A single‐center retrospective analysis of prognoses in patients with melanoma brain metastases and effectiveness of treatment in Japan

Abstract Background Melanoma brain metastasis (MBM) has a poor prognosis, although recent treatments, including immune checkpoint inhibitors and targeted therapy, have improved the prognosis. However, these systemic therapies have been reported to be less efficient for Asian patients. We investigated the survival of Asian patients with MBM and the effectiveness of systemic therapies. Methods We retrospectively reviewed the survival rates of patients diagnosed with MBM between January 2011 and December 2021 at the National Cancer Center Hospital in Tokyo, Japan. In addition, we identified factors associated with survival using Cox regression analysis. Results A total of 135 patients were included. The median overall survival (OS) after an MBM diagnosis was 7.8 months (95% confidence interval [CI] 6.1–9.6). The 6‐month and 1‐year survival rates were 60.7% and 34.8%, respectively. We identified the prognostic factors of MBM, including non‐acral primary location, low serum LDH levels, systemic therapy of single‐agent immune checkpoint inhibitors (ICIs) or targeted therapies (TTs), and radiotherapy of stereotactic irradiation (STI). We found no significant difference in effectiveness between single‐agent ICIs, the combination of Nivolumab and Ipilimumab (COMBI‐ICI), and TTs (COMBI‐ICI vs. single‐agent ICI, hazard ratio 0.71, 95% confidence interval 0.27–1.88, p = 0.49; COMBI‐ICI vs. TT: hazard ratio 0.46, 95% confidence interval 0.14–1.55, p = 0.21). Conclusions Systemic therapy and radiotherapy have improved the survival of MBM patients, but the survival of Asian patients remains poor. Our findings suggest that COMBI‐ICIs are not significantly more effective than single‐agent ICI or TT in treating MBM.


| INTRODUCTION
Melanoma is the third most common source of brain metastases following lung and breast cancer. 1 Melanoma brain metastases (MBMs) are important targets for treatment because they are associated with significant morbidity.Previously, patients with MBMs had poor prognosis, with an estimated median overall survival (OS) of approximately 4 months. 2However, several systemic therapies have evolved and successfully improved outcomes.Immune checkpoint inhibitors (ICIs), such as nivolumab, ipilimumab, and pembrolizumab, have been approved, followed by therapies targeting BRAF V600 mutation.Targeted therapies (TTs) include BRAF inhibitors (dabrafenib, vemurafenib, and encorafenib) and MEK inhibitors (trametinib, cobimetinib, and binimetinib).In combination with radiotherapy, these new drugs have successfully improved the outcomes of MBM patients. 3][6][7] Although many prospective and retrospective studies have shown the effectiveness of ICIs and TTs in patients with MBM, the cohorts in these studies were primarily Caucasian, and data regarding the outcomes of Asian patients with MBM are scarce.Furthermore, some studies have shown that ICIs are not as effective in Asians as in Caucasians. 8,9However, the effectiveness of ICIs and TTs for Asian patients with MBM has rarely been reported.Therefore, it is important to investigate the effectiveness of ICIs and TTs for Asian patients with MBM to treat them appropriately.This study aimed to elucidate the outcome of MBM in Asian patients and investigate the factors associated with the outcome and the best treatment choice.We emphasize the importance of recognizing treatment effect heterogeneity across different racial groups when treating patients with MBM.

| Study design
We retrospectively identified patients diagnosed with MBM at the National Cancer Center Hospital in Tokyo, Japan.Medical records of all patients were reviewed to extract data on demographics, tumors, and treatment characteristics.We included all Asian patients who had been diagnosed with MBM between January 2011 and December 2021.We excluded patients belonging to other ethnicities.In addition, we assessed outcomes, including overall survival (OS) and 6-month and 1-year survival rates, and further investigated the association between the characteristics and these outcomes in patients with MBM.

