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

Abstract

Summary Background Dabrafenib plus trametinib (D+T) improves outcomes in BRAF V600–mutant metastatic melanoma without brain metastases; however, activity of D+T has not been studied in active melanoma brain metastases (MBM). Here, we report results from the phase 2 trial COMBI-MB. Our aim was to build upon the current body of evidence of targeted therapy in melanoma brain metastases through an evaluation of D+T in patients with BRAF V600–mutant melanoma brain metastases. Methods This ongoing open-label, phase 2 study (NCT02039947) evaluated dabrafenib 150 mg twice daily plus trametinib 2 mg once daily in four melanoma patient cohorts: (A) BRAF V600E, asymptomatic MBM, no prior local brain therapy; (B) BRAF V600E, asymptomatic MBM, prior local brain therapy; (C) BRAF V600D/K/R, asymptomatic MBM, with or without prior local brain therapy; and (D) BRAF V600D/E/K/R, symptomatic MBM, with or without prior local brain therapy. The primary objective was to assess intracranial response rate (IRR) in cohort A in the all-treated-subjects population. Secondary endpoints included IRR in cohorts B–D; extracranial and overall response rates; disease control rates; duration of intracranial, extracranial, and overall response; progression-free survival; overall survival; and safety. Findings A total of 125 patients were enrolled (A: n=76; B: n=16; C: n=16; D: n=17). At the data cutoff (November 28, 2016; median follow-up 8·5 months) investigator-assessed IRR was 58% (n=44/76) in cohort A. Intracranial response by investigator assessment was also achieved in 9 (56%) of 16 patients in cohort B, 7 (44%) of 16 patients in cohort C, and 10 (59%) of 17 patients in cohort D. Safety results were consistent with prior D+T studies, with 60 (48%) of 125 patients across cohorts experiencing grade 3/4 adverse events. The most common serious adverse events across cohorts were pyrexia (n=9/125; 7%) and ejection fraction decreased (n=5/125; 4%). Interpretation D+T was active with a manageable safety profile in patients with BRAF V600–mutant MBMs, but the median duration of response was relatively short. These results provide evidence of clinical benefit with D+T and support the need for additional research to further improve outcomes in patients with MBMs. Funding Novartis.

Tolerance and efficacy of BRAF plus MEK inhibition in patients with melanoma who previously have received programmed cell death protein 1‐based therapy

“…1,22 In contrast, the current retrospective study cohort represents a higher risk, "real-world" population of patients with melanoma: 80% had M1c or M1d disease and 55% had an elevated LDH at the initiation of targeted therapy. 23 It also is consistent with other retrospective analyses examining the efficacy of BRAF targeted therapy before or after anti-PD-1/ PD-L1 therapy. In the subset of patients who were BRAF-MEK-naive after treatment with PD-1, the median time receiving targeted therapy was only 5.8 months, and the median OS was 15.6 months.…”

BRAF-Targeted Therapy in the Treatment of BRAF -Mutant High-Grade Gliomas in Adults

“…For comparison, the intracranial response rate recently reported for combination dabrafenib/trametinib in patients with melanoma brain metastases was 56% and 58% in cohorts with or without prior local therapy, respectively. 25 Together, these results provide proof-of-principle evidence that BRAF-targeted therapies in adults with high-grade CNS malignancies should be explored further.…”

Drug delivery to melanoma brain metastases: Can current challenges lead to new opportunities?

“…Targeted therapies such as BRAF and MEK inhibitors, and immune checkpoint inhibitors such as anti-CTLA4 and anti-PD1 therapies have shown significant efficacy in patients with MBM, with some studies reporting that the intracranial responses were comparable to the extracranial responses (Gibney et al 2015; Margolin et al 2012; Di Giacomo, Margolin 2015; Cohen et al 2016; Davies et al 2017). While encouraging, the improvements in OS were limited, and certainly do not represent a possible cure for MBM patients.…”

“…The small molecule targeted therapies inhibiting MAP kinase signaling (e.g., BRAF inhibitors such as vemurafenib and dabrafenib, MEK inhibitors such as trametinib and cobimetinib) and the large molecule immune checkpoint inhibitors (e.g., cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors such as ipilimumab and programmed cell death receptor (PD-1) inhibitors such as nivolumab) have shown some improvements in overall survival (OS) and progression-free survival (PFS) by a few months in patients with melanoma brain metastases (MBM) (Dummer et al 2014; Rochet et al 2012; Long et al 2012; Falchook et al 2012; Spagnolo et al 2016; Davies et al 2017). While encouraging, such modest improvements in OS are far from satisfactory, and do not represent a high probability of cure for patients suffering from this lethal condition.…”

“…The results of some clinical studies suggest that the observed intracranial responses are poor compared to extracranial responses (Rochet et al 2012; Larkin et al 2014; Harding et al 2015; McArthur et al 2016; Spagnolo et al 2016). However, there are important observations from other trials that indicate the intracranial responses are comparable to the extracranial responses (Gibney et al 2015; Margolin et al 2012; Di Giacomo, Margolin 2015; Cohen et al 2016; Spagnolo et al 2016; Davies et al 2017), creating a broad spectrum of reported efficacy of these therapies in MBM. Lack of durable efficacy may be due to many factors, and in MBM it may be related to resistance mechanisms that include both inadequate delivery and specific brain microenvironment characteristics that each could lead to changes in expression of genetic drivers.…”