Frequent brain metastases during treatment with BRAF/MEK inhibitors: A retrospective single institutional study

Abstract

Recent clinical trials revealed that both immune checkpoint inhibitors (ICI) and BRAF/MEK inhibitors significantly prolonged survival in melanoma patients when used for both advanced stage disease and postoperative adjuvant therapy. Although BRAF/MEK inhibitors are associated with a higher objective response rate than ICI, most patients relapse during treatment. However, progression patterns during treatment with BRAF/MEK inhibitors have not been extensively investigated. Here, we retrospectively collected the data of melanoma patients initially treated with BRAF/MEK inhibitors or anti-programmed death 1 (PD-1) antibody monotherapy at the University of Tsukuba Hospital and compared their results. The v 2-test revealed that frequency of brain metastasis (BM) development was significantly higher in cases treated with BRAF/MEK inhibitors compared with those with anti-PD-1 antibody monotherapy. In addition, BM-free survival in cases treated with BRAF/MEK inhibitors was significantly shorter than those treated with anti-PD-1 antibody monotherapy. Our results indicate that BM development during treatment with BRAF/MEK inhibitors may be more frequent than anti-PD-1 antibody monotherapy, even though the extracranial metastases are well controlled. Therefore, we recommend frequent brain examinations during treatment with BRAF/MEK inhibitors to detect BM at an early stage and to promptly administrate ICI with local radiation therapy.

Burden and Risk Factors of Brain Metastases in Melanoma: A Systematic Literature Review

“…Forty-six full-text articles with the outcomes of interest (e.g., proportion and risk factors of MBM) were evaluated, and seven were excluded due to duplication or presenting results on the same population. A total of 39 articles were included in this SLR, and 38 full-text articles were extracted for the proportion results [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. Among of them, 29 studies included patients with MBM at diagnosis (Stage IV) ( Supplementary Table S1 ) and 9 studies reported MBM proportion with brain metastasis occurring after diagnosis ( Supplementary Table S2 ).…”

Cures with B-Raf inhibitors as single agents in metastatic B-Raf mutated melanoma: Curb your enthusiasm?

“…As a result, frequent brain imaging during treatment with B-raf/MEK inhibitors seems warranted in order to detect early brain involvement and to promptly administer an immune checkpoint inhibitor in combination with local radiation therapy or surgery. 8 Our case may suggest that it might somewhat farfetched to proclaim that cures and long-term survival can be achieved with single agents B-Raf inhibitors in patients with metastatic melanoma. We believe that long-term responders to B-Raf inhibitors with or without MEK inhibition should be monitored very closely clinico-radiologically for a potential relapse.…”

“…In this setting, the disease is often refractory to second-line agents, and leads almost unequivocally to dismal outcomes. In addition, Nakamura et al 8 showed that brain metastasis-free survival in patients treated with B-Raf/MEK inhibitors was significantly shorter than in those treated with anti-PD1 antibody monotherapy. This suggests that development of brain metastases during treatment with B-raf/MEK inhibitors might be more frequent than during anti-PD1 antibody monotherapy.…”

“…As a result, frequent brain imaging during treatment with B-raf/MEK inhibitors seems warranted in order to detect early brain involvement and to promptly administer an immune checkpoint inhibitor in combination with local radiation therapy or surgery. 8…”

BRAF Mutations in Melanoma: Biological Aspects, Therapeutic Implications, and Circulating Biomarkers

“…Therefore, the efficacy of BRAFi/MEKi therapy or immunotherapy may differ between Western and Eastern melanoma patients [ 94 ]. These findings are of particular relevance, for example, for the management of melanoma brain metastases, since it was observed that the development of metastases was significantly higher in patients treated with BRAFi/MEKi than in those treated with immune checkpoint inhibitors [ 95 ]. Hence, the use of immunotherapy should be considered as a first-line therapy for brain metastases [ 96 ].…”