Abstract
Simple Summary
Cutaneous melanoma is highly prone to metastasize to the brain, with a historically poor overall survival of only 4–5 months. Over the past decade, novel drugs such as targeted therapies and immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced melanoma. However, most prospective studies have excluded patients with melanoma brain metastasis (MBM) or included only patients with stable (steroid-free) or asymptomatic MBM. To assess the impact of novel treatments in patients with MBM in a real-world setting, we studied a cohort of consecutive patients over a period of sixteen years (2005 to 2021) in a large, tertiary referral center for melanoma (Erasmus MC, Rotterdam, the Netherlands). We found a significant improvement in overall survival in the modern (post-2015) era, associated with stereotactic radiotherapy and especially ICIs. These findings support that ICIs, if clinically feasible, should be considered first in clinical practice after a diagnosis of MBM.
Abstract
Background: Melanoma brain metastasis (MBM) is associated with poor outcome, but targeted therapies (TTs) and immune checkpoint inhibitors (ICIs) have revolutionized treatment over the past decade. We assessed the impact of these treatments in a real-world setting. Methods: A single-center cohort study was performed at a large, tertiary referral center for melanoma (Erasmus MC, Rotterdam, the Netherlands). Overall survival (OS) was assessed before and after 2015, after which TTs and ICIs were increasingly prescribed. Results: There were 430 patients with MBM included; 152 pre-2015 and 278 post-2015. Median OS improved from 4.4 to 6.9 months (HR 0.67, p < 0.001) after 2015. TTs and ICIs prior to MBM diagnosis were associated with poorer median OS as compared to no prior systemic treatment (TTs: 2.0 vs. 10.9 and ICIs: 4.2 vs. 7.9 months, p < 0.001). ICIs directly after MBM diagnosis were associated with improved median OS as compared to no direct ICIs (21.5 vs. 4.2 months, p < 0.001). Stereotactic radiotherapy (SRT; HR 0.49, p = 0.013) and ICIs (HR 0.32, p < 0.001) were independently associated with improved OS. Conclusion: After 2015, OS significantly improved for patients with MBM, especially with SRT and ICIs. Demonstrating a large survival benefit, ICIs should be considered first after MBM diagnosis, if clinically feasible.
Keywords: melanoma, brain neoplasms/metastasis, immunotherapy, immune checkpoint inhibitors, molecular targeted therapy, BRAF/MEK inhibitors, radiotherapy, survival
1. Introduction
Cutaneous melanoma has the highest risk of brain metastasis (MBM) of all solid tumors, spreading to the brain in over 50% of patients with metastatic disease [1,2,3]. Overall survival (OS) used to be <5 months, but several novel treatments have become available in the last decade, which have changed the perspectives of patients with MBM [2].
Whole brain radiotherapy (WBRT) and chemotherapy have limited efficacy in MBM, and WBRT is associated with cognitive impairment in the few long-term survivors [4,5,6]. These days, stereotactic radiotherapy (SRT) and especially targeted therapies (TTs; BRAF-MEK inhibitors) and immune checkpoint inhibitors (ICIs; anti-PD[L]1 and anti-CTLA4) have revolutionized treatment for patients with MBM [7,8,9,10,11,12,13,14]. Combined dabrafenib–trametinib showed an intracranial response rate (IRR) of 58%, but with limited duration of response (6.5 months) [7]. More durable responses are reported for ICIs, especially for combined nivolumab–ipilimumab. The ABC trial reported an IRR of 51% with a 5-year OS of 51% [8,9,10], and the CHECKMATE-204 trial had an IRR of 57% with a 1-year OS of 81.5% for this combination [11,15]. However, only a few phase II and III trials included limited numbers of patients with previously treated and/or symptomatic MBM, and these reported considerably lower IRRs (between 6% and 17% for ICIs) [8,11,15,16].
To assess the eligibility of individual patients for these novel treatments, the Melanoma-molGPA is often used in clinical practice as a prognostic scoring tool. This index is based on age, Karnofsky performance status (KPS), presence of extracranial metastasis (ECM), number of MBMs and, more recently, BRAF-mutation status [17,18,19]. However, since the index was derived from a retrospective cohort (n = 823) of patients between 2006 and 2015, its validity for modern cohorts is uncertain [17,20].
In the Netherlands, TTs and ICIs have been implemented in clinical practice for patients with MBM since their reimbursement almost a decade ago [21]. To assess the real-world impact of these treatments on MBM, we studied OS in a cohort of consecutive patients diagnosed with MBM over a period of sixteen years (2005 to 2021). Additionally, we examined the validity of the Melanoma-molGPA index for patients diagnosed with MBM in the modern treatment era.
2. Materials and Methods
2.1. Patient Selection
This retrospective cohort study was performed at Erasmus MC Cancer Institute (Rotterdam, The Netherlands), a large, tertiary referral center for patients with melanoma. In this center, the treatment plan for patients with MBM is routinely discussed in a local multidisciplinary board which includes experienced medical oncologists, neuro-oncologists, radiotherapists, and neurosurgeons. We identified all consecutive patients with a diagnosis of cutaneous or mucosal melanoma and MBM referred to the Erasmus MC between 1 January 2005 and 1 July 2021 (Figure A1). The study was approved by the local Institutional Review Board (MEC-2020-0681).
2.2. Data Collection and Definitions
Two trained data managers (E.L.v.d.M., L.S.H.) retrieved data from the electronic patient records. All data were reassessed by two clinical physicians (S.H.A.E.D., J.L.M.J.). The following baseline characteristics were collected: age, sex, KPS, lactate dehydrogenase (LDH) level, BRAF-status, presence of symptoms of MBM (e.g., headache, nausea, epilepsy, focal deficits), number of MBMs, and status of ECM. Diagnosis of MBM was the date of first brain imaging (magnetic resonance imaging or computed tomography (CT)) that confirmed parenchymal MBM. Diagnosis of ECM was the date of first imaging (CT or 2-deoxy-2-[18F]fluoro-D-glucose-positron emission tomography-CT) of at least thorax and abdomen that confirmed metastasis (M1-disease). Melanoma brain metastasis was considered synchronous when diagnosed within one month of diagnosis of ECM and metachronous when diagnosed at least one month after diagnosis of ECM. The Melanoma-molGPA was calculated for each individual patient.
