Dabrafenib plus trametinib

Previously untreated. An international, double-blind, phase III trial (COMBI-d [NCT01584648]) without crossover included 423 previously untreated patients with unresectable stage IIIC or stage IV melanoma and BRAF V600E or V600K pathogenic variants. Patients were randomly assigned to receive either the combination of dabrafenib (150 mg by mouth twice a day) plus trametinib (2 mg by mouth every day) or dabrafenib plus placebo. The primary end point was investigator-assessed PFS. The protocol included a prespecified interim analysis for OS at the time of analysis of the primary end point. Patients were stratified by baseline LDH levels and BRAF genotype.[28][Level of evidence B1]

Previously untreated. An international, double-blind, phase III trial (COMBI-d [NCT01584648]) without crossover included 423 previously untreated patients with unresectable stage IIIC or stage IV melanoma and BRAF V600E or V600K pathogenic variants. Patients were randomly assigned to receive either the combination of dabrafenib (150 mg by mouth twice a day) plus trametinib (2 mg by mouth every day) or dabrafenib plus placebo. The primary end point was investigator-assessed PFS. The protocol included a prespecified interim analysis for OS at the time of analysis of the primary end point. Patients were stratified by baseline LDH levels and BRAF genotype.[28][Level of evidence B1]

Median PFS was 9.3 months for the combination versus 8.8 months for dabrafenib plus placebo. The HRdeath or progression was 0.75 (95% CI, 0.57–0.99; P = .03). Updated data at the time of final analysis of OS revealed a median PFS of 11.0 months for the combination versus 8.8 months for dabrafenib plus placebo. The HRPFS or death was 0.67 (95% CI, 0.53–0.84; P = .0004; unadjusted for multiple testing).[29]

Previously untreated. An international, double-blind, phase III trial (COMBI-d [NCT01584648]) without crossover included 423 previously untreated patients with unresectable stage IIIC or stage IV melanoma and BRAF V600E or V600K pathogenic variants. Patients were randomly assigned to receive either the combination of dabrafenib (150 mg by mouth twice a day) plus trametinib (2 mg by mouth every day) or dabrafenib plus placebo. The primary end point was investigator-assessed PFS. The protocol included a prespecified interim analysis for OS at the time of analysis of the primary end point. Patients were stratified by baseline LDH levels and BRAF genotype.[28][Level of evidence B1]

A prespecified final analysis of OS was conducted at 70% of events. Median OS was 25.1 months in the dabrafenib-plus-trametinib group (66% of events) versus 18.7 months in the dabrafenib-plus-placebo group (76% of events). The HR was 0.71 (95% CI, 0.55–0.92; P = 0.01).

Previously untreated. An international, double-blind, phase III trial (COMBI-d [NCT01584648]) without crossover included 423 previously untreated patients with unresectable stage IIIC or stage IV melanoma and BRAF V600E or V600K pathogenic variants. Patients were randomly assigned to receive either the combination of dabrafenib (150 mg by mouth twice a day) plus trametinib (2 mg by mouth every day) or dabrafenib plus placebo. The primary end point was investigator-assessed PFS. The protocol included a prespecified interim analysis for OS at the time of analysis of the primary end point. Patients were stratified by baseline LDH levels and BRAF genotype.[28][Level of evidence B1]

Permanent discontinuations of study drugs were reported in 9% of patients who received the combination and in 5% of patients treated with dabrafenib only.

Previously untreated. An international, double-blind, phase III trial (COMBI-d [NCT01584648]) without crossover included 423 previously untreated patients with unresectable stage IIIC or stage IV melanoma and BRAF V600E or V600K pathogenic variants. Patients were randomly assigned to receive either the combination of dabrafenib (150 mg by mouth twice a day) plus trametinib (2 mg by mouth every day) or dabrafenib plus placebo. The primary end point was investigator-assessed PFS. The protocol included a prespecified interim analysis for OS at the time of analysis of the primary end point. Patients were stratified by baseline LDH levels and BRAF genotype.[28][Level of evidence B1]

The incidence of grade 3 to grade 4 adverse events was similar between the groups (35% with the combination and 37% with dabrafenib only). Pyrexia occurred more frequently with the combination and was treated with immediate temporary cessation of the study drug in either group; prophylactic glucocorticoids may prevent recurring episodes. Hyperproliferative cutaneous events, including cutaneous SCCs, were considered related to paradoxical activation of the MAPK pathway and occurred less frequently with the addition of the MEK inhibitor. Rare, but serious, adverse events included decreased ejection fraction and chorioretinopathy.

