Clinical experience with combination BRAF/MEK inhibitors for melanoma with brain metastases: a real-life multicenter study

Abstract

BRAF and MEK kinase inhibitors can be highly effective in treating BRAF-mutant melanomas, but their safety and activity in patients with active/symptomatic brain metastases are unclear. We sought to shed light on this open clinical question. We conducted a multicenter retrospective study on real-life patients with melanoma and active brain metastases treated with combination BRAF/MEK inhibitors. A total of 65 patients were included (38 men and 27 women; median age: 49 years). Of them, 53 patients received dabrafenib/trametinib, 10 received vemurafenib/cobimetinib, one received encorafenib/binimetinib, and one received vemurafenib/trametinib. We did not observe any unexpected treatment-related safety signals in our cohort. Overall, 17 patients continued on therapy through the cutoff date. After initiation of therapy, steroid dose could be decreased in 22 of 33 patients (11 tapered off entirely), anticonvulsants were stopped in four of 21, and narcotics were stopped in four of 12. Median progression-free survival from the start of therapy was 5.3 months (95% confidence interval: 3.6-6.1), and median overall survival was 9.5 months (95% confidence interval: 7.7-13.5). A total of 20 patients were surviving at the cutoff date. Univariate analysis of age, sex, ulceration status, thickness, stage, location, or lactate dehydrogenase did not reveal significant predictors of progression-free survival or overall survival within our cohort, but multivariate analysis suggested that older age, lower risk location of original lesion, and nodular melanoma are poor prognostic indicators. Combination therapy with BRAF/MEK inhibitors is a viable treatment option for patients with BRAF-mutant melanoma and brain metastases, but further studies should help to define the optimal treatment approach in this population.

Intracranial antitumor activity with encorafenib plus binimetinib in patients with melanoma brain metastases: A case series

“…In addition, a recent prospective study evaluating the combination of dabrafenib plus trametinib in a cohort of patients with MBMs who had BRAF V600E mutations and no prior central nervous system–directed therapy or prior BRAF/MEK inhibitor reported a median progression‐free survival of 5.6 months and a median overall survival of 10.8 months . These results were also consistent with a recent retrospective case series in 65 patients with melanoma and active brain metastases treated with a combination of BRAF/MEK inhibitors, in which a median progression‐free survival of 5.3 months and a median overall survival of 9.5 months were observed . Notably for dabrafenib‐trametinib data, an intracranial progression‐free survival of 5.6 months is significantly shorter than the median progression‐free survival of 10.1 months reported in phase 3 studies, indicating a shorter duration of response and disease control for targeted therapy in the brain.…”

“…Even though the majority of the patients in this analysis had been previously treated with BRAF/MEK inhibitors, these data are largely consistent with the available literature for BRAF/MEK inhibitor treatment of brain metastases in patients with melanoma, none of which has included patients with prior BRAF/MEK inhibitor treatment. Intracranial response rates varying between 20% and 40% have been observed for dabrafenib and vemurafenib in exploratory studies . In addition, a recent prospective study evaluating the combination of dabrafenib plus trametinib in a cohort of patients with MBMs who had BRAF V600E mutations and no prior central nervous system–directed therapy or prior BRAF/MEK inhibitor reported a median progression‐free survival of 5.6 months and a median overall survival of 10.8 months .…”

“…Surgery, whole brain radiation therapy, and, more recently, stereotactic radiosurgery have been the accepted standard‐of‐care management of MBMs. Although surgery and radiation therapy continue to have a role in the management of symptomatic and large MBMs, recent prospective and retrospective clinical trials evaluating targeted therapies and checkpoint inhibitors have demonstrated significant clinical activity in patients with melanoma and active brain metastases . BRAF mutations, the most frequent genetic alterations, are observed in 50% of melanomas and may predispose patients to developing brain metastases .…”

What the Oncologist Needs From the Pathologist for Tyrosine Kinase Inhibitor Therapies

“…Some clinicians feel that IO approaches offer a better chance of a ''tail'' on the survival curve; however, long-term follow-up shows that a substantial number of BRAF-mutated patients remain alive at 5 years when treated with dual TKI therapy. 24 Patients with very bulky disease and a high tumor burden, especially if they are very symptomatic, will tend to respond very quickly to TKIs if they have a BRAF mutation. Patients with symptomatic brain metastases would be more likely to get TKIs rather than IO agents.…”

“…Patients with symptomatic brain metastases would be more likely to get TKIs rather than IO agents. 24 Thus, rapid availability of the BRAF results is necessary to know if that clinical option is available.…”