In addition, details of previous systemic treatments (i.e., given at any time prior to diagnosis of MBM) and treatments given directly after diagnosis of MBM (before the first physician assessed progression of MBM) were collected. Local treatments included surgical resection, SRT, and WBRT. Systemic treatments included chemotherapy (e.g., dacarbazine), TTs (e.g., vemurafenib, dabrafenib, encorafenib, alone or combined with cobimetinib, trametinib, binimetinib, respectively) and ICIs (e.g., pembrolizumab, atezolizumab, nivolumab, ipilimumab, or nivolumab–ipilimumab).
2.3. Statistical Analysis
Data cut-off was 4 March 2022. We created a total cohort and two consecutive time cohorts split 1 January 2015, as novel systemic treatments were increasingly prescribed after 2015 in the Netherlands (Table A1, Figure A3). The primary outcome was OS, defined as the time between diagnosis of MBM and death of any cause.
Continuous variables were described with medians (interquartile range (IQR)) and categorical variables with frequencies. The Mann–Whitney U test was used for continuous, and the Chi-squared test for categorical variables. For categorical variables with groups < 10 patients, the Fisher exact test was used. Missing data were omitted from analysis.
Kaplan–Meier (KM) and Cox Proportional Hazards (CPH) methods were used for time-to-event analysis and assessed with the Logrank and Likelihood ratio tests, respectively. For multivariate CPH modeling, backward elimination (i.e., including variables with p < 0.2 in univariate analysis) was applied, and interaction testing was performed. No correction for multiple testing was performed in these exploratory analyses. A two-sided p-value of 0.05 was taken as statistically significant. All analyses were performed using R version 4.0.2 (the R-Project, Auckland, New Zealand).
3. Results
3.1. Baseline Characteristics
We included 430 patients in total; 152 (35.3%) patients were categorized in the pre-2015 cohort and 278 (64.7%) in the post-2015 cohort (Figure A1). The majority of patients had a follow-up of at least 12 months (420 of 430 patients, 97.6%). Baseline characteristics at diagnosis of MBM are shown in Table 1. Overall, 133 (30.9%) patients had a KPS ≤ 70 and 321 of 430 (74.6%) patients had symptomatic MBM, with fewer symptomatic patients post-2015 (n = 193 of 278, 69.4%) as compared to pre-2015 (n = 128 of 152, 84.4%; p = 0.001).
Table 1.
Baseline characteristics of patients at diagnosis of melanoma brain metastasis (MBM).
| Patients (%) | ||||
| Total | Pre-2015 | Post-2015 | p-Value 1 | |
|---|---|---|---|---|
| Variable | 430 | 152 | 278 | |
| Age at diagnosis of MBM, years | 0.005 | |||
| Median (interquartile range) | 63.1 (52.3–71.7) |
60.6 (49.2–69.1) |
64.5 (53.4–72.9) |
|
| Sex | 0.192 | |||
| Women | 173 (40.2) | 68 (44.7) | 105 (37.8) | |
| Men | 257 (59.8) | 84 (55.3) | 173 (62.2) | |
| Karnofsky performance status (KPS) | 0.722 | |||
| ≤70 | 133 (30.9) | 43 (28.3) | 90 (32.4) | |
| 80 | 141 (32.8) | 51 (33.6) | 90 (32.4) | |
| 90–100 | 131 (30.5) | 42 (27.6) | 89 (32.0) | |
| Unknown 2 | 25 (5.8) | 16 (10.5) | 9 (3.2) | |
| LDH at MBM diagnosis | 0.136 | |||
| ≤ULN | 162 (37.7) | 40 (26.3) | 122 (43.9) | |
| >ULN | 168 (39.1) | 55 (36.2) | 113 (47.8) | |
| Unknown 2 | 100 (23.3) | 57 (37.5) | 43 (15.5) | |
| BRAF mutational status | 0.013 | |||
| Wildtype | 145 (33.7) | 45 (29.6) | 100 (36.0) | |
| V600E+ or K | 192 (44.7) | 35 (23.0) | 157 (56.5) | |
| Other | 15 (3.5) | 2 (1.3) | 13 (4.7) | |
| Unknown 2 | 78 (18.1) | 70 (46.1) | 8 (2.9) | |
| Time between first diagnosis of melanoma and diagnosis of MBM, months | ||||
| Median (interquartile range) | 37.0 (11.0–68.0) |
36.5 (12.0–59.3) |
37.0 (10.0–70.0) |
0.720 |
| Time between first diagnosis of ECM and diagnosis of MBM, months 3 | ||||
| Median (interquartile range) | 8.0 (5.0–17.0) |
9.0 (4.0–15.0) |
8.0 (5.0–19.0) |
0.40 |
| Symptomatic MBM | 0.001 | |||
| Yes | 321 (74.6) | 128 (84.2) | 193 (69.4) | |
| No | 109 (25.3) | 24 (15.8) | 85 (30.6) | |
| Number of MBMs | 0.533 | |||
| 1 | 123 (28.6) | 38 (25.0) | 86 (30.9) | |
| 2 | 57 (13.3) | 23 (15.1) | 34 (12.2) | |
| 3 | 35 (8.1) | 14 (9.2) | 21 (7.6) | |
| ≥4 | 215 (50.0) | 77 (50.7) | 137 (49.3) | |
| Status of ECM | 0.391 | |||
| No ECM | 75 (17.4) | 31 (20.4) | 44 (15.8) | |
| MBM synchronous with ECM | 187 (43.5) | 65 (42.8) | 122 (43.9) | |
| MBM metachronous with ECM | 153 (35.6) | 49 (32.2) | 104 (37.4) | |
| Unknown 2 | 15 (3.5) | 7 (4.6) | 8 (2.9) | |
1p-values are given for the comparison between pre- and post-2015 time cohorts; significant p-values (<0.05) are italic. 2 The “unknown” category was omitted from statistical testing. 3 Analysed in patients with metachronous MBM (n = 153). Abbreviations: LDH: lactate dehydrogenase, ULN: upper limit of normal (247 U/L), ECM: extracranial metastasis.
3.2. Treatments over Time
Prior to the diagnosis of MBM, 104 of 430 (24.2%) patients had received one or more systemic treatments (Table 2). Fewer patients had received previous chemotherapy post-2015 compared to pre-2015 (1.4% vs. 6.6%; p = 0.008), whereas TTs and ICIs prior to MBM diagnosis had been administered more often after 2015 (3.3% to 13.3%, p < 0.001; 2.0% to 25.2%, p < 0.001, respectively).
Table 2.