Previously untreated. An international, open-label, phase III trial (COMBI-v [NCT01597908]) included 704 previously untreated patients with metastatic melanoma and BRAF V600 pathogenic variants. Patients were randomly assigned to receive standard doses of either the combination of dabrafenib plus trametinib or vemurafenib as first-line therapy. The primary end point was OS.[30][Level of evidence A1]

Previously untreated. An international, open-label, phase III trial (COMBI-v [NCT01597908]) included 704 previously untreated patients with metastatic melanoma and BRAF V600 pathogenic variants. Patients were randomly assigned to receive standard doses of either the combination of dabrafenib plus trametinib or vemurafenib as first-line therapy. The primary end point was OS.[30][Level of evidence A1]

An interim analysis for OS was planned when 202 of the final 288 events occurred. Per protocol, the DMSB used adjusted efficacy boundaries for actual events (222) (2-sided P < .0214 for efficacy and P > .2210 for futility). The DMSB recommended stopping for efficacy, and the interim analysis is considered to be the final analysis of OS. A protocol amendment was issued to allow crossover to the combination therapy arm.

Previously untreated. An international, open-label, phase III trial (COMBI-v [NCT01597908]) included 704 previously untreated patients with metastatic melanoma and BRAF V600 pathogenic variants. Patients were randomly assigned to receive standard doses of either the combination of dabrafenib plus trametinib or vemurafenib as first-line therapy. The primary end point was OS.[30][Level of evidence A1]

A total of 100 patients (28%) in the combination arm and 122 (35%) in the vemurafenib group had died (HR, 0.69; 95% CI, 0.53–0.89; P = .005). Median OS for patients treated with vemurafenib was 17.2 months; the median has not been reached in the combination therapy arm.

Previously untreated. A pooled analysis of the 563 patients who were randomly assigned to receive dabrafenib plus trametinib in the COMBI-d (double-blinded) and COMBI-v (open label) trials (described above) provides estimated 5-year outcomes.[31] After the study, 53% of patients received subsequent treatment; two-thirds of these patients received immunotherapy.

Previously untreated. A pooled analysis of the 563 patients who were randomly assigned to receive dabrafenib plus trametinib in the COMBI-d (double-blinded) and COMBI-v (open label) trials (described above) provides estimated 5-year outcomes.[31] After the study, 53% of patients received subsequent treatment; two-thirds of these patients received immunotherapy.

Sixty-three percent of patients died (64% in COMBI-d and 61% in COMBI-v) after a median follow-up of 22 months (range, 0−76 months).

Previously untreated. A pooled analysis of the 563 patients who were randomly assigned to receive dabrafenib plus trametinib in the COMBI-d (double-blinded) and COMBI-v (open label) trials (described above) provides estimated 5-year outcomes.[31] After the study, 53% of patients received subsequent treatment; two-thirds of these patients received immunotherapy.

The estimated 5-year OS rate was 34% (95% CI, 30%−38%), and the investigator-assessed PFS rate was 19% (95% CI, 15%−22%).

Previously untreated. A pooled analysis of the 563 patients who were randomly assigned to receive dabrafenib plus trametinib in the COMBI-d (double-blinded) and COMBI-v (open label) trials (described above) provides estimated 5-year outcomes.[31] After the study, 53% of patients received subsequent treatment; two-thirds of these patients received immunotherapy.

A complete response, which occurred in 109 patients (19%), was associated with an OS rate of 71% (95% CI, 62%−79%) at 5 years.