| General information |
| Database: | DB00188 |
| Objective: | The combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomizedphase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. |
| Authors: | Larkin J, et al |
| Title: | Combined vemurafenib and cobimetinib in BRAFmutated melanoma. |
| Journal: | N Engl J Med. |
| Year: | 2014 |
| PMID: | 25265494 |
| Trial Design |
| Clinical Trial Id: | NCT01689519 |
| Agent: | cobimetinib
|
| Target: | MEK
|
| Cancer Type: | melanoma |
| Cancer Subtype: | advanced BRAF(V600E/K) mut(+) melanoma |
| Therapy Type: | com |
| Therapeutic Combination Type: | 1 |
| Therapeutic Combination Content: | vemurafenib+cobimetinib |
| Study Type: | a randomizedphase III study |
| Key Patients Feature: | previously untreated unresectable locally advanced or metastatic BRAF V600 mutationpositive melanoma |
| Biomarker: | BRAF V600 mutated |
| Biomark Analysis: | NA |
| Control Group Info: | vemurafenib and placebo |
| Treatment Info: | pts receive vemurafenib and cobimetinib (combination group) or vemurafenib and placebo (control group). |
| Primary End Point: | investigatorassessed progression free survival. |
| Secondary End Point: | NA |
| Patients Number: | 495 |
| Trial Results |
| DLT_MTD: | NA |
| Objective Response Rate: | NA |
| Disease Control Rate: | The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P<0.001), including rates of complete response of 10% in the combination group and 4% in the control group. |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | The median progression free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval [CI], 0.39 to 0.68; P<0.001). |
| Median OS A vs. C: | PFS as assessed by independent review was similar to investigatorassessed progression free survival. Interim analyses of overall survival showed 9month survival rates of 81% (95% CI, 75 to 87) in the combination group and 73% (95% CI, 65 to 80) in the control group. |
| Adverse Event(agent arm): | Vemurafenib and cobimetinib was associated with a nonsignificantly higher incidence of adverse events of grade 3 or higher, as compared with vemurafenib and placebo (65% vs. 59%), and there was no significant difference in the rate of studydrug discontinuation. The number of secondary cutaneous cancers decreased with the combination therapy. |
| Conclusions: | The addition of cobimetinib to vemurafenib was associated with a significant improvement in progression free survival among patients with BRAF V600mutated metastatic melanoma, at the cost of some increase in toxicity. |