Treatment patterns before and directly after diagnosis of melanoma brain metastasis (MBM).
| Patients (%) | ||||
|---|---|---|---|---|
| Total | Pre-2015 | Post-2015 | p-Value 1 | |
| Variable | 430 | 152 | 278 | |
| Treatments prior to MBM diagnosis | ||||
| Systemic treatments | ||||
| Chemotherapy | 0.008 | |||
| Yes | 14 (3.3) | 10 (6.6) | 4 (1.4) | |
| No | 416 (96.7) | 142 (93.4) | 274 (98.6) | |
| Targeted therapy | <0.001 | |||
| Yes | 42 (9.8) | 5 (3.3) | 37 (13.3) | |
| No | 388 (90.2) | 147 (96.7) | 241 (86.7) | |
| Immune checkpoint inhibition | <0.001 | |||
| Yes | 73 (17.0) | 3 (2.0) | 70 (25.2) | |
| No | 357 (83.0) | 149 (98.0) | 208 (74.8) | |
| Treatments directly after MBM diagnosis | ||||
| Local treatments | ||||
| SRT | 0.684 | |||
| Yes | 62 (14.4) | 20 (13.2) | 42 (15.1) | |
| No | 368 (85.6) | 132 (86.8) | 236 (84.9) | |
| WBRT | ||||
| Yes | 120 (27.9) | 84 (55.3) | 35 (12.6) | <0.001 |
| No | 310 (72.1) | 68 (44.7) | 243 (87.4) | |
| Surgical resection | 0.203 | |||
| Yes | 52 (12.1) | 23 (15.1) | 29 (10.4) | |
| No | 378 (87.9) | 129 (84.9) | 249 (89.6) | |
| Systemic treatments | ||||
| Chemotherapy | <0.001 | |||
| Yes | 22 (5.1) | 22 (14.5) | 4 (1.4) | |
| No | 408 (94.9) | 130 (85.5) | 274 (98.6) | |
| Targeted therapy | <0.001 | |||
| Yes | 110 (25.6) | 16 (10.5) | 94 (33.8) | |
| No | 320 (74.4) | 136 (89.5) | 184 (66.2) | |
| Immune checkpoint inhibition | <0.001 | |||
| Yes | 101 (23.5) | 4 (2.6) | 98 (35.3) | |
| No | 329 (76.5) | 148 (97.4) | 180 (64.7) | |
| Best supportive care | 0.726 | |||
| Yes | 73 (17.0) | 24 (15.8) | 49 (17.6) | |
| No | 357 (83.0) | 128 (84.2) | 229 (82.4) | |
1p-Values were calculated to compare pre- and post-2015 time cohorts; significant p-values (<0.05) are in italic. Abbreviations: SRT: stereotactic radiotherapy, WBRT: whole brain radiotherapy.
Directly after diagnosis of MBM, 358 of 430 (83.3%) patients received one or more systemic and/or local treatments (Table 2). The frequency of SRT and surgical resection directly after diagnosis of MBM did not significantly change over time, whereas the frequency of WBRT and chemotherapy significantly decreased after 2015 (55.3% to 12.6%, p < 0.001; 14.5% to 1.4%, p < 0.001; respectively). The prescription of TTs and ICIs directly after diagnosis of MBM significantly increased after 2015 (10.5% to 33.8%, p < 0.001; 2.6% to 35.3%, p < 0.001; respectively).
3.3. Overall Survival
In the total cohort, median OS was 5.9 months (IQR 2.07–15.41), with 1- and 3-year OS rates of 30.2% and 12.5%, respectively (Figure 1a). Here, 21 of 430 (4.9%) patients had a survival time of at least 5 years since diagnosis of MBM, of whom 17 (81.0%) were diagnosed with MBM post-2015. At data cut-off, 65 of 430 (15.1%) patients, of whom 61 were diagnosed with MBM post-2015, were alive with a median follow-up of 23.8 (IQR 11.6–41.2) months. Median OS was significantly longer post-2015 as compared to pre-2015 (6.9 (IQR 2.07–23.39) vs. 4.4 (IQR 1.92–10.73) months, HR0.63, p < 0.001), especially in subgroups of patients with synchronous MBM, LDH levels > ULN and a KPS > 70 (Figure 1b and Figure 2, Table A2).
Figure 1.
(a) Kaplan–Meier curve of overall survival in the total cohort (n = 430) of patients with melanoma brain metastasis (MBM). (b) Kaplan–Meier curves of overall survival of patients diagnosed with MBM pre-2015 (n = 152) and post-2015 (n = 278).
Figure 2.
Forrest plot reflecting the hazard ratios (with 95% confidence interval) for patients diagnosed with melanoma brain metastasis (MBM) post-2015 (versus pre-2015) in several subgroups. Abbreviations: LDH: lactate dehydrogenase, ULN: upper limit of normal (247 U/L), KPS: Karnofsky performance status.
For patients receiving SRT and surgical resection directly after diagnosis of MBM, OS improved after 2015 (Table A3). Systemic treatments were not analyzed over time since their frequencies significantly changed over time (Table 2). To assess the impact of treatments in the modern era, we analyzed treatment subgroups in the post-2015 cohort (n = 278) only.
In these univariate analyses, a specific treatment before the diagnosis of MBM or directly after was compared to not having that specific treatment at that time. In addition, patients with symptomatic MBM were analyzed separately.
3.3.1. Local Treatments Post-2015
Forty-two patients received SRT directly after diagnosis of MBM, of whom 39 (92.9%) had <4 MBMs. In these patients, SRT significantly improved OS as compared to patients without SRT (median OS 30.3 (IQR 9.0–NA) vs. 7.6 (IQR 2.6–32.3) months, HR0.46, p < 0.001; Figure 3a, Table A4). In patients with <4 MBMs and symptomatic MBM, SRT remained associated with improved OS (Figure A4a).
Figure 3.
Kaplan–Meier estimates for local treatments in patients with melanoma brain metastasis (MBM) of the post-2015 cohort and with <4 MBMs (n = 141). (a) Stereotactic radiotherapy (SRT) versus no stereotactic radiotherapy (no SRT) directly after diagnosis of MBM. (b) Surgical resection versus no surgical resection directly after diagnosis MBM.
In patients with <4 MBMs and symptomatic MBM, surgical resection directly after diagnosis of MBM was associated with improved OS as compared to no surgical resection (median OS 21.5 (IQR 11.3–29.6) vs. 5.7 (IQR 2.3–25.9) months, HR0.58, p = 0.046; Figure A4b).
