Improved Overall Survival in Melanoma with Combined Dabrafenib and Trametinib

Abstract

BACKGROUND The BRAF inhibitors vemurafenib and dabrafenib have shown efficacy as monotherapies in patients with previously untreated metastatic melanoma with BRAF V600E or V600K mutations. Combining dabrafenib and the MEK inhibitor trametinib, as compared with dabrafenib alone, enhanced antitumor activity in this population of patients. METHODS In this open-label, phase 3 trial, we randomly assigned 704 patients with metastatic melanoma with a BRAF V600 mutation to receive either a combination of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) or vemurafenib (960 mg twice daily) orally as first-line therapy. The primary end point was overall survival. RESULTS At the preplanned interim overall survival analysis, which was performed after 77% of the total number of expected events occurred, the overall survival rate at 12 months was 72% (95% confidence interval [CI], 67 to 77) in the combination-therapy group and 65% (95% CI, 59 to 70) in the vemurafenib group (hazard ratio for death in the combination-therapy group, 0.69; 95% CI, 0.53 to 0.89; P=0.005). The prespecified interim stopping boundary was crossed, and the study was stopped for efficacy in July 2014. Median progression-free survival was 11.4 months in the combination-therapy group and 7.3 months in the vemurafenib group (hazard ratio, 0.56; 95% CI, 0.46 to 0.69; P<0.001). The objective response rate was 64% in the combination-therapy group and 51% in the vemurafenib group (P<0.001). Rates of severe adverse events and study-drug discontinuations were similar in the two groups. Cutaneous squamous-cell carcinoma and keratoacanthoma occurred in 1% of patients in the combination-therapy group and 18% of those in the vemurafenib group. CONCLUSIONS Dabrafenib plus trametinib, as compared with vemurafenib monotherapy, significantly improved overall survival in previously untreated patients with metastatic melanoma with BRAF V600E or V600K mutations, without increased overall toxicity. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01597908.).

Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation‐positive advanced cutaneous melanoma

“…The most common AE in the 12 patients in phase 1 and phase 2 combined were pyrexia, increased aspartate aminotransferase, peripheral edema, nasopharyngitis, increased blood alkaline phosphatase, stomatitis, erythema and headache. The relatively common AE in this Japanese study were also relatively common in clinical studies of dabrafenib and trametinib combination conducted in global studies 18, 24, 25. Similarly, the majority of AE observed in this Japanese study belong to grade 1 or 2, and it has been reported that the majority of AE were grade 1 or 2 in global clinical studies as well 18, 24, 25…”

“…Pyrexia was the most common AE in our study and was also the most common AE in the global combination studies 18, 24, 25. Incidentally, pyrexia has been reported as a common AE with BRAF‐inhibitor monotherapy in the range of 16–26% when given as monotherapy 18, 19, 26, 27.…”

Emerging findings into molecular mechanism of brain metastasis

“…BRAF inhibitors dabrafenib combined with mitogen‐activated extracellular signal‐regulated kinase (MEK) inhibitors like trametinib could increase anti‐tumor activity and reduce side‐effect 105, 106. In conclusion, targeted therapy such as small molecule kinase inhibitors have achieved outstanding development, but still needs to pay more attention and take more effort on investigation and preferable application in clinic.…”

Severe gastrointestinal toxicity with administration of trametinib in combination with dabrafenib and ipilimumab

“…Advances in treating metastatic melanoma with immunotherapy (Hodi et al., 2010), and with the targeted BRAF inhibitor, dabrafenib, and MEK inhibitor, trametinib, have produced important improvements in clinical outcomes (Flaherty et al., 2012a,b; Long et al., 2014; and Robert et al., 2015). Differences in the mechanisms of action suggest that combinations may lead to further improvements.…”

“…While patient numbers are small, this experience of two intestinal perforations in seven patients after one or two doses of ipilimumab, administered with dabrafenib and trametinib therapies, raises the possibility of added toxicity with the triplet combination over ipilimumab as a single agent, where grade 3–5 colitis occurs in 5% and intestinal perforations in 1.1% of patients (Ipilimumab package insert, 2014). In support of this interpretation, the clinical combination of dabrafenib and trametinib has rarely been associated with colitis, and no cases of colitis leading to colonic perforation have been reported (Hu‐Lieskovan et al., 2014; Long et al., 2014; and Robert et al., 2015). The study cohort evaluating dabrafenib 150 mg BID and ipilimumab 3 mg/kg continues enrollment with only one resolved case of grade 3 colitis in 25 patients to date.…”