Practice Update | Onology

EDITOR’S PICKS 7

Dabrafenib plus trametinib in patients with BRAF(V600)-mutant melanoma brain metastases (COMBI-MB) The Lancet Oncology Take-home message

(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 BRAF(V600)-mutant melanoma without brain metastases, but the median dura- tion 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. Dabrafenib plus trametinib in patients with BRAF(V600)-mutant melanoma brain metas- tases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol 2017 Jun 02;[EPub Ahead of Print], MA Davies, P Saiag, C Robert, et al. that group of patients who have sympto- matic brain metastases at presentation. We know that a number of patients with brain metastases have symptomatic dis- ease at presentation and most of these patients are treated with some form of radiation. Because melanoma is a radi- ation-resistant disease, a focus on techniques such as stereotactic radiosur- gery is often employed in themanagement of these patients. The next set of clinical trials may want to focus on the treat- ment of patients with symptomatic brain metastases using a combination of either stereotactic radiosurgery with some form of targeted therapy or immune checkpoint blockade in these patients.

• This multicenter, multicohort, open-label, phase 2 trial was designed to evaluate the activity and safety of the dabrafenib plus trametinib combination in patients with BRAF V600-mutant melanoma brain metastases. The primary analysis included 76 patients with asymptomatic brain metastases and no prior local therapy. After a median of 8.5 months of follow-up, 58% patients had experienced an intracranial response. The toxicity profile was acceptable. • The authors conclude that the results of this trial support the safety and efficacy profile of this treatment combination, which is consistent with prior studies con- ducted in patients without the presence of intracranial disease. Further data are needed to improve outcomes in this particular subpopulation. Abstract

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 COMMENT By Manmeet Ahluwalia MD, FACP T raditionally, the treatment for brain metastases mostly focused on radi- ation-based approaches, including stereotactic radiosurgery. Recently, we have seen a number of trials that have looked at treating patients with brain metastases either with targeted therapies or immune checkpoint blockade. This is a phase II trial of a combination of dabrafenib and trametinib in four different cohorts of patients with BRAF(V600)-mutant mela- noma brainmetastases. As expected, most of patients had the V600E BRAF mutation, which is the most common type of BRAF mutation seen in patients with melanoma. The outcomes are impressive, with response rates of 58% in patients who were radiation-naïve and who had asymptomatic brain metastases. This is in comparison with the previously reported response rates of around 30% seen with dabrafenib alone in patients with asymptomatic brain metastases as reported in the BREAK-MB study. This trial supports the use of targeted ther- apy for oncogene-driven tumors such as BRAF-mutated tumors in patients who have asymptotic brain metastases. How- ever, what this trial does not address is

BACKGROUND Dabrafenib plus trametinib improves clinical outcomes in BRAF(V600)-mu- tant 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 aimwas to build on the current body of evidence of targeted therapy in melanoma brain metas- tases through an evaluation of dabrafenib plus trametinib in patients with BRAF(V600)-mutant melanoma brain metastases. METHODS This ongoing, multicentre, multico- hort, 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 metasta- ses enrolled from 32 hospitals and institutions in Europe, North America, and Australia: (A) BRAF(V600E)-positive, asymptomatic mela- noma brain metastases, with no previous local brain therapy, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; (B) BRAF(V600E)-positive, asympto- matic melanoma brain metastases, with previous local brain therapy, and an ECOG performance status of 0 or 1; (C) BRAF(V600D/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) BRAF(V600D/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. 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 8.5months (IQR 5.5–14.0), 44 (58%; 95%CI 46–69) of 76 patients in cohort A achieved an intracranial response. Intracranial response by investiga- tor assessment was also achieved in nine (56%;

Dr Ahluwalia is the Dean and Diane Miller Family Endowed Chair in Neuro- Oncology in the Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, where he subspecializes in treatment

of patients with brain tumors and brain metastases. He is also Associate Professor in the Department of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University.

VOL. 1 • NO. 2 • 2017