| General information |
| Database: | DB00189 |
| Objective: | Resistance to therapy with BRAF kinase inhibitors is associated with reactivation of the mitogenactivated protein kinase (MAPK) pathway. To address this problem, they conducted a phase 1 and 2 trial of combined treatment with dabrafenib, a selective BRAF inhibitor, and trametinib, a selective MAPK kinase (MEK) inhibitor. |
| Authors: | Flaherty KT |
| Title: | Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. |
| Journal: | N Engl J Med |
| Year: | 2012 |
| PMID: | 23020132 |
| Trial Design |
| Clinical Trial Id: | NCT01072175 |
| Agent: | dabrafenib and trametinib
|
| Target: | BRAF¡¢MEK
|
| Cancer Type: | melanoma |
| Cancer Subtype: | advanced BRAF(V600E/K) mut(+) melanoma |
| Therapy Type: | com |
| Therapeutic Combination Type: | 1 |
| Therapeutic Combination Content: | dabrafenib + trametinib |
| Study Type: | a openlabelphase I and II study |
| Key Patients Feature: | patients with metastatic melanoma and BRAF V600 mutations |
| Biomarker: | BRAF V600 mutations |
| Biomark Analysis: | NA |
| Control Group Info: | dabrafenib monotherapy |
| Treatment Info: | They evaluated the PK activity and safety of oral dabrafenib (75 or 150 mg twice daily) and trametinib (1, 1.5, or 2 mg daily) in 85 patients and then randomly assigned 162 patients to receive combination therapy with dabrafenib (150 mg) plus trametinib (1 or 2 mg) or dabrafenib monotherapy |
| Primary End Point: | the incidence of cutaneous squamouscell carcinoma, survival free of melanoma progression, and response. |
| Secondary End Point: | overall survival and pharmacokinetic activity |
| Patients Number: | 247 |
| Trial Results |
| DLT_MTD: | Doselimiting toxic effects were infrequently observed in patients receiving combination therapy with 150 mg of dabrafenib and 2 mg of trametinib (combination 150/2). |
| Objective Response Rate: | The rate of complete or partial response with combination 150/2 therapy was 76%, as compared with 54% with monotherapy (P=0.03). |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | Median progression free survival in the combination 150/2 group was 9.4 months, as compared with 5.8 months in the monotherapy group (hazard ratio for progression or death, 0.39; 95% confidence interval, 0.25 to 0.62; P<0.001). |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | Cutaneous squamouscell carcinoma was seen in 7% of patients receiving combination 150/2 and in 19% receiving monotherapy (P=0.09), whereas pyrexia was more common in the combination 150/2 group than in the monotherapy group (71% vs. 26%). |
| Conclusions: | Dabrafenib and trametinib they were safely combined at full monotherapy doses. The rate of pyrexia was increased with combination therapy, whereas the rate of proliferative skin lesions was nonsignificantly reduced. progression free survival was significantly improved. |