SEAMARK: phase II study of first-line encorafenib and cetuximab plus pembrolizumab for MSI-H/dMMR BRAFV600E-mutant mCRC.

Colorectal cancer (CRC) occurs when there is an abnormal growth of cells (known as a tumor) in the colon or rectum. Some people with CRC have changes in their tumor genes (known as gene mutations). A gene is a piece of DNA that tells the cell to make specific molecules, such as proteins. Mutations in a gene called BRAF can turn on signals that help the cancer cells grow. Gene mutations that impair DNA repair mechanisms can also make the cancer cells grow more quickly and allow the immune system to detect the cancer cells as being foreign to the body. Targeted therapy is a type of cancer treatment that turns off specific genes and proteins involved in cancer cell survival and growth. BRAF and EGFR inhibitors are targeted therapies that work well together in treating people with BRAF-mutant CRC. BRAF proteins can help cancer cells grow, and BRAF inhibitors block these proteins to prevent, slow, or stop the growth of the cancer cells. Immunotherapy is a type of cancer treatment that helps a person's immune system fight cancer. Immunotherapy is effective for treating CRC that has mutations in the DNA repair mechanisms. By combining targeted therapy and immunotherapy, patients may be able to live longer without their disease getting worse. In the SEAMARK study, we will use a treatment combination including a BRAF inhibitor (encorafenib), an EGFR inhibitor (cetuximab) and an immunotherapy (pembrolizumab) in patients with CRC who have a BRAF mutation and deficiencies in the DNA repair mechanism. Clinical Trial Registration: NCT05217446 (ClinicalTrials.gov), 2021-003715-26 (EudraCT).