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 - Debus: Department of Dermatology, Nuremberg General Hospital, Paracelsus Medical University, Nuremberg, Germany
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 - Original Article (Journal)
C2 - 37028819
SN - 2051-1426
VL - 11
JO - JOURNAL FOR IMMUNOTHERAPY OF CANCER
JF - JOURNAL FOR IMMUNOTHERAPY OF CANCER
IS - 4
ER -