Evaluating the effectiveness and safety of triple combination therapy with immunotherapy and targeted therapy for patients with advanced-stage melanoma.

This study evaluated the effectiveness and safety of triple combination therapy with immune and targeted therapies in patients with stage III-IV melanoma. The data showed that triple combination therapy was associated with increased survival benefits with manageable side effects for these patients.

Melanoma is an aggressive form of skin cancer that is often caused by specific gene mutations (abnormalities). It has a high tendency to spread to other parts of the body (metastasis). Patients with advanced-stage melanoma often have a poorer prognosis.

BRAF and MEK are the most common mutated (abnormal) genes in melanoma. These mutations allow tumors to grow at a rapid rate. Using drugs that target these mutations can slow disease progression and improve survival. BRAF inhibitors like vemurafenib (Zelboraf) and MEK inhibitors like cobimetinib (Cotellic) are used to treat these tumors. Immunotherapy uses the body’s own immune system to fight cancer. PD-L1 is a protein that can be found in high numbers on cancer cells. These proteins can stop the immune system from killing cancerous cells. Pembrolizumab (Keytruda) and nivolumab (Opdivo) are examples of PD-1 and PD-L1 inhibitors that work by blocking PD-L1. This causes the immune system to attack tumor cells and kill them. Immunotherapy has been found to be effective in advanced melanoma.

Different combination therapies are being tested to improve the outcomes of these patients. It is not clear if combining 3 different immunotherapies and targeted therapies (triple therapy) can improve the outcomes of patients with advanced-stage melanoma.

This study analyzed 5 studies and involved overall 1266 patients with stage III/IV melanoma. Patients were divided into 2 groups according to the treatment combination they received. Group 1 included patients who were treated with a triple combination of PD-1/PD-L1, BRAF, and MEK inhibitors. Group 2 included patients who were treated with a combination of 2 drugs or a single drug.

Patients in group 1 were 1.12 times more likely to have a better survival at 2 years than patients in group 2. The overall survival rate after 2 years was 63.7% for group 1 compared to 56.3% for group 2. 

Patients in group 1 were 29% more likely to survive without cancer worsening than patients in group 2. The objective response rate (ORR; partial or complete disappearance of cancer) was slightly higher (67.1%) for group 1 compared to group 2 (62.7% ). 

There was no significant difference in the rate of side effects between groups. Triple combination therapy was associated with a higher risk of developing low thyroid function, joint and muscle pain, an increase in liver enzymes (liver damage), physical weakness, and fever compared with the control group.

This study concluded that triple combination therapy of PD-1/PD-L1, BRAF, and MEK inhibition was associated with increased survival benefits with manageable side effects for the treatment of patients with stage III/IV melanoma.

The number of studies analyzed was very small. Further randomized controlled clinical trials are needed to verify the conclusions.