Elsevier

The Lancet Oncology

Volume 18, Issue 7, July 2017, Pages 863-873
The Lancet Oncology

Articles
Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial

https://doi.org/10.1016/S1470-2045(17)30429-1Get rights and content

Summary

Background

Dabrafenib plus trametinib improves clinical outcomes in BRAFV600-mutant metastatic melanoma without brain metastases; however, the activity of dabrafenib plus trametinib has not been studied in active melanoma brain metastases. Here, we report results from the phase 2 COMBI-MB trial. Our aim was to build on the current body of evidence of targeted therapy in melanoma brain metastases through an evaluation of dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases.

Methods

This ongoing, multicentre, multicohort, open-label, phase 2 study evaluated oral dabrafenib (150 mg twice per day) plus oral trametinib (2 mg once per day) in four patient cohorts with melanoma brain metastases enrolled from 32 hospitals and institutions in Europe, North America, and Australia: (A) BRAFV600E-positive, asymptomatic melanoma brain metastases, with no previous local brain therapy, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; (B) BRAFV600E-positive, asymptomatic melanoma brain metastases, with previous local brain therapy, and an ECOG performance status of 0 or 1; (C) BRAFV600D/K/R-positive, asymptomatic melanoma brain metastases, with or without previous local brain therapy, and an ECOG performance status of 0 or 1; and (D) BRAFV600D/E/K/R-positive, symptomatic melanoma brain metastases, with or without previous local brain therapy, and an ECOG performance status of 0, 1, or 2. The primary endpoint was investigator-assessed intracranial response in cohort A in the all-treated-patients population. Secondary endpoints included intracranial response in cohorts B, C, and D. This study is registered with ClinicalTrials.gov, number NCT02039947.

Findings

Between Feb 28, 2014, and Aug 5, 2016, 125 patients were enrolled in the study: 76 patients in cohort A; 16 patients in cohort B; 16 patients in cohort C; and 17 patients in cohort D. At the data cutoff (Nov 28, 2016) after a median follow-up of 8·5 months (IQR 5·5–14·0), 44 (58%; 95% CI 46–69) of 76 patients in cohort A achieved an intracranial response. Intracranial response by investigator assessment was also achieved in nine (56%; 95% CI 30–80) of 16 patients in cohort B, seven (44%; 20–70) of 16 patients in cohort C, and ten (59%; 33–82) of 17 patients in cohort D. The most common serious adverse events related to study treatment were pyrexia for dabrafenib (eight [6%] of 125 patients) and decreased ejection fraction (five [4%]) for trametinib. The most common grade 3 or worse adverse events, regardless of study drug relationship, were pyrexia (four [3%] of 125) and headache (three [2%]).

Interpretation

Dabrafenib plus trametinib was active with a manageable safety profile in this melanoma population that was consistent with previous dabrafenib plus trametinib studies in patients with BRAFV600-mutant melanoma without brain metastases, but the median duration of response was relatively short. These results provide evidence of clinical benefit with dabrafenib plus trametinib and support the need for additional research to further improve outcomes in patients with melanoma brain metastases.

Funding

Novartis.

Introduction

Among common cancers, metastatic melanoma has the highest risk of spreading to the CNS.1, 2 The development of brain metastases in patients with melanoma has been observed at an incidence of up to 43% in clinical studies and 75% in autopsy studies.2, 3 Historically, brain metastases in patients with metastatic melanoma have been associated with poor overall survival (median 4–5 months), and the poorest outcomes are observed in those presenting with neurological symptoms and leptomeningeal involvement.4, 5 Various targeted therapies (ie, BRAF and MEK inhibitors) and checkpoint inhibitor immunotherapies (ie, anti-CTLA-4 and anti-PD-1 antibodies, alone or combined) available for the treatment of BRAFV600-mutant melanoma have significantly improved clinical outcomes in patients with metastatic disease.6, 7, 8, 9, 10 However, patients with active brain metastases have typically been excluded from large trials to date, and treatments specifically indicated for the treatment of melanoma brain metastases remain an unmet need.

