ESMO 2014: Combination Dabrafenib/Trametinib Improves OS in Comparison with Vemurafenib in Patients With BRAF-Mutation Positive Melanoma

Results of the COMBI-v randomised, open-label, phase III study in the first-line treatment of patients with unresectable or metastatic cutaneous melanoma

First-line treatment with combination therapy dabrafenib plus trametinib improves overall survival (OS) in comparison with vemurafenib in patients with BRAF V600E/K mutation-positive unresectable or metastatic cutaneous melanoma. The results of a randomised, open-label, phase III, COMBI-v study were presented by Dr Caroline Robert of the InstitutGustave Roussy, Villejuif, France at Presidential Symposium 2 during ESMO Congress 2014 in Madrid, Spain.

Dabrafenib, a BRAF inhibitor and trametinib, a MEK inhibitor demonstrated superior progression-free survival (PFS) vs chemotherapy in patients with BRAF V600E/K mutation-positive metastatic melanoma. However, the emergence of disease resistance and development of cutaneous squamous cell carcinoma are associated with BRAF inhibition. Simultaneous inhibition of BRAF and MEK mitigated these effects as shown in the phase I/II study of dabrafenib/trametinib combination vs treatment with single agent dabrafenib and in the phase III study of dabrafenib/trametinib combination vs dabrafenib monotherapy with an improvement in overall response rate (ORR), PFS and reduced frequency of cutaneous squamous cell carcinoma.

The COMBI-v phase III study was conducted to establish superiority of dabrafenib/trametinib combination over vemurafenib with respect to OS in patients with BRAF V600E/K mutation-positive metastatic melanoma.

Patients were randomised 1:1 to receive dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) vs vemurafenib monotherapy (960 mg twice daily) as first-line therapy.

Eligible patients were ≥ 18 years old and had an ECOG performance status ≤ 1, with histologically confirmed, unresectable stage IIIC or IV, BRAF V600E/K mutation-positive metastatic melanoma. All patients were treatment-naive with no brain metastasis except those treated and stable status longer than 12 weeks. Stratification was according V600E vs V600K mutation and LDH level.

The primary endpoint was OS; secondary endpoints were PFS, ORR, duration of response, and safety.

The study crossover was prohibited.

First-line combination therapy dabrafenib plus trametinib improves overall survival compared to vemurafenib in patients with BRAF V600E/K mutation-positive melanoma

First-line combination therapy dabrafenib plus trametinib improves overall survival compared to vemurafenib in patients with BRAF V600E/K mutation-positive melanoma. © Caroline Robert

From June 2012 to October 2013, 1644 patients were screened and 704 patients were randomised (352 patients in each arm).

A pre-specified interim OS analysis was planned when 70% (202 of 288) of the total number of expected deaths, required for the protocol-specified final analysis, are observed. The study could be stopped for efficacy if the one-sided p value was < 0.0107. However, due to data entry lag, there were 222 (77%) observed death events at data cut-off.

It was pre-specified that if the Independent Data Monitoring Committee (IDMC) recommends stopping at interim, interim analysis would become the final one.

The IDMC recommended stopping the study based on an interim analysis which demonstrated an OS benefit that crossed the pre-specified efficacy stopping boundary for dabrafenib/trametinib combination. At the time of analysis, the median OS was not reached in the dabrafenib/trametinib arm and 17.2 months in the vemurafenib arm (hazard ratio, HR 0.69, p = 0.002). The OS data in subgroup analysis favoured the dabrafenib/trametinib arm.

The PFS was 11.4 vs 7.3 months in favour of  the dabrafenib/trametinib arm (HR 0.56, p < 0.001). Difference in best confirmed response rate was 13% among two study arms, again in favour of dabrafenib/trametinib treatment (p < 0.001). Duration of response was 13.8 months in the dabrafenib/trametinib arm and 7.5 months in the vemurafenib arm. 

Rates of adverse events were generally similar in both arms and consistent with data from previous trials. However, all grades and grade 3 of arthralgia, rash, alopecia, hyperkeratosis, photosensitivity and skin papilloma were more present among patients treated with vemurafenib. Grade 3 pyrexia was more present in dabrafenib/trametinib arm.

Among BRAF inhibitor-related adverse events, cutaneous small-cell carcinoma and keratoacanthoma, hyperkeratosis, skin papilloma, hand-foot syndrome, alopecia, photosensitivity plus sunburn, and non-cutaneous malignancy were more present in vemurafenib arm.

Among MEK inhibitor-related adverse events, decrease in ejection fraction was more present in dabrafenib/trametinib arm.


Dr Robert concluded that dabrafenib/trametinib vs vemurafenib resulted in significant improvement in OS for combination treatment with 31% reduction in the risk of death (median OS not reached for combination vs 17.2 months in vemurafenib arm) and significant improvement in PFS for combination treatment with 44% reduction in the risk of progression or death (median PFS of 11.4 months for combination vs 7.3 months for vemurafenib treated patients).

Dr Christian Blank, who discussed the study results, said that N-RAS mutation was discovered in 1985, loss of CDKN2 in 1994, PTEN loss in 1997, B-RAF mutation in 2002, CSK4 mutation in 2005, c-KIT mutation in 2006, GNAQ mutation in 2009, and erbB4 mutation in 2009. Among these genetic changes observed in melanoma, the oncology community was excited with findings from 2009 coming from phase 1 study of BRAF inhibition in advanced melanoma and fast induced responses. After this, he spoke about the rationale for dual targeting of the MAPK pathway.

The observed response rate in the COMBI-v study was 64% with 13% of complete responses and 51% of partial responses, stable disease was observed in 26% of patients. Median PFS was 7.3 months and OS was 17.2 months. COMBI-v confirms improved efficacy for combinations of BRAF inhibitor and MEK inhibitor therapies as compared to single BRAF inhibition in BRAFV600 mutant melanoma. This combination lead to decreased toxicity occurring from paradoxical MAPK pathway activation in BRAF wild-type cells. Dabrafenib and trametinib toxicity is similar to the toxicity observed from single treatment. If the mature data confirm the presented observations BRAF and MEK inhibition would be the new standard targeted therapy in BRAFV600 melanoma.

Dr Blank questioned why gaining 4 months of PFS translates only into 2 months of overall survival benefit. In addition, he asked what kind of pricing this overall survival benefit will justify.


LBA4_PR - COMBI-v: A randomised, open-label, Phase III study comparing the combination of dabrafenib (D) and trametinib (T) to vemurafenib (V) as first-line therapy in patients (pts) with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma

The study describes investigational use of dabrafenib/trametinib combination and was funded by GlaxoSmithKline.