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. 2023 Feb 25;15(5):1461.
doi: 10.3390/cancers15051461.

Impact of Novel Treatments in Patients with Melanoma Brain Metastasis: Real-World Data

Sophie H A E Derks  1   2   3 , Joost L M Jongen  1 , Edgar L van der Meer  1 , Li Shen Ho  1 , Cleo Slagter  4 , Arjen Joosse  2 , Maja J A de Jonge  2 , Joost W Schouten  5 , Esther Oomen-de Hoop  2 , Martin J van den Bent  1 , Astrid A M van der Veldt  2   3
Affiliations

Impact of Novel Treatments in Patients with Melanoma Brain Metastasis: Real-World Data

Sophie H A E Derks et al. Cancers (Basel). .

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: BRAF/MEK inhibitors; brain neoplasms/metastasis; immune checkpoint inhibitors; immunotherapy; melanoma; molecular targeted therapy; radiotherapy; survival.

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Conflict of interest statement

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.

Figures

Figure A1
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.
Figure A2
Figure A2
Number of patients referred each year to the Erasmus MC with newly diagnosed melanoma brain metastasis.
Figure A3
Figure A3
Number of started treatments each year at the Erasmus MC, at any time after diagnosis of melanoma brain metastasis.
Figure A4
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 A4
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
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.
Figure A5
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.
Figure A6
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.
Figure 1
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
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.
Figure 3
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.
Figure 4
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.
Figure 4
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.
Figure 5
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.
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