Impact of radiotherapy and sequencing of systemic therapy on survival outcomes in melanoma patients with previously untreated brain metastasis: a multicenter DeCOG study on 450 patients from the prospective skin cancer registry ADOREG

Abstract

BackgroundDespite of various therapeutic strategies, treatment of patients with melanoma brain metastasis (MBM) still is a major challenge. This study aimed at investigating the impact of type and sequence of immune checkpoint blockade (ICB) and targeted therapy (TT), radiotherapy, and surgery on the survival outcome of patients with MBM.MethodWe assessed data of 450 patients collected within the prospective multicenter real-world skin cancer registry ADOREG who were diagnosed with MBM before start of the first non-adjuvant systemic therapy. Study endpoints were progression-free survival (PFS) and overall survival (OS).ResultsOf 450 MBM patients, 175 (38.9%) received CTLA-4+PD-1 ICB, 161 (35.8%) PD-1 ICB, and 114 (25.3%) BRAF+MEK TT as first-line treatment. Additional to systemic therapy, 67.3% of the patients received radiotherapy (stereotactic radiosurgery (SRS); conventional radiotherapy (CRT)) and 24.4% had surgery of MBM. 199 patients (42.2%) received a second-line systemic therapy. Multivariate Cox regression analysis revealed the application of radiotherapy (HR for SRS: 0.213, 95% CI 0.094 to 0.485, p<0.001; HR for CRT: 0.424, 95% CI 0.210 to 0.855, p=0.016), maximal size of brain metastases (HR for MBM >1 cm: 1.977, 95% CI 1.117 to 3.500, p=0.019), age (HR for age >65 years: 1.802, 95% CI 1.016 to 3.197, p=0.044), and ECOG performance status (HR for ECOG ≥2: HR: 2.615, 95% CI 1.024 to 6.676, p=0.044) as independent prognostic factors of OS on first-line therapy. The type of first-line therapy (ICB vs TT) was not independently prognostic. As second-line therapy BRAF+MEK showed the best survival outcome compared with ICB and other therapies (HR for CTLA-4+PD-1 compared with BRAF+MEK: 13.964, 95% CI 3.6 to 54.4, p<0.001; for PD-1 vs BRAF+MEK: 4.587 95% CI 1.3 to 16.8, p=0.022 for OS). Regarding therapy sequencing, patients treated with ICB as first-line therapy and BRAF+MEK as second-line therapy showed an improved OS (HR for CTLA-4+PD-1 followed by BRAF+MEK: 0.370, 95% CI 0.157 to 0.934, p=0.035; HR for PD-1 followed by BRAF+MEK: 0.290, 95% CI 0.092 to 0.918, p=0.035) compared with patients starting with BRAF+MEK in first-line therapy. There was no significant survival difference when comparing first-line therapy with CTLA-4+PD-1 ICB with PD-1 ICB.ConclusionsIn patients with MBM, the addition of radiotherapy resulted in a favorable OS on systemic therapy. In BRAF-mutated MBM patients, ICB as first-line therapy and BRAF+MEK as second-line therapy were associated with a significantly prolonged OS.

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

“…4 Recently, in a large retrospective study, our group could not detect differences in survival outcomes in 450 melanoma patients with brain metastases (MBM) who received different first-line therapies in addition to different types of radiotherapy. 5 Prospective studies without additional locoregional therapies in MBM patients, as well as a meta-analysis, showed higher intracranial effectiveness and better survival outcomes with first-line therapy with CTLA-4+PD-1 compared with PD-1. [6][7][8] In melanoma patients without MBM it is currently unclear, which treatment strategy is preventing the development of MBM best.…”

Melanoma Brain Metastases: A Systematic Review of Opportunities for Earlier Detection, Diagnosis, and Treatment

“…The BRAF V600 mutation correlates with hyperactivation of the MAPK signaling pathway. Biomarkers are a viable option for the diagnosis of MBM and further studies implicate the NRAS and CKIT mutation as indicators, though unreliable markers [ 50 , 51 ]. Detection imaging through WB-DWI had a lower SE in detecting metastases and was reported to be effective at detecting extracranial metastasis [ 23 ].…”

“…Incorporating radiotherapy, SRS is becoming preferred compared to WBRT due to its precise approach targeting metastatic tumors and minimizing adverse effects such as memory loss, as seen with WBRT [ 24 , 33 ]. The combination of BRAF + MEK inhibitors was shown to yield superior outcomes and prolong OS [ 49 , 50 ]. The addition of trametinib has been reported to improve OS compared to dabrafenib alone in patients with BRAF Val600 mutation-positive melanoma [ 56 , 57 ].…”

“…The addition of trametinib has been reported to improve OS compared to dabrafenib alone in patients with BRAF Val600 mutation-positive melanoma [ 56 , 57 ]. A second-line therapy of combined BRAF + MEK displayed the highest survival outcome when relative to immune checkpoint blockade therapy [ 50 ]. The most optimal treatment appears to be a combination including SRS and immunotherapy.…”

Patterns of Care and Survival in Cancer Patients with Brain Metastases Receiving Immune Checkpoint Inhibitors

“…The literature suggests that SRS-associated toxicity rates are fairly low after such combinations [28][29][30]. In a multicenter study of melanoma patients with previously untreated brain metastases, the addition of radiotherapy (SRS or other regimes) resulted in a favorable OS on systemic therapy [31]. A German group retrospectively analyzed data of 93 patients with 319 distinct brain metastases from different cancer types (67% malignant melanoma) who received PD-1 inhibitors and radiotherapy between 2014 and 2020 [32].…”