| General information |
| Database: | DB00658 |
| Objective: | Brain metastases are common in patients with metastatic melanoma and median overall survival from their diagnosis is typically 1722 weeks. they assessed dabrafenib in patients with Val600Glu or Val600Lys BRAFmutant melanoma metastatic to the brain. |
| Authors: | Long GV, et al |
| Title: | Dabrafenib in patients with Val600Glu or Val600Lys BRAFmutant melanoma metastatic to the brain (BREAKMB): a multicentre, openlabel, phase 2 trial. |
| Journal: | Lancet Oncol. |
| Year: | 2012 |
| PMID: | 23051966 |
| Trial Design |
| Clinical Trial Id: | NCT01266967 |
| Agent: | dabrafenib
|
| Target: | BRaf protooncogene serine/threonineprotein kinase
|
| Cancer Type: | melanoma |
| Cancer Subtype: | Val600Glu or Val600Lys BRAFmutant melanoma metastatic to the brain |
| Therapy Type: | mono |
| Therapeutic Combination Type: | NA |
| Therapeutic Combination Content: | NA |
| Study Type: | a multicentre, openlabel, phase II trial |
| Key Patients Feature: | they enrolledpatients with histologically confi rmed Val600Glu orVal600Lys BRAFmutant melanoma and asymptomaticbrain metastases. Tumour BRAFmutation status wasiden tified by Response Genetics (Los Angeles, CA, USA)by use of an allelespecifi c, investigationaluseonly PCRassay. Eligible patients had at least one measurable brainmetastasis between 5 mm and 40 mm in diameter, wereaged at least 18 years, and had an Eastern CooperativeOncology Group (ECOG) performance status of 0 or1 and adequate organ function. they excluded patientswho had leptomeningeal disease, primary duralmetastases, or a history of other clinically significantmalignancies in the 5 years before screening |
| Biomarker: | Val600Glu BRAFmutant |
| Biomark Analysis: | NA |
| Control Group Info: | single arm |
| Treatment Info: | Patients were split into two cohorts: those in cohort A had not received previous local treatment for brain metastases and those in cohort B had progressive brain metastases after previous local treatments. Patients received 150 mg oral dabrafenib twice a day until disease progression, death, or unacceptable adverse events. |
| Primary End Point: | the proportion of patients with Val600Glu BRAFmutant melanoma who achieved an overall intracranial response |
| Secondary End Point: | NA |
| Patients Number: | 172 |
| Trial Results |
| DLT_MTD: | NA |
| Objective Response Rate: | 29 (39.2%, 95% CI 28.051.2) of 74 patients with Val600Glu BRAFmutant melanoma in cohort A achieved an overall intracranial response, as did 20 (30.8%, 19.943.4) of 65 in cohort B. One (6.7%, 0.231.9) of 15 patients with Val600Lys BRAFmutant melanoma achieved an overall intracranial response in cohort A, as did four (22.2%, 6.447.6) of 18 such patients in cohort B. |
| Disease Control Rate: | 60% in cohort A; 58% in cohort B. |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | in cohort A: Val600Glu BRAF mutant vs Val600Lys BRAF mutant 16.1 (15.7-21.9) weeks vs 8.1 (3.1-16.1). in cohort B: Val600Glu BRAF mutant vs Val600Lys BRAF mutant 16.6 (15.9-23.7) weeks vs 15.9 (7.9-22.4). |
| Median OS A vs. C: | in cohort A: Val600Glu BRAF mutant vs Val600Lys BRAF mutant 33.1 (25.6-NR) weeks vs 16.3 (6.9-22.4). in cohort B: Val600Glu BRAF mutant vs Val600Lys BRAF mutant 31.4 (25.7-NR) weeks vs 21.9 (15.3-NR). |
| Adverse Event(agent arm): | Treatmentrelated adverse events of grade 3 or worse occurred in 38 (22%) patients. Eleven (6%) patients developed squamouscell carcinoma (five [6%] patients in cohort A, of whom one also had keratoacanthoma; six [7%] in cohort B). Four grade 4 treatmentrelated adverse events occurred in cohort A: one blood amylase increase, one convulsion, one lipase increase, and one neutropenia. Two grade 4 events occurred in cohort B: one agranulocytosis and one intracranial haemorrhage. 51 (30%) patients had a serious adverse event. The three most frequent serious adverse events were pyrexia (ten [6%] patients), intracranial haemorrhage (ten [6%]; one treatmentrelated), and squamouscell carcinoma (11 [6%]). |
| Conclusions: | Dabrafenib has activity and an acceptable safety profile in patients with Val600Glu BRAFmutant melanoma and brain metastases irrespective of whether they are untreated or have been previously treated but have progressed. |