3.3.2. Systemic Treatments Post-2015
In patients with BRAF V600E+/K-mutated melanoma (n = 157), TTs prior to the diagnosis of MBM were associated with a shorter median OS as compared to no prior TTs (2.0 (IQR 0.8–7.1) vs. 10.9 (IQR 5.2–27.0) months, HR2.67, p < 0.001; Figure 4a, Table A4). In patients with prior TTs, 58.3% of patients had also been previously treated with ICIs (Table A5a). Of all patients with TTs directly after diagnosis of MBM (n = 89), 64 (71.9%) had symptomatic MBM (Figure A5a). No significantly different OS was found between patients with and without TTs directly after MBM diagnosis (7.8 (IQR 4.8–17.0) vs. 7.4 (IQR 1.5–33.4) months, HR1.15, p = 0.43; Figure 4c, Table A4).
Figure 4.
Kaplan–Meier estimates of systemic treatments given to patients with melanoma brain metastasis (MBM) of the post-2015 cohort (n = 278). (a) TTs or no TTs prior to diagnosis of MBM in patients with a targetable BRAF V600E or K+ mutation (n = 157). (b) ICIs or no ICIs prior to diagnosis of MBM. (c) TTs or no TTs directly after diagnosis of MBM in patients with a BRAF V600E or K+ mutation (n = 157). (d) ICIs or no ICIs directly after diagnosis of MBM.
Patients treated with ICIs prior to the diagnosis of MBM had a poorer median OS as compared to patients without prior ICIs (4.2 (IQR 1.0–10.2) vs. 7.9 (IQR 3.1–27.0) months, HR 1.67, p < 0.001) and 30.0% of patients with prior ICIs had also been previously treated with TTs (Figure 4b, Table A4 and Table A5b). Patients with ICIs directly after diagnosis of MBM had a better median OS as compared to patients without ICIs directly after MBM (21.5 (IQR 9.4–NA) vs. 4.2 (IQR 1.4–8.0) months, HR 0.28, p < 0.001; Figure 4d, Table A4), which was also confirmed in a subgroup of symptomatic patients (18.5 (IQR 9.0–34.4) vs. 4.0 (IQR 1.1–7.6) months, HR 0.33, p < 0.001; Figure A5b). Of all patients (n = 98) with ICIs directly after MBM diagnosis, 44 (44.9%) were alive at data cut-off, and 17 (17.3%) patients had a survival time of at least 5 years after diagnosis of MBM. In 23 of 98 (23.5%) patients, ICIs were combined with SRT.
3.4. Independent Prognostic Variables
In multivariate analysis of the post-2015 cohort (n = 278), symptomatic MBM (HR 1.74 [1.21–2.50], p = 0.003) and metachronous MBM (HR 2.73 [1.50–4.95], p < 0.001) were independently associated with poorer OS, whereas a KPS of >70 (HR 0.51 [0.37–0.70], p < 0.001), SRT (HR 0.49 [0.28–0.86], p = 0.013) and ICIs directly after diagnosis of MBM (HR 0.32 [0.22–0.47], p < 0.001) were independently associated with an improved OS (Table 3).
Table 3.
Cox proportional hazards model for overall survival of patients diagnosed with melanoma brain metastasis (MBM) in the post-2015 cohort (n = 278).
| Univariate Analysis | Multivariate Analysis | |||
|---|---|---|---|---|
| Variable | HR [95%CI] | p-Value | HR [95%CI] | p-Value |
| Age at MBM diagnosis | 1.012 [1.002–1.023] |
0.017 | - | - |
| Time between primary diagnosis melanoma and MBM | 1.001 [0.999–1.003] |
0.244 | - | - |
| Female sex (ref. male) | 0.945 [0.717–1.245] |
0.686 | - | - |
| LDH > ULN (ref. ≤ ULN) | 1.701 [1.269–2.279] |
<0.001 | 1.305 [0.941–1.808] |
0.110 |
| KPS > 70 (ref. ≤ 70) | 0.331 [0.250–0.440] |
<0.001 | 0.511 [0.371–0.703] |
<0.001 |
| ≥4 MBMs (ref. 1–3) | 1.983 [1.509–2.606] |
<0.001 | - | - |
| BRAF V600E+/K mutation (ref. wildtype) | 0.913 [0.686–1.215] |
0.546 | - | - |
| Symptomatic MBM (ref. no) | 1.918 [1.410–2.609] |
<0.001 | 1.741 [1.210–2.504] |
0.003 |
| MBM synchronous with ECM (ref. no ECM) | 1.499 [0.978–2.298] |
0.063 | 1.412 [0.790–2.524] |
0.244 |
| MBM metachronous to ECM (ref. no ECM) | 2.815 [1.830–4.330] |
<0.001 | 2.726 [1.501–4.951] |
<0.001 |
| Previous TTs (ref. no) | 2.247 [1.565–3.225] |
<0.001 | - | - |
| Previous ICIs (ref. no) | 1.665 [1.232–2.250] |
<0.001 | 0.687 [0.456–1.035] |
0.072 |
| TTs after MBM diagnosis (ref. no) |
1.062 [0.803–1.404] |
0.673 | - | - |
| ICIs after MBM diagnosis (ref. no) |
0.280 [0.205–0.384] |
<0.001 | 0.323 [0.221–0.472] |
<0.001 |
| Surgical resection (ref. no) |
0.566 [0.357–0.899] |
0.009 | 0.656 [0.348–1.237] |
0.192 |
| SRT (ref. no) | 0.412 [0.271–0.626] |
<0.001 | 0.493 [0.283–0.860] |
0.013 |
Significant p-values (<0.05) in multivariate analysis are in italic. Abbreviations: LDH: lactate dehydrogenase, ULN: upper limit of normal (247 U/L), KPS: Karnofsky performance status, ECM: extracranial metastasis, TTs: targeted therapies, ICIs: immune checkpoint inhibitors, SRT: stereotactic radiotherapy.
3.5. Melanoma-molGPA
The Melanoma-molGPA could be assessed for 268 of 278 (96.4%) patients post-2015. The melanoma-molGPA subclasses (I, II, III, and IV, respectively) showed a subsequent improvement of OS (median OS 3.0, 6.9, 24.5, and 30.3 months, respectively, p < 0.001; Figure 5, Table A6).
Figure 5.
Kaplan–Meier estimates for overall survival of patients diagnosed with melanoma brain metastases (MBM) in the post-2015 cohort of patients with available model input parameters (n = 268) according to the different prognostic classes (I to IV) of melanoma-molGPA score.
