COMBI-d
A Study Comparing Trametinib and Dabrafenib Combination Therapy to Dabrafenib Monotherapy in Subjects With BRAF-mutant Melanoma
Phase 3N = 423NCT01584648
- Population
- Previously untreated unresectable stage IIIC or stage IV melanoma with a BRAF V600E or V600K mutation
- Design
- Double-blind randomised phase 3 trial of dabrafenib 150 mg twice daily plus trametinib 2 mg once daily versus dabrafenib plus placebo. Primary end point progression-free survival; overall survival, response rate, response duration and safety were secondary. A preplanned interim overall survival analysis was reported with the primary paper; overall survival was reported in the Lancet in 2015.
- Primary endpoint
- PFS
- Arms
- Dabrafenib plus trametinib (experimental, n = 211): Dabrafenib 150 mg orally twice daily plus trametinib 2 mg orally once daily
- Dabrafenib plus placebo (control, n = 212): Dabrafenib 150 mg orally twice daily plus placebo
- People
- Long GV, senior author Flaherty K
PFSHR 0.75 (95% CI 0.57–0.99)Δ median PFS+0.5 monthsΔ ORR+16 pointsOSHR 0.63 (95% CI 0.42–0.94)Δ 6-month OS+8 pointsOSHR 0.71 (95% CI 0.55–0.92)
Show the numbers
| Endpoint | Analysis | Dabrafenib plus trametinib | Dabrafenib plus placebo | Effect |
|---|---|---|---|---|
| PFSRandomised population as described in the abstract (analysis population not stated there) | primaryLong 2014 | median 9.3 months | median 8.8 months | HR 0.75 (95% CI 0.57–0.99)P=0.03 |
| ORRRandomised population as described in the abstract (analysis population not stated there) | primaryLong 2014 | 67% | 51% | P=0.002 |
| OSRandomised population as described in the abstract (analysis population not stated there) | interimLong 2014 | 93% at 6 mo | 85% at 6 mo | HR 0.63 (95% CI 0.42–0.94)P=0.02Preplanned interim overall survival analysis. The abstract states that a specified efficacy-stopping boundary (two-sided P=0.00028) was not crossed. |
| OSRandomised patients (423: 211 and 212) as described in the abstract | finalLong 2015 | median 25.1 months; 74% at 12 mo; 51% at 2 y | median 18.7 months (15.2–23.7); 68% at 12 mo; 42% at 2 y | HR 0.71 (95% CI 0.55–0.92)P=0.0107Overall survival was a secondary end point. The 95% confidence interval of the combination median is printed as 19.2 to not reached and is not recorded as a numeric interval. |
| PFSRandomised patients (423: 211 and 212) as described in the abstract | finalLong 2015 | median 11 months (8.0–13.9) | median 8.8 months (5.9–9.3) | HR 0.67 (95% CI 0.53–0.84)P=0.0004Based on 301 events; the abstract states the P value is unadjusted for multiple testing. |
| Endpoint | Analysis | Dabrafenib plus trametinib | Dabrafenib plus placebo | Effect |
|---|---|---|---|---|
| PFSRandomised population as described in the abstract (analysis population not stated there) | primaryLong 2014 | median 9.3 months | median 8.8 months | HR 0.75 (95% CI 0.57–0.99)P=0.03 |
| ORRRandomised population as described in the abstract (analysis population not stated there) | primaryLong 2014 | 67% | 51% | P=0.002 |
| OSRandomised population as described in the abstract (analysis population not stated there) | interimLong 2014 | 93% at 6 mo | 85% at 6 mo | HR 0.63 (95% CI 0.42–0.94)P=0.02Preplanned interim overall survival analysis. The abstract states that a specified efficacy-stopping boundary (two-sided P=0.00028) was not crossed. |
| OSRandomised patients (423: 211 and 212) as described in the abstract | finalLong 2015 | median 25.1 months; 74% at 12 mo; 51% at 2 y | median 18.7 months (15.2–23.7); 68% at 12 mo; 42% at 2 y | HR 0.71 (95% CI 0.55–0.92)P=0.0107Overall survival was a secondary end point. The 95% confidence interval of the combination median is printed as 19.2 to not reached and is not recorded as a numeric interval. |
| PFSRandomised patients (423: 211 and 212) as described in the abstract | finalLong 2015 | median 11 months (8.0–13.9) | median 8.8 months (5.9–9.3) | HR 0.67 (95% CI 0.53–0.84)P=0.0004Based on 301 events; the abstract states the P value is unadjusted for multiple testing. |
Data table
| Endpoint | HR | 95% CI |
|---|---|---|
| PFS | 0.75 | 0.57–0.99 |
| OS | 0.63 | 0.42–0.94 |
| OS | 0.71 | 0.55–0.92 |
| PFS | 0.67 | 0.53–0.84 |
- Dabrafenib plus trametinib (experimental)
- Dabrafenib plus placebo (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | Dabrafenib plus trametinib | Dabrafenib plus placebo |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 6 | 63.9% | 62.3% |
| 12 | 40.9% | 38.9% |
| 17 | 28.2% | 26.2% |
| 23 | 18.0% | 16.3% |
- Dabrafenib plus trametinib (experimental)
- Dabrafenib plus placebo (control)
Data table (modelled values)
| Months | Dabrafenib plus trametinib | Dabrafenib plus placebo |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 6 | 86.8% | 83.6% |
| 13 | 72.0% | 65.6% |
| 19 | 60.4% | 52.5% |
| 26 | 51.0% | 42.0% |
Appears in
Sources
Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371(20):1877-88.
Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015;386(9992):444-51.