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Brain metastasis and survival outcomes after first-line therapy in metastatic melanoma

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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. / Franklin, Cindy; Mohr, Peter; Bluhm, Leonie; Meier, Friedegund; Garzarolli, Marlene; Weichenthal, Michael; Kähler, Katharina; Grimmelmann, Imke; Gutzmer, Ralf; Utikal, Jochen; Terheyden, Patrick; Herbst, Rudolf; Haferkamp, Sebastian; Pfoehler, Claudia; Forschner, Andrea; Leiter, Ulrike; Ziller, Fabian; Meiss, Frank; Ulrich, Jens; Kreuter, Alexander; Gebhardt, Christoffer; Welzel, Julia; Schilling, Bastian; Kaatz, Martin; Scharfetter-Kochanek, Karin; Dippel, Edgar; Nashan, Dorothee; Sachse, Michael; Weishaupt, Carsten; Löffler, Harald; Gambichler, Thilo; Loquai, Carmen; Heinzerling, Lucie; Grabbe, Stephan; Debus, Dirk; Schley, Gaston; Hassel, Jessica C; Weyandt, Gerhard; Trommer, Maike; Lodde, Georg; Placke, Jan-Malte; Zimmer, Lisa; Livingstone, Elisabeth; Becker, Jürgen Christian; Horn, Susanne; Schadendorf, Dirk; Ugurel, Selma.

In: J IMMUNOTHER CANCER, Vol. 11, No. 4, e005828, 04.2023.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Franklin, C, Mohr, P, Bluhm, L, Meier, F, Garzarolli, M, Weichenthal, M, Kähler, K, Grimmelmann, I, Gutzmer, R, Utikal, J, Terheyden, P, Herbst, R, Haferkamp, S, Pfoehler, C, Forschner, A, Leiter, U, Ziller, F, Meiss, F, Ulrich, J, Kreuter, A, Gebhardt, C, Welzel, J, Schilling, B, Kaatz, M, Scharfetter-Kochanek, K, Dippel, E, Nashan, D, Sachse, M, Weishaupt, C, Löffler, H, Gambichler, T, Loquai, C, Heinzerling, L, Grabbe, S, Debus, D, Schley, G, Hassel, JC, Weyandt, G, Trommer, M, Lodde, G, Placke, J-M, Zimmer, L, Livingstone, E, Becker, JC, Horn, S, Schadendorf, D & Ugurel, S 2023, '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', J IMMUNOTHER CANCER, vol. 11, no. 4, e005828. https://doi.org/10.1136/jitc-2022-005828

APA

Franklin, C., Mohr, P., Bluhm, L., Meier, F., Garzarolli, M., Weichenthal, M., Kähler, K., Grimmelmann, I., Gutzmer, R., Utikal, J., Terheyden, P., Herbst, R., Haferkamp, S., Pfoehler, C., Forschner, A., Leiter, U., Ziller, F., Meiss, F., Ulrich, J., ... Ugurel, S. (2023). 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. J IMMUNOTHER CANCER, 11(4), [e005828]. https://doi.org/10.1136/jitc-2022-005828

Vancouver

Franklin C, Mohr P, Bluhm L, Meier F, Garzarolli M, Weichenthal M et al. 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. J IMMUNOTHER CANCER. 2023 Apr;11(4). e005828. https://doi.org/10.1136/jitc-2022-005828