3.6. Switching from Targeted Therapy to Immune Checkpoint Inhibition
Here, 18 of 430 (4.2%) patients initiated with TTs directly after diagnosis of MBM and switched to ICIs when their performance status improved and/or imaging showed tumor response at a median time of 6.1 months (IQR 3.9–7.0) after the start of TTs (Table A7). Three of eighteen (16.7%) patients remained stable since the switch to ICIs and were alive at data cut-off, with a median survival time of 25.5 months (IQR 21.7–27.2) since ICI initiation. Three of eighteen (16.7%) patients had progressive disease after ICI initiation but received no further treatment due to poor clinical condition, with a median OS of 11.9 months (IQR 7.6–16.3) since ICI initiation. Twelve of eighteen (66.7%) patients had progressive disease on ICIs and switched back to TTs, with a median OS of 11.6 months (IQR 6.5–25.5) since ICI initiation.
4. Discussion
Since 2015, novel systemic therapies (TTs and ICIs) and SRT have replaced chemotherapy and WBRT for patients with MBM, resulting in a significantly improved OS. Compared to clinical trials, real-world patients with MBM usually have a worse clinical condition, which is illustrated by the high number of patients with poor KPS and symptomatic MBM in this cohort.
Surgical resection and SRT remained important treatment options after 2015, although their frequency directly after diagnosis of MBM did not significantly increase over time. Especially SRT was associated with a beneficial impact on survival (median OS 30.5 months) and remained independently associated with improved OS. Although the efficacy of SRT has been demonstrated in patients with up to 10 MBMs [22,23], SRT was almost exclusively reserved for patients with <4 MBMs in the current cohort.
The increased use of TTs (10.5% to 33.8%) and ICIs (2.6% to 35.3%) post-2015, directly after diagnosis of MBM, reflects the clinical approval of different novel drugs by the European Medicines Agency (EMA) and their reimbursement in the Netherlands since 2015 [24]. Bander et al. showed an even higher use of ICIs (77%) in their American cohort, likely resulting from the earlier approval of these drugs by the Food and Drug Administration (FDA) and from differences in therapeutic approaches between centers [25,26].
Patients who received TTs or ICIs to treat ECM, before the diagnosis of MBM, had poor survival (median OS of 2.0 and 4.2 months, respectively) as they had secondary resistance with intracranial disease progression on/after these treatments. Other real-world studies confirm the poor OS of patients with systemic treatments prior to the diagnosis of MBM [26,27]. Most importantly, a significantly favorable OS was seen with ICIs directly after the diagnosis of MBM (median OS 21.5 months), even in symptomatic patients (18.5 months). Although median follow-up is limited, the tail of the OS curve (Figure 4d) showed a considerable group of patients with long-term survival, as illustrated by >17% of patients with ICIs who lived >5 years after diagnosis of MBM. This confirms in a real-world setting the efficacy of ICIs in MBM, as reported by the benchmark phase II and III trials [10,15]. Therefore, ICIs should be considered first after diagnosis of MBM, if clinically feasible.
The Melanoma-molGPA, based on an MBM cohort between 2006 and 2015, remained a valid prognostic tool in patients diagnosed with MBM between 2015 and 2021 [17,18]. Therefore, clinicians may continue to use this tool to predict prognosis and assess the eligibility of individual patients for specific treatments.
Since TTs can induce rapid tumor responses, these drugs were frequently administered (>70%) to patients with symptomatic MBM and a poor performance status. However, TTs lack durable responses and it was recently demonstrated that first-line nivolumab–ipilimumab followed by BRAF/MEK-inhibition on progression had the most favorable OS in metastatic melanoma [28]. Nevertheless, in patients with a BRAF V600E+/K-mutation and an initial poor performance status, induction with TTs provides an opportunity for effective ICI treatment after performance has improved [29]. Although our study was not designed to compare treatment strategies, we assessed the outcome of 18 patients who were first treated with induction TTs after the diagnosis of MBM, followed by ICIs. Only three (16.7%) patients benefitted from the switch to ICIs, with stable disease and a median OS of 25.5 months since ICIs. Although (pre-)clinical studies have shown that an immune-resistant phenotype might arise after progression on BRAF/MEK-inhibition, it is unknown whether the switch to ICIs before progression on TTs could be effective, and it is worthwhile to further investigate this prospectively [8,30].
This study was designed to assess the potential survival gain in the brain for patients with MBM in a real-world setting after the introduction of novel systemic treatments. The retrospective design is a limitation, as is the lack of information on steroid use. The inclusion of a single center might provide additional bias. However, this tertiary center receives referrals from a large region in the Netherlands, and each consecutive patient is treated and followed in this center until end-of-life care or death. Therefore, this data set provides detailed information over a large period of time, fully capturing the changing treatment landscape.
5. Conclusions
Overall survival has improved for patients with MBM after 2015 and is associated with the use of SRT and ICIs directly after diagnosis of MBM. Immune checkpoint inhibitors (ICIs) showed an important survival benefit and should be considered first after the diagnosis of MBM, if clinically feasible. The Melanoma-molGPA remains a valid prognostic tool for clinicians in the modern treatment era for patients with MBM. To further improve the prognosis of patients with MBM, future research should focus on optimizing treatment sequencing, such as switching from TTs to ICIs, especially in patients with an initial poor performance.
Appendix A
Figure A1.
Flow chart of patient inclusion. Patients were subdivided into a pre-2015 cohort (diagnosis of melanoma brain metastasis (MBM) before 1 January 2015) and a post-2015 cohort (diagnosis of MBM after 1 January 2015). CT: computed tomography. MRI: magnetic resonance imaging.
Table A1.
