Intracranial Response 58% With Dabrafenib/Trametinib Combination in BRAF V600 Melanoma

Michael A. Davies, MD, PhD

Dabrafenib (Tafinlar) plus trametinib (Mekinist) achieved an intracranial response (IR) rate of 58% in melanoma that has metastasized to the brain. The median duration of overall response (OR) of 6.5 months was generally shorter than that observed in melanoma patients without brain metastases. These initial findings from the phase II COMBI-MB trial were presented during an oral abstract session at the 2017 ASCO Annual Meeting.¹

“These results support the use of dabrafenib plus trametinib as a treatment option for melanoma patients with brain metastases,” said lead investigator Michael A. Davies, MD, PhD, associate professor and deputy chair of the Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center in Houston. “These results also showcase the critical need for continued research to improve outcomes in this advanced melanoma population.”

This multicenter, open-label phase II trial evaluated the activity and safety of dabrafenib plus trametinib in 4 patient cohorts (n = 125) from 32 institutions. Key eligibility criteria were cutaneous melanoma metastatic to the brain; positive test forBRAFV600E, K, or R mutations; and no more than 2 prior metastatic melanoma systemic treatments. Additionally, patients could not have previously been treated withBRAFinhibitors orMEKinhibitors. Unlike some other trials, corticosteroid use was permitted in the COMBI-MB trial at stable or decreasing doses in 3 of the 4 cohorts.

Patients in cohort A (n = 76) were asymptomatic for brain metastases, had an ECOG performance status of 0 or 1, and had not received prior local therapy. Cohorts B through D were considered exploratory due to their small sizes (n = 16, 16, and 17, respectively). All study patients received 150 mg dabrafenib twice daily plus 2 mg trametinib daily.

The primary endpoint was IR rate in cohort A (null hypothesis: IR rate of 35% or less) at data cutoff of November 28, 2016. Secondary endpoints were IR rates in cohorts B, C, and D, as well as extracranial response (ER) and OR rates. Duration of IR, ER, and OR; progression-free survival (PFS); OS; and safety were also secondary endpoints.

To date, of 76 patients in cohort A, 44 (58%) have died and 14 (18%) are still on study treatment, while 17 (22%) are in follow-up. The median follow-up is 8.5 months (5.5-14.0 interquartile range).

In cohort A, the overall IR was 44 (58%; 95% CI 46-69). A total of 59 patients in this cohort (78%) achieved IR disease control, whether via complete response (CR) (n = 3, 4%), partial response (PR) (n = 41, 54%), or stable disease (SD) (n = 15, 20%). Fourteen patients (18%) experienced progressive disease (PD) and 3 patients (4%) were not evaluable.

Regarding IR duration of response in cohort A, 29 of 44 patients (66%) experienced a survival event. The median response duration was 6.5 months (95% CI 4.9-10.3) and the 6-month rate was 63% (95% CI 45-76) in this cohort.

The overall ER in cohort A was 42 patients (55%; 95% CI 43-67). A total of 60 patients (79%) achieved extracranial disease control (CR plus PR plus SD). This cohort’s median duration of response was 10.2 months (95% CI of 5.8-not estimable). The 6-month rate was 69% (95% CI 50-82).

In cohort A, 44 patients (58%; 95% CI 46-69) showed OR. The cohort’s overall median duration of response was 6.5 months (95% CI 4.9-10.3) and the 6-month rate was 57% (95% CI 41-71).

PFS in the main study cohort was 5.6 months (95% CI 5.3-7.4). The patterns of disease progression in cohort A were that 36 patients (47%) had only intracranial progression, while 19 patients (25%) had both intracranial and extracranial progression. Seven patients (9%) experienced extracranial progression only and 14 patients (18%) had experienced no disease progression.

Davies also shared preliminary OS data for cohort A. Forty-four patients (58%) experienced a survival event and the median OS was 10.8 months (95% CI 8.7-19.6).

In cohort A, 62 patients (82%) experienced an AE related to study treatment. Of these, 35 patients (46%) experienced dose interruption, and 17 patients (22%) required dose reduction. Six patients (8%) discontinued treatment due to AEs.

Of the 76 cohort A patients, 26 (34%) experienced serious AEs; 11 patients (14%) experienced AEs that were related to study treatment. This cohort did include 1 fatal AE, an intracranial tumor hemorrhage that was determined to be unrelated to study treatment.

Common AEs were as expected, including fever, nausea, diarrhea and vomiting. Davies characterized headaches as being “a bit more common” than expected, with 27 cohort A patients (36%) reporting them. There was 1 grade 3/4 headache in this cohort.

Davies concluded by saying that clinical benefit and tolerability were “achievable” with dabrafenib plus trametinib in some patients withBRAFV600-mutant melanoma metastasized to the brain, noting that the primary endpoint of IR rate in the main study cohort was met.

Full findings to date from the COMBI-MB trial were published inLancet Oncologyon June 4, 2017.²

References:

1. Davies MA, Robert C, Long GV et al. COMBI-MB: A phase II study of combination dabrafenib (D) and trametinib (T) in patients (pts) with BRAFV600-mutant (mut) melanoma brain metastases (MBM).J Clin Oncol35, 2017 (suppl; abstr 9506).
2. Davies MA, Saiag P, Robert C, et al. Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial [published online June 4, 2017].Lancet Oncol.doi: 10.1016/S1470-2045(17)30429-1.