In the phase 2 BREAK-MB trial,11 dabrafenib monotherapy showed clinical activity and had a manageable safety profile in patients with BRAFV600E-mutant melanoma brain metastases (n=139), including patients with or without previous local treatment for brain metastases. In patients with BRAFV600E-mutant melanoma without previous local treatment (n=74), 39% of patients achieved an overall intracranial response and 38% achieved an overall response by investigator assessment. In patients with BRAFV600E-mutant melanoma with previous local treatment (n=65), 31% of patients achieved both an investigator-assessed overall intracranial response and an overall response. In both BRAFV600E groups, 6-month overall survival was 61%. Fewer patients with BRAFV600K-mutant disease included in the study (n=33) had a response, regardless of whether they had received previous local treatment (overall intracranial response was achieved in 22% of patients who did not have previous treatment and 7% of patients who had previous treatment). Small cohorts of molecularly unselected patients with asymptomatic brain metastases have also been shown to have a response to ipilimumab (16% of 51 patients achieved a brain metastasis response) and pembrolizumab (22% of 18 patients achieved a brain metastasis response) in prospective clinical trials.12, 13

Research in context

Evidence before this study

We searched PubMed for clinical studies published up to March 7, 2017, with the search terms “BRAF”, “melanoma”, and “brain metastases”, and identified 144 articles, of which four were primary analyses of phase 1 or 2 clinical trials of BRAF inhibitor regimens in patients with BRAFV600-mutant melanoma brain metastases. BRAF inhibitor monotherapy has previously been shown to have clinical activity and tolerability in patients with BRAF-mutant melanoma who developed metastases in the brain. Although the BRAF and MEK inhibitor combination therapy has been shown to be superior to BRAF inhibitor monotherapy in patients with BRAFV600-mutant metastatic melanoma without brain metastases, the clinical effect of this regimen on melanoma brain metastases has not been characterised.

Added value of this study

Intracranial outcomes showed that dabrafenib plus trametinib was active in patients with BRAFV600-mutant melanoma brain metastases and the primary study endpoint was met; however, responses did not last as long as those previously observed for the combination in patients with melanoma without brain metastases. No unexpected safety issues were observed with dabrafenib plus trametinib in this setting. Our findings represent the first report, to our knowledge, of a phase 2 trial evaluating BRAF and MEK inhibitor combination therapy in patients with melanoma brain metastases and provide evidence that clinical benefit and tolerability are achievable with dabrafenib plus trametinib in a subset of patients with BRAFV600-mutant melanoma that has metastasised to the brain.

Implications of all the available evidence

Continued follow-up in this study is necessary to determine the full effect of dabrafenib plus trametinib on overall survival in this setting; however, these preliminary results support the use of this targeted therapy combination as a treatment option for these patients, in whom effective treatments remain a critical unmet medical need.

The combination of dabrafenib and trametinib has been shown to improve progression-free survival and overall survival compared with that seen for BRAF inhibitor monotherapy, with a manageable safety profile in phase 2 and phase 3 trials of patients with BRAFV600E/K-mutant stage IIIC unresectable or stage IV metastatic melanoma without brain metastases.6, 7, 14, 15, 16, 17, 18, 19 However, this combination targeted therapy has not been previously evaluated prospectively in patients with BRAFV600-mutant melanoma brain metastases.

Here, we report the primary analysis of the phase 2 COMBI-MB trial evaluating dabrafenib plus trametinib in patients with active BRAFV600-mutant melanoma brain metastases.

Section snippets

Study design and patients

This multicentre, open-label, multicohort, phase 2 trial evaluated the activity and safety of dabrafenib plus trametinib in four patient cohorts enrolled from 32 hospitals and institutions in Europe, North America, and Australia (appendix p 9): cohort A included patients with BRAFV600E-mutant, asymptomatic melanoma brain metastases, without previous local brain-directed therapy, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; cohort B included patients with BRAF

Results

Between Feb 28, 2014, and Aug 5, 2016, 125 patients were enrolled, of whom 76 were in cohort A, 16 were in cohort B, 16 were in cohort C, and 17 were in cohort D (figure 1). Lactate dehydrogenase concentrations were elevated (higher than the upper limit of normal) in 28 (37%) of 76 patients in cohort A, three (19%) of 16 patients in cohort B, six (38%) of 16 patients in cohort C, and five (29%) of 17 patients in cohort D, and extracranial metastases were present in 68 (89%) of 76 patients in

Discussion

This primary analysis of the COMBI-MB study, representing the first report, to our knowledge, of a phase 2 trial evaluating BRAF and MEK inhibitor combination therapy in patients with BRAFV600E-mutant melanoma brain metastases, provides evidence of activity of dabrafenib plus trametinib in patients with active melanoma brain metastases. The primary endpoint of investigator-assessed intracranial response in cohort A was met. Intracranial responses were also observed in cohorts B, C, and D;

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