Efficacy, safety and factors associated with disease progression in patients with unresectable (stage III) or distant metastatic (stage IV) BRAF V600-mutant melanoma: An open label, non-randomized, phase IIIb study of trametinib in combination with dabrafenib

Abstract

Background: BRAF and MEK inhibitors combination, including dabrafenib (D) and trametinib (T) have transformed the treatment of BRAF V600-mutant advanced melanoma patients, including patients with brain metastasis (BM). In a large phase IIIb, singlearm, open-label, multicenter French study, we assessed safety, response to treatment, progression-free survival (PFS) and factors associated with progression, and stratified the population into risk groups. Methods: Patients with unresectable, advanced, BRAF V600-mutant melanoma were included, including those with the presence of BM, Eastern Cooperative Oncology Group Performance Status (ECOG PS) 2, elevated lactate dehydrogenase (LDH) or previous melanoma treatments. Responses were determined locally, without central review. PFS was estimated using the KaplaneMeier analysis and modelled with multivariate Cox model. Risk subgroups were identified using a regression tree analysis. Results: Between March 2015 and November 2016, 856 patients received at least one D þ T dose. Overall, 92% had stage IV melanoma, 38% ECOG PS 1, 32% BM and 37.5% elevated LDH. Median PFS was 8.02 months (95% confidence interval [CI] 7.33e8.77). Significant factors associated with lower PFS were ECOG PS 1, elevated LDH, 3 metastatic sites and presence of BM. Patients with <3 metastatic sites, ECOG Z 0 and no BM had the highest probability of PFS at 6 months (83%, 95% CI 76e87) and 12 months (56%, 95% CI 47 e64), respectively. Conclusions: This is the largest prospective study in advanced BRAF V600-mutant melanoma patients treated with D þ T, conducted in conditions close to 'real-world practice'. We confirm previous findings that LDH, ECOG PS and 3 metastatic sites are associated with shorter PFS, but the real-world setting introduces BM as a major prognostic factor.

Hemoglobin and neutrophil levels stratified according to International Metastatic Renal Cell Carcinoma Database Consortium risk predict the effectiveness of ipilimumab plus nivolumab in patients with advanced metastatic renal cell carcinoma

“…In the first step, patients were divided into two subgroups according to the largest difference in PFS. In the next step, the process was repeated until either subgroup included at least 10% of all treated patients or no additional splitting was possible 19 . Internal validation was performed by bootstrapping in R (The R Foundation for Statistical Computing, Vienna, Austria) using 2000 resamplings 20 .…”

“…In the next step, the process was repeated until either subgroup included at least 10% of all treated patients or no additional splitting was possible. 19 Internal validation was performed by bootstrapping in R (The R Foundation for Statistical Computing, Vienna, Austria) using 2000 resamplings. 20 Statistical analyses were performed using GraphPad Prism 9 software, R, and EZR (Saitama Medical Center, Jichi Medical University) 21…”

A Unique Case of Intracranial Amelanotic Melanoma with BRAF V600E Mutation Successfully Treated via Molecular-targeted Therapy

“…When assessing the efficacy of dabrafenib and trametinib for treating 125 cases of BRAFmutant melanoma, results from the phase-2 COMBI-MB trial revealed a shorter median progression-free survival (4.2-7.2 months) and duration of clinical response (4.5-8.3 months) for patients with brain metastasis as opposed to those in patients without brain metastasis. 4,8) However, this trial did not report the potential differences between melanotic and amelanotic melanomas. Furthermore, the correct interpretation of results from this trial was complicated by the occurrence of toxic side effects, which led to the interruption of treatment in 50% of the patients and discontinuation in 10% of the patients.…”

“…3) Thus, there is a need for the development of better treatments for the improvement of outcomes in patients with brain metastasis caused by melanoma. 4) Although both primary and metastatic melanoma generally display black coloration, reflecting the presence of melanin pigment, lack of pigmentation as a primary morphological feature cannot be exploited to completely rule NMC Case Report Journal Vol. 10,2023 out the presence of melanoma.…”

“… 3 ) Thus, there is a need for the development of better treatments for the improvement of outcomes in patients with brain metastasis caused by melanoma. 4 )…”