Efficacy of BRAF Inhibitors in Combination With Stereotactic Radiosurgery for the Treatment of Melanoma Brain Metastases: A Systematic Review and Meta-Analysis

Abstract

BackgroundBRAF inhibitors have improved the outcome for patients with BRAF mutant metastatic melanoma and have shown intracranial responses in melanoma brain metastases. Stereotactic radiosurgery (SRS) is being used as a local treatment for melanoma brain metastasis (MBM) with better local control and survival. We searched for studies comparing the combination of two treatments with SRS alone to detect any clinical evidence of synergism.Materials and MethodsPubMed, EMBASE, Medline, and Cochrane library were searched until May 2020 for studies with desired comparative outcomes. Outcomes of interest that were obtained for meta-analysis included survival as the primary, and local control as the secondary outcome.ResultsA total of eight studies involving 976 patients with MBM were selected. Survival was significantly improved for patients receiving BRAF inhibitor plus SRS in comparison to SRS alone as assessed from the time of SRS induction (SRS survival: hazard ratio [HR] 0.67 [0.58–0.79], p <0.00001), from the time of brain metastasis diagnosis (BM survival: HR 0.65 [0.54, 0.78], p < 0.00001), or from the time of primary diagnosis (PD survival: HR 0.74 [0.57–0.95], p = 0.02). Dual therapy was also associated with improved local control, indicating an additive effect of the two treatments (HR 0.53 [0.31–0.93], p=0.03). Intracranial hemorrhage was higher in patients receiving BRAF inhibitors plus SRS than in those receiving SRS alone (OR, 3.16 [1.43–6.96], p = 0.004).ConclusionsBRAF inhibitors in conjunction with SRS as local treatment appear to be efficacious. Local brain control and survival improved in patients with MBM receiving dual therapy. Safety assessment would need to be elucidated further as the incidence of intracranial hemorrhage was increased.

Improving Brain Metastases Outcomes Through Therapeutic Synergy Between Stereotactic Radiosurgery and Targeted Cancer Therapies

“…• PD-1 inhibitors improved survival, with more pronounced effect in patients not carrying the BRAF mutation • Among the patients treated with BRAFi, 10.4% developed intracerebral hematoma (ICH), in comparison to 3% of patients not treated with BRAFi (P = .03) melanoma brain metastases found that dual therapy of BRAF inhibitors in combination with SRS improved survival (P < 0.00001) and local control (P = 0.03), further supporting the literature of synergy between these two therapies (73).…”

“…This study also illustrating that the timing of systemic therapy with relation to SRS delivery may affect clinical outcomes. Lastly, a 2021 meta-analysis including 8 studies and involving 976 patients with melanoma brain metastases found that dual therapy of BRAF inhibitors in combination with SRS improved survival (P < 0.00001) and local control (P = 0.03), further supporting the literature of synergy between these two therapies ( 73 ).…”

Impact of Previous Local Treatment for Brain Metastases on Response to Molecular Targeted Therapy in BRAF-Mutant Melanoma Brain Metastasis: A Systematic Review and Meta-Analysis

“…In a secondary analysis of the KEYNOTE-001 phase 1 trial, the benefit for NSCLC patients with previous radiotherapy receiving pembrolizumab was evident in terms of PFS (HR 0.56 [95% CI: 0.34, 0.91], p = 0.019) and OS (HR 0.58 [95% CI: 0.36, 0.94], p = 0.026) (49). In a metaanalysis of BRAF-mutant MBM patients, those administered BRAF inhibitors concurrently or after SRS induction showed superior benefit than patients receiving prior SRS (HR 0.39 [95% CI: 0.24, 0.65], p = 0.0003) (50). Similarly, in a retrospective study, MBM patients receiving BRAF inhibitor after SRS were noted to have better survival compared to those receiving BRAF inhibitors concurrently (24 months vs. 10.1 months, p = 0.007) (51).…”

The role of systemic therapy in melanoma brain metastases: a narrative review

“…When it comes to the synergistic effect seen between BRAF inhibitors and SRS, the radiosensitizing effect of this drug class on melanoma cells plays an important role. This effect, originally seen in preclinical studies (131), has been validated in the clinical setting by pooled analyses which have shown a significant survival advantage with the combination of BRAFi and SRS compared to SRS alone (132). Combination therapy, however, carries the potential for increased toxicities such as the increased risk of radiation necrosis with ICI/SRS combination (133) and intracranial hemorrhage with BRAF inhibitor/SRS combination (132).…”