirk Schadendorf0Lucie Heinzerling1Jessica C Hassel2Lisa Zimmer3Ralf Gutzmer4Alexander Kreuter5Andrea Forschner6Elisabeth Livingstone7Bastian Schilling8Selma Ugurel9Peter Mohr10Thilo Gambichler11Patrick Terheyden12Sebastian Haferkamp13Friedegund Meier14Claudia Pfoehler15Dirk Debus16Rudolf Herbst17Carmen Loquai18Frank Meiss19Carsten Weishaupt20Jochen Utikal21Martin Kaatz22Jens Ulrich23Edgar Dippel24Michael Weichenthal25Maike Trommer26Jürgen Christian Becker27Ulrike Leiter28Cindy Franklin29Christoffer Gebhardt30Katharina Kahler31Leonie Bluhm32Imke Grimmelmann33Marlene Garzarolli34Dorothee Nashan35Michael Sachse36Julia Welzel37Gerhard Weyandt38Susanne Horn39Fabian Ziller40Harald Löffler41Stephan Grabbe42Gaston Schley43Georg Lodde44Jan-Malte Placke45Anca Sindrilaru46Department of Dermatology, Venerology and Allergology, University Hospital Essen and German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, GermanyDepartment of Dermatology and Allergology, Ludwig-Maximilian University, Munich, GermanyDepartment of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, GermanyDepartment of Dermatology, Venerology and Allergology, University Hospital Essen and German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, GermanyDepartment of Dermatology, Muelenkreiskliniken Minden and Ruhr University Bochum, Minden, GermanyDepartment of Dermatology, Venerology and Allergology, Helios St. Elisabeth Klinik Oberhausen, University Witten-Herdecke, Oberhausen, GermanyCenter for Dermatooncology, Department of Dermatology, Eberhard-Karls University of Tübingen, Tubingen, GermanyDepartment of Dermatology, Venereology and Allergology, University Hospital Essen and German Cancer Consortium (DKTK) Partner Site Essen, Essen, GermanyDepartment of Dermatology, University Hospital Würzburg, Würzburg, GermanyDepartment of Dermatology, Venerology and Allergology, University Hospital Essen and German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, GermanyDepartment of Dermatology, Elbe Kliniken Buxtehude, Buxtehude, GermanyDepartment of Dermatology, Ruhr-University Bochum, Bochum, GermanyDepartment of Dermatology, Allergology and Venerology, University Medical Center Schleswig Holstein Lübeck Campus, Lubeck, GermanyDepartment of Dermatology, University Hospital Regensburg, Regensburg, GermanyDepartment of Dermatology, University Hospital Carl Gustav Carus, Dresden, GermanyDepartment of Dermatology, Saarland University Hospital and Saarland University Faculty of Medicine, Homburg, GermanyDepartment of Dermatology, Nuremberg Hospital, Nurnberg, GermanyDepartment of Dermatology, HELIOS Hospital Erfurt, Erfurt, GermanyDepartment of Dermatology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, GermanyDepartment of Dermatology and Venerology, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, GermanyDepartment of Dermatology, University Hospital of Muenster, Muenster, GermanySkin Cancer Unit/ Department of Dermatology, Venerology and Allergology, German Cancer Research Center (DKFZ), University Medical Centre Mannheim, Heidelberg, Mannheim, GermanyDepartment of Dermatology, DRK Hospital Chemnitz-Rabenstein, Rabenstein, GermanyDepartment of Dermatology and Allergy, Harzklinikum Dorothea Christiane Erxleben GmbH, Quedlinburg, GermanyDepartment of Dermatology, Ludwigshafen City Hospital, Ludwigshafen, GermanyDepartment of Dermatology, Skin Cancer Center, University Hospital Schleswig-Holstein - Campus Kiel, Kiel, GermanyDepartment of Radiation Oncology and Cyberknife Center, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, GermanyDepartment of Dermatology, Venereology and Allergology, University Hospital Essen and German Cancer Consortium (DKTK) Partner Site Essen, Essen, GermanyCenter for Dermatooncology, Department of Dermatology, Eberhard-Karls University of Tübingen, Tubingen, GermanyDepartment of Dermatology and Venereology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, GermanyDepartment of Dermatology and Venerology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Dermatology, Skin Cancer Center, Schleswig-Holstein University Hospital, Campus Kiel, Kiel, GermanyDepartment of Dermatology, Elbe-Kliniken Buxtehude, Buxtehude, GermanySkin Cancer Center Hannover, Department of Dermatology, Hannover Medical School, Hanover, GermanyDepartment of Dermatology, University Hospital Carl Gustav Carus, TU Dresden and, Skin Cancer Center at the University Cancer Center Dresden and National Center for Tumor Diseases (NCT), Dresden, GermanyDepartment of Dermatology, Hospital of Dortmund, Dortmund, GermanyDepartment of Dermatology, Hospital Bremerhaven Reinkenheide, Bremerhaven, GermanyDepartment of Dermatology and Allergology, University Hospital Augsburg, Augsburg, GermanyDepartment of Dermatology and Allergology, Hospital Bayreuth, Bayreuth, GermanyDepartment of Dermatology, Venereology and Allergology, University Hospital Essen and German Cancer Consortium (DKTK) Partner Site Essen, Essen, GermanyDepartment of Dermatology, DRK Hospital Chemnitz-Rabenstein, Chemnitz, GermanyDepartment of Dermatology, SLK-Kliniken Heilbronn, Heilbronn, GermanyDepartment of Dermatology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, GermanyDepartment of Dermatology and Venereology, Helios Klinikum Schwerin, Schwerin, GermanyDepartment