Combining dabrafenib, trametinib and pembrolizumab for the treatment of BRAF-mutant melanoma

This study investigated the effect of combined dabrafenib (Tafinlar), trametinib (Mekinist) and pembrolizumab (Keytruda) in melanoma. They found that this combination improved survival in advanced melanoma. 

Melanoma or skin cancer is a common cancer. Genetic mutations can lead to the development of melanoma. Targeting these mutations may slow tumor cell growth. BRAF and MEK genes are most commonly mutated in melanoma. These mutations allow tumors to grow at a rapid rate. Using drugs that target these mutations can improve survival. Dabrafenib (D) is a drug that targets BRAF-mutant cancer cells. Trametinib (T) is a drug that inhibits MEK. D+T is a double combination treatment (DCT) commonly used to treat BRAF-mutated melanoma. 

A new class of cancer drugs has also been developed in recent years. These are called immune checkpoint inhibitors (ICIs). ICIs target proteins that tumor cells overexpress to evade the immune system. BRAF and MEK mutations may increase immune system evasion. Pembrolizumab (P) is an ICI that targets the PD-1 protein. It is unclear if triple combination treatment (TCT) is effective in BRAF-mutated melanoma. 

This study included 120 patients with a BRAF^V600–mutated melanoma. Patients were randomly assigned to TCT with D+T+P or DCT with D+T. The main outcomes were progression-free survival (PFS; survival without cancer growing or spreading) and overall response rate (ORR). Treatment continued until disease progression. The average follow-up for all patients was 9.6 months.

Average PFS was 16 months in TCT versus 10.3 months in DCT patients. 51.7% of TCT patients experienced disease progression compared to 68.3% of DTC patients. At 12 months, the PFS rate was 59.3% in TCT patients versus 45.2% in DCT patients.

The ORR was 63.3% in the TCT patients and 71.7% in the DTC patients. However, the average duration of response was longer in the TCT group (18.7 months) compared to the DTC group (12.5 months).

The rates of side effects were similar in both TCT and DCT groups. The most common side effects were fever, rash, and diarrhea.

The authors concluded that the combination of D+T+P improved survival in advanced melanoma.

This study was funded by Merck, the manufacturer of pembrolizumab.