Which sequence of treatment should be given first- immunotherapy or targeted therapy for patients with BRAF-mutated metastatic melanoma?

This study evaluated which sequence of treatment should be given first – immunotherapy or targeted therapy – for the most clinical benefit in patients with BRAF-mutated metastatic melanoma. The data showed that immunotherapy followed by targeted therapy significantly improved survival outcomes in these patients.

Melanoma is an aggressive form of skin cancer that is often caused by specific gene mutations (abnormalities) such as BRAFV600. It has a high tendency to spread to other parts of the body (metastasis). The standard treatment for advanced melanoma is a combination of immunotherapy, chemotherapy, surgical removal of tumors, and targeted therapy.

Immunotherapy uses the body’s own system to fight against cancer cells. Tumor cells try to avoid death by switching off our immune system. They bind to proteins on the surface of the immune cells such as PD-1/PD-L1 or CTLA-4. ICIs such as nivolumab (Opdivo) and ipilimumab (Yervoy) block these interactions and turn on the immune system to attack and kill the cancer cells.

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 improve survival. Dabrafenib (Tafinlar) is a drug that targets BRAF-mutant cancer cells. Trametinib (Mekinist) is a drug that inhibits MEK. It has been shown that dabrafenib combined with trametinib improved survival outcomes in advanced melanoma patients with BRAF mutations. However, which sequence of treatment (immunotherapy followed by targeted therapy or targeted therapy followed by immunotherapy) provides the most clinical benefit in patients with BRAF-mutated metastatic melanoma is still unknown.

This study involved 265 patients with BRAF-mutated metastatic melanoma. Patients were randomly assigned into two groups. Group 1 received an immunotherapy combination (ipilimumab and nivolumab) followed by a targeted drug combination (dabrafenib and trametinib). Group 2 received a targeted drug combination followed by an immunotherapy combination. The average follow-up time was 27.7 months.

After 2 years, 71.8% of the patients in group 1 were alive versus 51.5% in group 2. This difference was statistically significant.

After 2 years, 41.9% of the patients in group 1 were alive without cancer worsening versus 19.2% in group 2. The average survival without cancer worsening was 11.8 months in group 1 versus 8.5 months in group 2.

The objective response (partial or complete disappearance of cancer cells) rates were similar between the two groups (46% in group 1 versus 43% in group 2)

Serious side effects were similar between the two groups. The most common side effects were immune-related and fever.

This study concluded that immunotherapy followed by targeted therapy significantly improved survival outcomes in patients with BRAF-mutated metastatic melanoma.

The sample size was very small. The sequence of treatment evaluated in this study might not apply to patients treated with other immunotherapy regimens.