Yearly incidence of patients with newly diagnosed melanoma brain metastasis (MBM) referred to the Erasmus MC, and yearly treatment prescriptions (at any time after MBM diagnosis).
| Year of Prescription | No. of Patients | Chemo-therapy | Targeted Therapy | Immune Checkpoint Inhibition | Stereotactic Radiotherapy | Whole Brain Radiotherapy | Surgical Resection |
|---|---|---|---|---|---|---|---|
| 2005 | 1 | 1 | 0 | 0 | 1 | 0 | 1 |
| 2007 | 3 | 1 | 0 | 0 | 2 | 1 | 3 |
| 2008 | 4 | 1 | 0 | 0 | 2 | 2 | 1 |
| 2009 | 22 | 8 | 0 | 0 | 0 | 19 | 4 |
| 2010 | 12 | 3 | 0 | 0 | 1 | 7 | 2 |
| 2011 | 20 | 1 | 2 | 0 | 5 | 13 | 4 |
| 2012 | 30 | 5 | 8 | 1 | 4 | 23 | 3 |
| 2013 | 21 | 2 | 3 | 1 | 9 | 13 | 3 |
| 2014 | 37 | 7 | 6 | 3 | 7 | 19 | 7 |
| 2015 | 33 | 0 | 12 | 9 | 5 | 17 | 2 |
| 2016 | 35 | 0 | 11 | 7 | 5 | 11 | 1 |
| 2017 | 47 | 0 | 17 | 17 | 9 | 12 | 9 |
| 2018 | 40 | 0 | 18 | 23 | 15 | 4 | 8 |
| 2019 | 60 | 0 | 38 | 40 | 17 | 2 | 11 |
| 2020 | 45 | 0 | 20 | 24 | 12 | 3 | 14 |
| 2021 * | 20 | 0 | 16 | 13 | 6 | 1 | 3 |
* Only the first 6 months of 2021 were included.
Figure A2.
Number of patients referred each year to the Erasmus MC with newly diagnosed melanoma brain metastasis.
Figure A3.
Number of started treatments each year at the Erasmus MC, at any time after diagnosis of melanoma brain metastasis.
Table A2.
Overall survival for subgroups of patients diagnosed with melanoma brain metastasis (MBM) in the total cohort (n = 430), pre-2015 cohort (n = 152) and post-2015 cohort (n = 278). Significance testing was performed to compare the pre-2015 and post-2015 cohorts, with significant p-values (<0.05) in italic.
| Total Cohort | Pre-2015 Cohort | Post-2015 Cohort | HR [95%CI] (Ref. = Pre-2015 Cohort) |
p-Value between Time Cohorts | |
|---|---|---|---|---|---|
| Variables | Median OS (Months) | Median OS (Months) | Median OS (Months) | ||
| 5.88 | 4.44 | 6.87 | 0.626 [0.507–0.773] |
<0.001 | |
| Symptoms of MBM | |||||
| Asymptomatic | 10.05 | 4.57 | 14.13 | 0.418 [0.255–0.684] |
<0.001 |
| Symptomatic | 5.03 | 4.37 | 5.68 | 0.768 [0.607–0.971] |
0.027 |
| KPS | |||||
| ≤70 | 2.07 | 2.60 | 1.81 | 0.956 [0.659–1.389] |
0.816 |
| >70 | 9.04 | 6.77 | 11.30 | 0.516 [0.392–0.679] |
<0.001 |
| LDH level | |||||
| ≤ULN | 9.36 | 7.00 | 10.05 | 0.720 [0.488–1.061] |
0.097 |
| >ULN | 3.55 | 2.73 | 4.67 | 0.627 [0.447–0.880] |
0.007 |
| ECM status | |||||
| None | 11.53 | 11.20 | 20.73 | 0.635 [0.374–1.078] |
0.092 |
| Synchronous MBM | 6.44 | 4.17 | 8.97 | 0.456 [0.329–0.634] |
<0.001 |
| Metachronous MBM | 4.01 | 3.55 | 4.22 | 0.798 [0.563–1.130] |
0.210 |
| Number of MBMs | |||||
| <4 | 9.66 | 6.93 | 12.71 | 0.597 [0.439–0.813] |
0.001 |
| ≥4 | 3.94 | 2.99 | 5.19 | 0.621 [0.464–0.832] |
0.001 |
Abbreviations: KPS: Karnofsky performance status, LDH: lactate dehydrogenase, ULN: upper limit of normal (247 U/L), ECM: extracranial metastasis.
Table A3.
Overall survival (OS) for local treatment directly after MBM diagnosis, in patients with <4 melanoma brain metastases (MBMs) in the total cohort (n = 216), pre-2015 cohort (n = 75) and post-2015 cohort (n = 141).
| Total Cohort | Pre-2015 Cohort | Post-2015 Cohort | HR [95%CI] (Ref. = Pre-2015 Cohort) |
p-Value between Time Cohorts | |
|---|---|---|---|---|---|
| Median OS (Months) | Median OS (Months) | Median OS (Months) | |||
| Local treatments, <4 MBMs (n = 216) | |||||
| SRT | |||||
| Yes | 20.4 | 12.8 | 30.3 | 0.515 [0.272–0.974] |
0.04 |
| No | 6.8 | 6.0 | 7.6 | 0.620 [0.436–0.883] |
0.007 |
| Surgical resection | |||||
| Yes | 11.5 | 9.9 | 21.5 | 0.470 [0.249–0.890] |
0.02 |
| No | 7.6 | 6.5 | 9.4 | 0.617 [0.432–0.882] |
0.007 |
Abbreviations: SRT: stereotactic radiotherapy.
Table A4.
Overall survival (OS) for treatment subgroups of patients with melanoma brain metastasis (MBM) in the post-2015 cohort (n = 278) and for local treatments in the post-2015 cohort of patients with <4 MBMs (n = 141).
| Median OS (Months) | 1-Year Probability OS (%) | HR [95%CI] | p-Value | |
|---|---|---|---|---|
| Treatments prior to diagnosis of MBM | ||||
| Systemic treatments (n = 278) | ||||
| No prior TTs 1 | 10.94 | 0.47 | ref. | |
| Prior TTs 1 | 1.95 | 0.11 | 2.670 [1.793–3.974] |
<0.001 |
| No prior ICIs | 7.89 | 0.40 | ref. | |
| Prior ICIs | 4.24 | 0.24 | 1.665 [1.232–2.250] |
<0.001 |
| Treatments directly after diagnosis of MBM | ||||
| Local treatments, <4 MBMs (n = 141) | ||||
| No SRT | 7.62 | 0.42 | ref. | |
| SRT | 30.33 | 0.72 | 0.456 [0.284–0.734] |
<0.001 |
| No surgical resection | 9.36 | 0.47 | ref. | |
| Surgical resection | 21.49 | 0.66 | 0.769 [0.466–1.268] |
0.303 |
| Systemic treatments (n = 278) | ||||
| No TTs 1 | 7.41 | 0.42 | ref. | |
| TTs 1 | 7.79 | 0.36 | 1.154 [0.804–1.653] |
0.435 |
| No ICIs | 4.24 | 0.16 | ref. | |
| ICIs | 21.49 | 0.72 | 0.280 [0.205–0.384] |
<0.001 |
1 In patients with a targetable BRAF-mutation (n = 157). Abbreviations: TTs: targeted therapies, ICIs: immune checkpoint inhibitors, SRT: stereotactic radiotherapy.