of Dermatology, Venerology and Allergology, University Hospital Essen and German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, GermanyDepartment of Dermatology, Venereology and Allergology, University Hospital Essen and German Cancer Consortium (DKTK) Partner Site Essen, Essen, GermanyDepartment of Dermatology and Venereology, University Hospital Ulm, Ulm, GermanyBackground Despite the availability of effective systemic therapies, a significant number of advanced melanoma patients develops brain metastases. This study investigated differences in incidence and time to diagnosis of brain metastasis and survival outcomes dependent on the type of first-line therapy.Methods Patients with metastatic, non-resectable melanoma (AJCCv8 stage IIIC–V) without brain metastasis at start of first-line therapy (1L-therapy) were identified from the prospective multicenter real-world skin cancer registry ADOREG. Study endpoints were incidence of brain metastasis, brain metastasis-free survival (BMFS), progression-free survival (PFS), and overall survival (OS).Results Of 1704 patients, 916 were BRAF wild-type (BRAFwt) and 788 were BRAF V600 mutant (BRAFmut). Median follow-up time after start of 1L-therapy was 40.4 months. BRAFwt patients received 1L-therapy with immune checkpoint inhibitors (ICI) against CTLA-4+PD-1 (n=281) or PD-1 (n=544). In BRAFmut patients, 1L-therapy was ICI in 415 patients (CTLA-4+PD-1, n=108; PD-1, n=264), and BRAF+MEK targeted therapy (TT) in 373 patients. After 24 months, 1L-therapy with BRAF+MEK resulted in a higher incidence of brain metastasis compared with PD-1±CTLA-4 (BRAF+MEK, 30.3%; CTLA-4+PD-1, 22.2%; PD-1, 14.0%). In multivariate analysis, BRAFmut patients developed brain metastases earlier on 1L-therapy with BRAF+MEK than with PD-1±CTLA-4 (CTLA-4+PD-1: HR 0.560, 95% CI 0.332 to 0.945, p=0.030; PD-1: HR 0.575, 95% CI 0.372 to 0.888, p=0.013). Type of 1L-therapy, tumor stage, and age were independent prognostic factors for BMFS in BRAFmut patients. In BRAFwt patients, tumor stage was independently associated with longer BMFS; ECOG Performance status (ECOG-PS), lactate dehydrogenase (LDH), and tumor stage with OS. CTLA-4+PD-1 did not result in better BMFS, PFS, or OS than PD-1 in BRAFwt patients. For BRAFmut patients, multivariate Cox regression revealed ECOG-PS, type of 1L-therapy, tumor stage, and LDH as independent prognostic factors for PFS and OS. 1L-therapy with CTLA-4+PD-1 led to longer OS than PD-1 (HR 1.97, 95% CI 1.122 to 3.455, p=0.018) or BRAF+MEK (HR 2.41, 95% CI 1.432 to 4.054, p=0.001), without PD-1 being superior to BRAF+MEK.Conclusions In BRAFmut patients 1L-therapy with PD-1±CTLA-4 ICI resulted in a delayed and less frequent development of brain metastasis compared with BRAF+MEK TT. 1L-therapy with CTLA-4+PD-1 showed superior OS compared with PD-1 and BRAF+MEK. In BRAFwt patients, no differences in brain metastasis and survival outcomes were detected for CTLA-4+PD-1 compared with PD-1.https://jitc.bmj.com/content/11/4/e005828.full |
| spellingShingle | Dirk Schadendorf Lucie Heinzerling Jessica C Hassel Lisa Zimmer Ralf Gutzmer Alexander Kreuter Andrea Forschner Elisabeth Livingstone Bastian Schilling Selma Ugurel Peter Mohr Thilo Gambichler Patrick Terheyden Sebastian Haferkamp Friedegund Meier Claudia Pfoehler Dirk Debus Rudolf Herbst Carmen Loquai Frank Meiss Carsten Weishaupt Jochen Utikal Martin Kaatz Jens Ulrich Edgar Dippel Michael Weichenthal Maike Trommer Jürgen Christian Becker Ulrike Leiter Cindy Franklin Christoffer Gebhardt Katharina Kahler Leonie Bluhm Imke Grimmelmann Marlene Garzarolli Dorothee Nashan Michael Sachse Julia Welzel Gerhard Weyandt Susanne Horn Fabian Ziller Harald Löffler Stephan Grabbe Gaston Schley Georg Lodde Jan-Malte Placke Anca Sindrilaru Brain metastasis and survival outcomes after first-line therapy in metastatic melanoma: a multicenter DeCOG study on 1704 patients from the prospective skin cancer registry ADOREG Journal for ImmunoTherapy of Cancer |
| title | Brain metastasis and survival outcomes after first-line therapy in metastatic melanoma: a multicenter DeCOG study on 1704 patients from the prospective skin cancer registry ADOREG |
| title_full | Brain metastasis and survival outcomes after first-line therapy in metastatic melanoma: a multicenter DeCOG study on 1704 patients from the prospective skin cancer registry ADOREG |
| title_fullStr | Brain metastasis and survival outcomes after first-line therapy in metastatic melanoma: a multicenter DeCOG study on 1704 patients from the prospective skin cancer registry ADOREG |
| title_full_unstemmed | Brain metastasis and survival outcomes after first-line therapy in metastatic melanoma: a multicenter DeCOG study on 1704 patients from the prospective skin cancer registry ADOREG |
| title_short | Brain metastasis and survival outcomes after first-line therapy in metastatic melanoma: a multicenter DeCOG study on 1704 patients from the prospective skin cancer registry ADOREG |
| title_sort | brain metastasis and survival outcomes after first line therapy in metastatic melanoma a multicenter decog study on 1704 patients from the prospective skin cancer registry adoreg |
| url | https://jitc.bmj.com/content/11/4/e005828.full |
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