| |
BREAK-3 [22,64] |
METRIC [60] |
BRIM-3 [23,63] |
CA184-024 [24] |
EORTC 18032 [25] |
| Comparison |
Dabrafenib 150 mg bid vs DTIC 1000 mg/m2 q3w |
Trametinib 2 mg qdvs chemotherapy (DTIC 1000 mg/m2 q3w or paclitaxel) |
Vemurafenib 960 mg bid vs DTIC 1000 mg/m2 q3w |
DTIC 850 mg/m2 q3w+ipilimumab 10 mg/kg q3w for 4 cyclesvsDTIC 850 mg/m2 q3w |
Temozolomide 150 mg/m2 od on days 1 to 7 q2w vs DTIC 1000 mg/m2q3w |
| Design |
Multinational, multicenter, open-label, phase III RCT |
Multinational, multicenter, open-label, phase III RCT |
Multinational, multicenter, open-label, phase III RCT |
Multinational, multicenter, double-blind, phase III RCT |
Multinational, multicenter, open-label, phase III RCT |
| Number of patients |
250 (dabrafenib: 187; DTIC: 63) |
322 (trametinib: 214; chemotherapy: 108) |
675 (vemurafenib: 337; DTIC: 338) |
502 (ipilimumab+DTIC: 250; DTIC: 252) |
859 (temozolomide: 429; DTIC: 430) |
| Inclusion criteria |
• Patients aged ≥ 18 years, histologically confirmed advanced (unresectable stage III) or metastatic (stage IV) measurable disease according to RECIST Version 1.1
• BRAF V600E mutation–positive melanoma
• ECOG PS 0-1 |
• Patients with histologically confirmed cutaneous advanced or metastatic melanoma (stage IIIC or stage IV)
• BRAF V600E/K mutation–positive tumor
• Subjects may have received no prior treatment or up to one prior regimen of chemotherapy for advanced or metastatic melanoma with measurable disease according to RECIST Version 1.1
• ECOG PS 0-1 |
• Patients aged ≥ 18 years, with unresectable, stage IIIC or stage IV melanoma
• Positive for the BRAF V600E mutation on real-time polymerase chain reaction assay
• ECOG PS 0-1
• Life expectancy of ≥ 3 months
• Adequate hematologic, hepatic, and renal function |
• Patients aged ≥ 18 years with previously untreated stage III (unresectable) or stage IV melanoma with measurable lesions
• ECOG PS 0-1
• Life expectancy ≥ 16 weeks
• Baseline serum lactate dehydrogenase level did not affect eligibility |
• Patients aged ≥ 18 years with histologically confirmed, surgically incurable, or unresectable AJCC stage IV melanoma
• WHO or ECOG status 0–1
• Adequate hematologic, renal, and hepatic function
• Previous adjuvant cytokine or vaccine therapy for resected stage I to III disease, palliative surgery for distant metastatic disease, previous vaccine therapy (other than cytokine) for stage IV disease, and prior cytokine or chemotherapy for local–regional disease by isolated limb perfusion therapy
• Recovered from any effects of major surgery or previous adjuvant treatment
• Patients with cutaneous and mucosal melanoma allowed |
| Data cuts
available/used |
December 2011 (primary analysis)
June 2012 (updated analyses)
December 2012 (updated analyses for OS and AEs only) |
October 2011 (primary analysis) |
December 2010 (primary analysis)
February 2012 (updated analyses for PFS and OS) |
Unknown |
Unknown |
| Primary study outcome(s) |
PFS |
PFS |
PFS and OS |
OS |
OS |
| Median age, years (range) |
Dabrafenib53.0 (22–93);
DTIC 50.0 (21–82) |
Trametinib54.5 (23–85);
Chemotherapy 54.0 (21–77) |
Vemurafenib56.0 (21–86);
DTIC 52.0 (17–86) |
Ipilimumab+DTIC 57.5a; DTIC 56.4a |
- |
| Males, % |
59.6 |
53.7 |
56.4 |
60.0 |