Table A5.
(a) Baseline characteristics of patients with a BRAF V600E+/K mutated melanoma and melanoma brain metastasis (MBM) from the post-2015 cohort (n = 157) treated with and without targeted therapies (TTs) prior to MBM diagnosis. (b) Baseline characteristics of patients from the post-2015 cohort (n = 278) treated with or without immune checkpoint inhibitors (ICIs) prior to MBM diagnosis.
| (a) | |||
|---|---|---|---|
| Variables | Previous TTs (%) | No Previous TTs (%) | p-Value |
| 36 (100) | 121 (100) | ||
| Number of MBMs | 0.003 | ||
| 1–3 | 7 (19.4) | 57 (47.1) | |
| ≥4 | 29 (80.6) | 64 (52.9) | |
| ECM status | <0.001 | ||
| None | 1 (2.8) | 19 (15.7) | |
| Synchronous MBM | 1 (2.8) | 69 (57.0) | |
| Metachronous MBM | 33 (91.7) | 31 (25.6) | |
| Unknown 1 | 1 (2.8) | 2 (1.7) | |
| LDH status | 0.099 | ||
| ≤ULN | 15 (41.7) | 57 (47.1) | |
| >ULN | 20 (55.6) | 48 (39.7) | |
| Unknown 1 | 1 (2.8) | 16 (13.2) | |
| Symptomatic MBM | 0.040 | ||
| No | 6 (16.7) | 43 (35.5) | |
| Yes | 30 (83.3) | 78 (64.5) | |
| Previous ICIs | <0.001 | ||
| No | 15 (41.7) | 103 (85.1) | |
| Yes | 21 (58.3) | 18 (14.9) | |
| First line TTs | <0.001 | ||
| No | 28 (77.8) | 40 (33.1) | |
| Yes | 8 (22.2) | 81 (66.9) | |
| First line ICIs | 0.013 | ||
| No | 31 (86.1) | 77 (63.6) | |
| Yes | 5 (13.9) | 44 (36.4) | |
| Median time between primary diagnosis of ECM and MBM (months) 2 | 8.0 IQR (5.0–19.0) | 7.0 IQR (4.0–10.0) | 0.40 |
| (b) | |||
| Variables | Previous ICI (%) | No previous ICI (%) | p-Value |
| 70 (100) | 208 (100) | ||
| Number of MBMs | 0.10 | ||
| 1–3 | 29 (41.4) | 112 (53.8) | |
| ≥4 | 41 (58.6) | 96 (46.2) | |
| ECM status | <0.001 | ||
| None | 4 (5.7) | 40 (19.2) | |
| Synchronous MBM | 6 (8.6) | 116 (55.8) | |
| Metachronous MBM | 58 (82.9) | 46 (22.1) | |
| Unknown 1 | 2 (2.8) | 6 (2.9) | |
| LDH status | 0.018 | ||
| ≤ULN | 26 (37.1) | 96 (46.2) | |
| >ULN | 38 (54.3) | 75 (36.1) | |
| Unknown 1 | 6 (8.6) | 37 (17.8) | |
| Symptomatic MBM | 0.57 | ||
| No | 19 (27.1) | 66 (31.7) | |
| Yes | 51 (72.9) | 142 (68.3) | |
| Previous TTs | <0.001 | ||
| No | 49 (70.0) | 192 (92.3) | |
| Yes | 21 (30.0) | 16 (7.7) | |
| First line TTs | 0.22 | ||
| No | 51 (72.9) | 133 (63.9) | |
| Yes | 19 (27.1) | 75 (36.1) | |
| First line ICIs | <0.001 | ||
| No | 59 (84.3) | 121 (58.2) | |
| Yes | 11 (15.7) | 87 (41.8) | |
| Median time between primary diagnosis of ECM and primary diagnosis of MBM (months) 2 | 8.0 (IQR 6.0–19.0) | 7.5 (IQR 3.0–17.0) | 0.50 |
1 The “unknown” category was omitted from statistical testing. 2 Analyzed for patients with metachronous MBM only (previous TT, n = 33; no previous TT, n = 71). Abbreviations: ECM: extracranial metastasis, LDH: lactate dehydrogenase, ULN: upper limit of normal (247 U/L), ICIs: immune checkpoint inhibitors, TTs: targeted therapies. Significant p-values (<0.05) are in italic.
Figure A4.
Kaplan–Meier curves in symptomatic patients with <4 melanoma brain metastases (MBMs) of the post-2015 cohort (n = 85) and local treatments given directly after diagnosis of MBM. (a) Stereotactic radiotherapy (SRT) or no SRT directly after MBM diagnosis. (b) Surgical resection or no surgical resection directly after MBM diagnosis.
Figure A5.
Kaplan–Meier curves in symptomatic patients with melanoma brain metastasis (MBM) in the post-2015 cohort (n = 193) and systemic treatments given directly after diagnosis of MBM. (a) targeted therapies (TTs) or no TTs directly after diagnosis of MBM in patients with a positive BRAF V600E+/K-status (n = 108). (b) immune checkpoint inhibitors (ICIs) or no ICIs directly after diagnosis of MBM.
Table A6.
Median overall survival of the melanoma-molGPA classes of patients with melanoma brain metastasis (MBM) in the post-2015 cohort with available model input parameters (n = 268).
| Class | Number of Patients | % | Median OS | HR | p-Value |
|---|---|---|---|---|---|
| I (0–1) | 90 | 33.6 | 2.99 | ref. | <0.001 |
| II (1,5–2) | 116 | 43.3 | 6.87 | 0.627 [0.463–0.849] |
|
| III (2,5–3) | 47 | 17.5 | 24.51 | 0.290 [0.189–0.446] |
|
| IV (3,5–4) | 15 | 5.6 | 30.33 | 0.203 [0.097–0.423] |
|
| Unknown * | 10 |
* Patients where the score could not be determined (unknown) were excluded from percentage calculation and analysis.
Table A7.