| Patient characteristics
Demographic characteristics included age at diagnosis, sex, ethnicity, and pre-treatment Eastern Cooperative Oncology Group Performance Status (PS).The tumor characteristics included the presence or absence of neurological symptoms, number and size of the MBM, location of the primary tumor, number of extracranial metastatic organs, serum lactate dehydrogenase (LDH) levels, PD-L1 expression status, and BRAF V600 mutational status.The upper limit of the normal serum LDH level was 240 U/L.The number and size of the MBM and number of extracranial metastatic organs were evaluated using computed tomography (CT) scans.The MBM size referred to the largest brain metastasis in each patient.Treatment characteristics included the type of systemic therapy administered first after the diagnosis of MBM and the type of radiotherapy.Systemic therapy options included dacarbazine, combination of carboplatin and paclitaxel, nivolumab, ipilimumab, COMBI-ICI, combination of dacarbazine and ipilimumab, pembrolizumab, vemurafenib, dabrafenib, trametinib, combination of dabrafenib and trametinib, and combination of encorafenib and binimetinib.All regimens were categorized as single-agent ICI (nivolumab, ipilimumab, and pembrolizumab), COMBI-ICIs, TT (vemurafenib, dabrafenib, trametinib, combination of dabrafenib and trametinib, and combination of encorafenib and binimetinib), and chemotherapy (dacarbazine and combination of cisplatin and paclitaxel).Patients treated with combination of dacarbazine and ipilimumab were excluded because the regimen cannot be categorized into them, and it is not officially used now.Radiotherapy included stereotactic irradiation (STI) and whole-brain radiotherapy (WBRT).STI was delivered at a dose of 9-42 Gy in 1-15 fractions, and WBRT was delivered at a dose of 30-42.5 Gy in 1-13 fractions.

| Statistical analysis
We used the Kaplan-Meier method to evaluate OS and the 6-month and 1-year survival rates.The OS was calculated from the date of MBM diagnosis to death attributable to melanoma or the last follow-up before December 31, 2021.Data from patients who did not die were censored on December 31, 2021.The 6-month survival rate was defined as the rate of survival 6 months after the date of MBM diagnosis.We used the log-rank test to compare the Kaplan-Meier survival curves.Descriptive statistics are presented as frequencies for categorical variables and medians and ranges for continuous variables.We analyzed the demographic, tumor, and treatment characteristics as prognostic factors for OS using the chi-square test, Mann-Whitney U test, and Cox regression analyses.In addition, we examined the effectiveness of single-agent ICI, COMBI-ICIs, and TT in prolonging the survival of patients with MBM using the Kaplan-Meier method and Cox regression analyses.All the tests were two-sided.Statistical significance was set at p < 0.05.Statistical analyses were performed using Stata version 17 (StataCorp LLC).The study protocol was approved by the Institutional Review Board of the National Cancer Center, Japan (approval No. 2013-081).

| Survival of all patients.
Figure 1 shows the survival curve of all the patients included in our study.The median OS after an MBM diagnosis was 7.8 months (95% confidence interval [CI] 6.1-9.6).The 6-month and 1-year survival rates were 60.7% and 34.8%, respectively.

| Prognostic factors
Table 2 presents the results of the Cox regression analysis.Ethnicity was excluded as a variable because of an imbalanced number of subgroups.On univariate analysis, presence of neurologic symptoms, fewer extracranial metastatic organs, low serum LDH levels, systemic therapy of single-agent ICIs or TTs, and radiotherapy of STI significantly improved the outcomes.On multivariate analysis, non-acral primary location, low serum LDH level, systemic therapy of single-agent ICIs or TTs, and radiotherapy of STI significantly improved outcomes.Patients with acral melanoma as the primary location had shorter survival (hazard ratio [HR] 2.46, 95% confidence interval [CI] 1.21-4.98,p = 0.01).Patients with serum LDH levels higher than the upper limit of normal (ULN) had shorter survival than those with serum LDH levels lower than ULN (HR 3.84, 95% CI 2.01-7.36,p < 0.001).Patients who had received single-agent ICI or TT had longer survival than those who had received no systemic therapy (singleagent ICI: HR 0.27, 95% CI 0.12-0.61,p = 0.002; TT: HR 0.15, 95% CI 0.05-0.42,p < 0.001).Patients who received WBRT had shorter survival than those who received STI (HR 2.66, 95% CI 1.33-5.36,p = 0.006).

