by ecancer reporter Janet Fricker

Adding the MEK inhibitor trametinib to the BRAF inhibitor dabrafenib for patients with previously untreated metastatic melanoma with BRAF V600E or V600K mutations improved response rate and progression free survival compared to dabrafenib alone, reports The New England Journal of Medicine.

Dabrafenib is an oral inhibitor of BRAF that in phase III trials compared to chemotherapy has shown statistically significant improvements in PFS in patients who harbour the BRAF V600 mutation.

However Patients treated with BRAF inhibitors, commonly acquire resistance after six to seven months of treatment.

Trametinib is an inhibitor of MAPK kinase (MEK), a protein downstream of BRAF in the MAPK pathway.

Combining both drugs, researchers reasoned, would delay resistance. In the phase 3 study between May 2012 and January 2013,423 previously untreated patients who had unresectable stage IIIC or stage IV melanoma with a BRAF V600E or V600K mutations were randomised 1:1 to receive a combination of dabrafenib and trametinib (n=211) or dabrafenib and placebo (n=212).

Results showed that the median progression-free survival was 9.3 months in the dabrafenib/trametinib group versus 8.8 months in the dabrafenib-only group (HR 0.75; 95% CI 0.57 to 0.99; P=0.03).

The overall response rate was 67% in the combination arm versus 51% in the dabrafenib-only group (P=0.002).

At six months a preplanned interim analysis showed overall survival was 93% in the combination arm versus 85% in the dabrafenib-only arm (HR for death 0.63; 95% CI, 0.42 to 0.94; P=0.02).

Notably, for patients with elevated lactate dehydrogenase levels (considered a poor prognostic feature), median PFS was 7.1 months in the combination arm versus 3.8 months in the dabrafenib only arm (HR 0.64, 95% CI, 0.42 to 0.95).

“Our new report confirms the accumulating evidence that targeted combination therapies can extend life and halt disease progression among people with metastatic cancer who carry genetic mutations in their cancer that resist standard chemotherapy treatments and targeted monotherapies,” says Georgina Long, the corresponding author, from the Melanoma Institute Australia at the University of Sydney.

In the post hoc subgroup analysis, the authors note, patients with poorer prognostic features appeared to benefit more from the combination of dabrafenib and trametinib than the overall study population.

“Since events tend to occur earlier in patients with poorer prognostic features, longer follow-up will be required to assess the effects of combination therapy as compared with monotherapy in patients with better prognostic features, such as a normal lactate dehydrogenase level or stage M1a or M1b melanoma,” write the authors.

Reference

G Long, D Stroyakovskiy, H Gogas, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. NEJM.