A subgroup of 18 patients with melanoma brain metastasis (MBM) who switched from initial targeted therapies (TTs) to immune checkpoint inhibitors (ICIs) after MBM diagnosis.
| Variable | At Initiation of TTs n = 18 (100%) |
At Initiation of ICIs (TTs Switched to ICIs) n = 18 (100%) |
At First Progression 2 after Initiation of ICIs n = 18 (100%) |
|---|---|---|---|
| Symptomatic MBM 1 | |||
| Yes | 16 (88.9) | 2 (11.1) | 7 (38.9) |
| No | 2 (11.1) | 13 (72.2) | 4 (22.2) |
| Unknown | 0 (0) | 3 (16.7) | 7 (38.9) |
| Performance status 1 | |||
| KPS ≤70 | 6 (33.3) | 2 (11.1) | 6 (33.3) |
| KPS >70 | 12 (66.7) | 15 (83.3) | 4 (22.2) |
| Unknown | 0 (0) | 1 (5.6) | 8 (44.4) |
| LDH 1 | |||
| ≤ULN | 13 (72.2) | 10 (55.6) | 3 (16.7) |
| >ULN | 3 (16.7) | 5 (27.8) | 9 (69.2) |
| Unknown | 2 (11.1) | 1 (5.6) | 6 (33.3) |
| BM status 1 | |||
| New/progressive | 18 (100) | 2 (11.1) | 13 (72.2) |
| Stable/response | 0 (0) | 12 (66.7) | 3 (16.7) |
| Mixed response | 0 (0) | 3 (16.7) | 1 (5.6) |
| Unknown | 0 (0) | 1 (5.6) | 1 (5.6) |
| ECM status 1 | |||
| New/progressive | 15 (83.3) | 4 (22.2) | 4 (22.2) |
| Stable/response | 1 (5.6) | 8 (44.4) | 9 (50.0) |
| Mixed response | 0 (0) | 2 (11.1) | 3 (16.7) |
| No ECM | 2 (11.1) | 2 (11.1) | 1 (5.6) |
| Unknown | 0 (0) | 2 (11.1) | 1 (5.6) |
| Systemic treatment | |||
| Dabrafenib + trametinib |
8 (44.4) | NA | 7 (38.9) |
| Vemurafenib + cobimetinib |
7 (38.9) | NA | 2 (11.1) |
| Dabrafenib | 2 (11.1) | NA | 0 (0) |
| Vemurafenib | 1 (5.6) | NA | 0 (0) |
| Encorafenib + binimetinib |
0 (0) | NA | 3 (16.7) |
| Nivolumab + ipilimumab |
NA | 12 (66.7) | NA |
| Pembrolizumab | NA | 4 (22.2) | NA |
| Nivolumab | NA | 2 (11.1) | NA |
| No systemic treatment | NA | NA | 6 (33.3) |
1 Data were collected when found within +/− two weeks of initiation of TTs, initiation of ICIs, and first progression after start of ICIs, respectively. If not within that time frame, data were regarded as ‘unknown’. 2 First progression was defined as first imaging during treatment follow-up with clinician-assessed progression. Abbreviations: LDH: lactate dehydrogenase, ULN: upper limit of normal (247 U/L), BM: brain metastasis, ECM: extracranial metastasis.
Detailed Description Table A6: Switching from TT to ICI Treatment
Eighteen of four hundred and thirty (4.2%) patients of the total cohort, all with a diagnosis of melanoma brain metastasis (MBM) post-2015, initiated with targeted therapies (TTs) directly after diagnosis of MBM and later switched to immune checkpoint inhibitors (ICIs), after a generally improved clinical condition and/or improving disease status on imaging (Table A6). In 8 of these 18 (44.4%) patients, TTs were combined with surgical resection plus radiotherapy (SRT n = 2, WBRT n = 1), surgical resection alone (n = 2), and radiotherapy alone (SRT n = 2, WBRT n = 1). Median time between diagnosis of MBM and the start of TTs was 0.76 months. Patients switched to ICIs after a median time of 6.11 months (IQR 3.9–7.0) since the start of TTs. In all 18 patients, TTs were discontinued within one week prior to the start of ICIs.
In three (16.7%) patients, the switch from TTs to ICIs was successful since they had stable disease since ICI initiation until at least data cut-off. These three patients had a median survival time of 25.5 months (IQR 21.7–27.2) since ICI initiation.
Thirteen of eighteen (72.2%) patients had intracranial disease progression after ICI initiation, and four of eighteen (22.2%) patients had extracranial disease progression. Ultimately, 12 of 18 (66.7%) patients switched back from ICIs to TTs at a median time of 2.6 months (IQR 2.5–4.8) since ICI initiation. These 12 patients had a median OS of 11.6 months (IQR 6.5–25.5) since ICI initiation.
Three of eighteen (16.7%) patients progressed after ICI initiation, receiving no further treatment due to poor clinical condition: two patients died of progressive ECM (stable MBM) and one patient of combined progressive MBM and ECM. These three patients had a median OS of 11.9 months (IQR 7.6–16.3) since ICI initiation.
Figure A6.
Kaplan–Meier estimates for overall survival in patients with melanoma brain metastasis (MBM) in the pre-2015 cohort of patients with available model input parameters (n = 136) according to the different prognostic classes (I to IV) of melanoma-molGPA score.
Author Contributions
Conceptualization, S.H.A.E.D., J.L.M.J., M.J.v.d.B. and A.A.M.v.d.V.; data curation, E.L.v.d.M. and L.S.H.; formal analysis, S.H.A.E.D.; investigation, E.L.v.d.M. and L.S.H.; methodology, S.H.A.E.D. and E.O.-d.H.; project administration, M.J.v.d.B. and A.A.M.v.d.V.; software, S.H.A.E.D., E.L.v.d.M. and E.O.-d.H.; supervision, J.L.M.J., M.J.v.d.B. and A.A.M.v.d.V.; validation, S.H.A.E.D., J.L.M.J. and E.O.-d.H.; visualization, S.H.A.E.D.; writing—original draft, S.H.A.E.D.; writing—review and editing, J.L.M.J., C.S., A.J., M.J.A.d.J., J.W.S., E.O.-d.H., M.J.v.d.B. and A.A.M.v.d.V. All authors have read and agreed to the published version of the manuscript.
Institutional Review Board Statement
The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board (or Ethics Committee) of Erasmus MC (MEC-2020-0681, 4 February 2020).
Informed Consent Statement
Informed consent was waived due to the retrospective nature of the study.
Data Availability Statement
The data presented in this study are available within the article or as Appendix A.
Conflicts of Interest
A.A.M.v.d.V.: consultancy boards (fees paid to the institution) for BMS, MSD, Merck, Sanofi, Pierre Fabre, Roche, Novartis, Pfizer, Eisai, Ipsen. These funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. All other authors declare no conflict of interest.
Funding Statement
This research was funded by the Daniël den Hoed Foundation and the Erasmus MC Foundation.
Footnotes
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data presented in this study are available within the article or as Appendix A.