| Effectiveness of systemic therapy
Figure 2 shows the Kaplan-Meier curves comparing initial systemic therapy and radiotherapy.The median OS of patients treated with single-agent ICI was 8.4 months (95% CI 6.3-11.5),and the 6-month and 1-year survival rates were 66.5% and 37.3%, respectively.The median OS of patients treated with COMBI-ICI was 6.1 months (95% CI 4.9-not reached), and the 6-month and 1-year survival rates were 54.1% and 33.8%, respectively.The median OS of patients treated with TT was 11.1 months (95% CI 6.9-26.5),and the 6-month and 1-year survival rates were 74.2% and 43.7%, respectively.The median OS of patients treated with conventional chemotherapy was 6.7 months (95% CI 1.6-25.4),and the 6-month and 1-year survival rates were 55.6% and 33.3%, respectively.The median OS of patients not treated with systemic therapy was 4.5 months (95% CI 1.8-9.3),and the 6-month and 1-year    ICI and COMBI-ICIs (p = 0.46).Concerning radiotherapy, the median OS of patients treated with STI was 8.6 months (95% CI 6.9-11.5)and the 6-month and 1-year survival rates were 68.6% and 38.7%, respectively.The median OS of patients treated with WBRT was 3.3 months (95% CI 1.9-4.9),and the 6-month and 1-year survival rate was 25.7% and 17.1%, respectively.There was a significant difference in survival curves between the STI and WBRT groups (p < 0.001).Table 3 presents the characteristics of patients treated with ICI and TT, and Table 4 displays the results of the comparison of the effectiveness of each systemic therapy for MBM using Cox regression analysis.After adjusting for confounding factors, no difference in effectiveness was found between single-agent ICI, COMBI-ICI, and TT (COMBI-ICI vs. single-agent ICI, HR 0.71, 95% CI 0.27-1.88,p = 0.49; COMBI-ICI vs. TT: HR 0.46, 95% CI 0.14-1.55,p = 0.21).