58.6 |
| ECOG, % |
| 0 |
67.2 |
63.7 |
68.0 |
70.9 |
69.4 |
| 1 |
31.2 |
36.3 |
32.0 |
29.1 |
30.6 |
| Unknown |
1.6 |
|
|
|
|
| BRAFV600E mutation, % |
100 |
87.3 |
88.6 |
Unknown |
Unknown |
| Crossover allowed |
Yes |
Yes |
Yes |
No |
No |
| Outcome assessor |
Investigator and IRC |
Investigator and IRC |
Investigator and IRC |
IRCb |
Unknown |
| Frequency of response assessment |
Weeks 6 and 12 and then
every 9 weeks |
Weeks 6, 12, 21, and 30 and then every 12 weeks |
Weeks 6 and 12 and then
every 9 weeks |
Week 12; in patients with no disease progression, then at weeks 16, 20, and 24 and every 6 weeks through week 48 and then every 12 weeks |
Every 9 weeks |
| PFS, median and HR (95% CI) |
• 5.1 vs 2.7 months; 0.30 (0.18–0.51) (December 2011 data)
• 6.9 vs 2.7 months; 0.37 (0.24–0.58) (June 2012 data) |
• 4.8 vs 1.5 months; 0.45 (0.33–0.63) (ITT)
• 4.8 vs 1.4 months; 0.44 (0.31–0.64)c
• 4.8 vs 1.4 months; 0.44 (0.28–0.69)d |
• 5.3 vs 1.6 months; 0.26 (0.20–0.33) (December 2010 data)
• 6.9 vs 1.6 months; 0.38 (0.32–0.46) |
• 0.76 (0.63–0.93) |
• 2.3 vs 2.2 months; 0.92 (0.80–1.06) |
| OS,eHR (95% CI), % crossover |
• 0.61 (0.25–1.48) (Dec. 2011 data) (44%)
• 0.75 (0.44–1.29) (June 2012 data) (56%)
• 0.76 (0.48–1.21 (Dec. 2012 data) (57%) |
• 0.54 (0.32–0.92) (ITT) (47%)
• 0.53 (0.30–0.94) (50%)c
• 0.55 (0.26–1.13) (53%)d |
• 0.37 (0.26–0.55) (Dec. 2010 data) (0%)
• 0.76 (0.63–0.93) (Feb. 2012 data) (34%) |
• 0.72 (0.59–0.87) |
• 1.00 (0.86–1.17) |
| Key AEs, % |
Dabrafenibvs DTIC: grade 2 or higher (hyperkeratosis 1% vs 0%, palmar-plantar erythrodysesthesia 8%vs 0%, SCC/keratoacanthomas 6%vs 0%, neutropenia <1%vs 15%, nausea 1%vs 14%, pyrexia 11%vs 0%, arthralgia 6%vs 0%, fatigue 6%vs 5%)
|
Trametinibvs chemotherapy: grade 2 or higher (rash 27% vs 3%, fatigue 9% vs 10%, diarrhea 6% vs 5%, dermatitis 10% vs 0%, nausea 3% vs 11%, hypertension 15% vs 6%, peripheral edema 5% vs 0%, alopecia 2% vs 8%, constipation 1% vs 6%) |
Vemurafenibvs DTIC: grade 2 or higher (arthralgia 21% vs 1%, rash 18% vs 0%, fatigue 13% vs 13%, cutaneous SCC 12% vs< 1%, keratoacanthomas 8% vs 0%, nausea 8% vs 13%, alopecia 8% vs 0%; pruritus 7% vs 0%, hyperkeratosis 6% vs 0%) |
Ipilimumab+DTICvs DTIC: all grades (elevation of alanine aminotransferase levels 33.2%vs 5.6%, elevation of aspartate aminotransferase levels 29.1%vs 5.6%, diarrhea 36.4%vs 24.7%, pruritus 29.6%vs 8.8%, rash 24.7%vs 6.8%) |
Temozolomidevs DTIC: grade 3/4 (lymphopenia 45% vs 9%, thrombocytopenia 11% vs 6%, neutropenia 10% vs 16%, leukopenia 9% vs 8%, fatigue 6% vs 5%) |
| AE: Adverse Event; AJCC : American Joint Committee on Cancer; bid: twice per day; DTIC : Dacarbazine; ECOG PS: Eastern Cooperative Oncology Group Performance Status; HR: Hazard Ratio; IRC: Independent Review Committee; ITT: Intention-to-treat; OS: Overall Survival; PFS: Progression-Free Survival; q3w: every three weeks; qd: every day; RCT: Randomized Controlled Trial; RECIST : Response Evaluation Criteria in Solid Tumors; SCC: Squamous Cell Carcinoma; WHO: World Health Organization
aMean; bFor all efficacy outcomes except survival; cPrimary efficacy population (overall); dPrimary efficacy population (first-line subgroup); eReported HRs for OS not adjusted for crossover. |