Bibtex

@article{eda4db0b156740b6b2944fa8504b4085,
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",
abstract = "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.",
keywords = "Humans, CTLA-4 Antigen, Proto-Oncogene Proteins B-raf/genetics, Programmed Cell Death 1 Receptor, Prospective Studies, Melanoma/pathology, Skin Neoplasms/drug therapy, Brain Neoplasms/pathology, Registries, Mitogen-Activated Protein Kinase Kinases, Brain/pathology",
author = "Cindy Franklin and Peter Mohr and Leonie Bluhm and Friedegund Meier and Marlene Garzarolli and Michael Weichenthal and Katharina K{\"a}hler and Imke Grimmelmann and Ralf Gutzmer and Jochen Utikal and Patrick Terheyden and Rudolf Herbst and Sebastian Haferkamp and Claudia Pfoehler and Andrea Forschner and Ulrike Leiter and Fabian Ziller and Frank Meiss and Jens Ulrich and Alexander Kreuter and Christoffer Gebhardt and Julia Welzel and Bastian Schilling and Martin Kaatz and Karin Scharfetter-Kochanek and Edgar Dippel and Dorothee Nashan and Michael Sachse and Carsten Weishaupt and Harald L{\"o}ffler and Thilo Gambichler and Carmen Loquai and Lucie Heinzerling and Stephan Grabbe and Dirk Debus and Gaston Schley and Hassel, {Jessica C} and Gerhard Weyandt and Maike Trommer and Georg Lodde and Jan-Malte Placke and Lisa Zimmer and Elisabeth Livingstone and Becker, {J{\"u}rgen Christian} and Susanne Horn and Dirk Schadendorf and Selma Ugurel",
note = "{\textcopyright} Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.",
year = "2023",
month = apr,
doi = "10.1136/jitc-2022-005828",
language = "English",
volume = "11",
journal = "J IMMUNOTHER CANCER",
issn = "2051-1426",
publisher = "BioMed Central Ltd.",
number = "4",

}

RIS

TY - JOUR

T1 - Brain metastasis and survival outcomes after first-line therapy in metastatic melanoma

T2 - a multicenter DeCOG study on 1704 patients from the prospective skin cancer registry ADOREG

AU - Franklin, Cindy

AU - Mohr, Peter

AU - Bluhm, Leonie

AU - Meier, Friedegund

AU - Garzarolli, Marlene

AU - Weichenthal, Michael

AU - Kähler, Katharina

AU - Grimmelmann, Imke

AU - Gutzmer, Ralf

AU - Utikal, Jochen

AU - Terheyden, Patrick

AU - Herbst, Rudolf

AU - Haferkamp, Sebastian

AU - Pfoehler, Claudia

AU - Forschner, Andrea

AU - Leiter, Ulrike

AU - Ziller, Fabian

AU - Meiss, Frank

AU - Ulrich, Jens

AU - Kreuter, Alexander

AU - Gebhardt, Christoffer

AU - Welzel, Julia

AU - Schilling, Bastian

AU - Kaatz, Martin

AU - Scharfetter-Kochanek, Karin

AU - Dippel, Edgar

AU - Nashan, Dorothee

AU - Sachse, Michael

AU - Weishaupt, Carsten

AU - Löffler, Harald

AU - Gambichler, Thilo

AU - Loquai, Carmen

AU - Heinzerling, Lucie

AU - Grabbe, Stephan

AU - Debus, Dirk

AU - Schley, Gaston

AU - Hassel, Jessica C

AU - Weyandt, Gerhard

AU - Trommer, Maike

AU - Lodde, Georg

AU - Placke, Jan-Malte

AU - Zimmer, Lisa

AU - Livingstone, Elisabeth

AU - Becker, Jürgen Christian

AU - Horn, Susanne

AU - Schadendorf, Dirk

AU - Ugurel, Selma

N1 - © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

PY - 2023/4

Y1 - 2023/4

N2 - 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.

AB - 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.

KW - Humans

KW - CTLA-4 Antigen

KW - Proto-Oncogene Proteins B-raf/genetics

KW - Programmed Cell Death 1 Receptor

KW - Prospective Studies

KW - Melanoma/pathology

KW - Skin Neoplasms/drug therapy

KW - Brain Neoplasms/pathology

KW - Registries

KW - Mitogen-Activated Protein Kinase Kinases

KW - Brain/pathology

U2 - 10.1136/jitc-2022-005828

DO - 10.1136/jitc-2022-005828

M3 - SCORING: Journal article

C2 - 37028819

VL - 11

JO - J IMMUNOTHER CANCER

JF - J IMMUNOTHER CANCER

SN - 2051-1426

IS - 4

M1 - e005828

ER -