| DISCUSSION
In this study, we retrospectively investigated the survival of patients with MBM and associated factors.Consequently, Asian patients with MBM have a shorter prognosis than Caucasian patients, as discussed in the following section.To the best of our knowledge, this is the first study to present the possibility that COMBI-ICI is not superior to ICI and TT when treating Asian patients with MBM.
According to previous studies, owing to recent improvements in chemotherapy and radiotherapy, the OS of patients with MBM has increased from approximately 4-14 months. 2,10However, our study revealed that the outcomes of patients with MBMs in Japan did not improve as significantly as reported in other studies.Previous studies of Asian patients with MBMs showed a median OS of 7-8 months, which is comparable to our findings. 11,12lthough previous studies have shown limited effectiveness of ICI and TT in Asian patients with unresectable melanoma, Asian patients with MBMs may also respond poorly to these systemic therapies. 8e associated factors identified in multivariate analysis were primary location, serum LDH levels, type of initial systemic therapy, and type of radiotherapy.Univariate analysis identified presence of neurologic symptoms as being associated with higher overall survival, but this was not observed during multivariate analysis, indicating that this result could be a statistical artifact possibly due to the small sample size or confounding factors.
4][15][16] The results of our study suggest that the prognosis of MBM is also shorter when the subtype is acral melanoma, although mucosal melanoma has no shorter survival time than non-acral melanoma.8][19] The American Joint Committee on Cancer (AJCC) 8th edition articulates that LDH levels affect the TNM classification. 20e found no statistical difference in survival between patients with BRAF wild-type and BRAF mutant melanoma.It has been reported that patients with a V600K mutation may respond better to ICIs compared to those with a V600E mutation.However, in our study, all patients with BRAF mutant melanoma were treated with TTs as first-line therapy, so our results cannot support this hypothesis. 21ur study demonstrated that patients treated with ICI or TT had longer survival than those treated with conventional chemotherapy or those not treated with systemic therapy.In addition, there was no difference between the effectiveness of single-agent ICI, COMBI-ICIs, and TT, regardless of BRAF V600 mutational status.The effectiveness of ICI and TT for unresectable melanoma has been demonstrated in many studies involving Caucasian cohorts, with limited effectiveness demonstrated in studies involving Asian cohorts. 9,22,23While TT is only effective for BRAF-mutated melanoma, previous studies have demonstrated that COMBI-ICI is more effective for unresectable melanoma than TT and single-agent ICI, regardless of BRAF V600 mutational T A B L E 3 (Continued) status. 24,25][6][7][8] Based on these studies, it was recently recommended that COMBI-ICI be used for patients with MBM, regardless of BRAF V600 mutational status.However, the evidence underlying this recommendation is that studies on Caucasian cohorts and Asian patients are rare.Our study suggests that COMBI-ICIs might not be superior to ICI and TT when treating Asian patients with MBM, and that there may be a need to re-assess the recommendation of COMBI-ICIs as the first-line therapy in treating Asian patients with MBM.Next, we discuss the local treatment.Our study demonstrated that patients treated with STI had longer survival than those treated with WBRT.Previous studies have demonstrated the effectiveness of STI over WBRT. 11n general, STIs are preferred for up to four brain metastases. 26On the other hand, WBRT is preferred when there are more than five metastases, or when the size is over 3 cm.However, there was no difference in the number and size of MBM between patients who underwent STI and those who underwent WBRT in this study.Our results suggest the potential of STI in treating multiple metastases.
A major limitation of our study was the inherent potential bias of retrospective studies.Many of our patients had received systemic therapy for melanoma before being diagnosed with MBM, and they also received concurrent radiotherapy while being treated with first-line therapies.These other treatments could have affected the effectiveness of the first-line therapies.In addition, the number of patients with MBM treated with COMBI-ICI was relatively small, making the comparison between each treatment group less reliable.Furthermore, the follow-up period was short making it difficult to assess response durability.Therefore, further multicenter analyses and prospective studies with larger cohorts are required to confirm the efficacy of systemic therapy in Asian patients with MBM.

| CONCLUSIONS
We retrospectively investigated the survival of patients with MBMs at our facility.The survival of Asian patients with MBM is poor.ICI, TT, and STI were associated with improved survival; however, we found no significant superiority of COMBI-ICI over single-agent ICI or TT in terms of effectiveness.Further investigations using larger cohorts, multicenter analyses, and prospective studies are necessary to assess the effectiveness of systemic therapy in Asian patients with MBM.
Demographic and clinical characteristics of patients, n = 135.Prognostic factors for Overall Survival: Cox regression analysis.
T A B L E 1Abbreviations: COMBI-ICI, combination therapy of nivolumab and ipilimumab; ICI, immune checkpoint inhibitor; LDH, lactate dehydrogenase;MBM, melanoma brain metastasis; PS, performance status; STI, stereotactic irradiation; TT, targeted therapy; ULN, upper limit normal; WBRT, whole brain radiation therapys.aMBMsizemeansthe largest brain metastasis in each patient.T A B L E 1 (Continued)F I G U R E 1 Kaplan-Meier analysis of overall survival (OS) of patients with Melanoma Brain Metastasis.MBM, melanoma brain metastasis.T A B L E 2survival rates were 31.8% and 15.9%, respectively.For all patients, there was no significant difference in survival curves between single-agent ICI, the combination of nivolumab and ipilimumab, and TT (p = 0.33).In patients with BRAF-mutant melanoma, there was no significant difference among single-agent ICI, COMBI-ICI, and TT (p = 0.23).For patients with BRAF wild-type melanoma, there was no significant difference between single-agent a MBM size means the largest brain metastasis in each patient.
Demographic and clinical characteristics of patients treated with immune checkpoint inhibitors and targeted therapy.