Patients with metastatic colorectal cancer and tumors harboring the BRAF V600E mutation who received triple therapy with dabrafenib (Tafinlar), trametinib (Mekinist), and panitumumab (Vectibix) showed an improved best overall response and prolonged progression-free survival compared to panitumumab plus either drabrafenib or trametinib, according to results reported by Corcoran et al at the 2016 European Society for Medical Oncology (ESMO) Congress in Copenhagen (Abstract 455O)1.
Dabrafenib acts by inhibiting BRAF and trametinib by inhibiting MEK1 and MEK2; both agents block the MAPK pathway. Both drugs have demonstrated activity and have been approved for BRAF V600E–mutated melanoma, for use either as single agents or in combination. BRAF V600E mutations have also been reported in 5% to 10% of metastatic colorectal cancer cases; however, BRAF- and MEK-inhibiting monotherapies have been shown to have little activity in metastatic colorectal cancer, where the presence of a BRAF V600E mutation often signals a poorer prognosis.
Lead author Ryan B. Corcoran, MD, PhD, Translational Research Director for the Gastrointestinal Cancer Center at Massachusetts General Hospital and a Damon Runyon Clinical Investigator, presented findings from a study testing whether combined inhibition of the EGFR pathway with panitumumab and dual inhibition of the MAPK pathway could provide clinical benefit in BRAF-mutated metastatic colorectal cancer. This study evaluated the efficacy and safety of panitumumab plus dabrafenib or trametinib, and in triple combination with both.
The trial enrolled 134 patients with BRAF-mutated metastatic colorectal cancer who were randomized to receive panitumumab plus dabrafenib (n = 20), panitumumab plus trametinib (n = 31), or triple combination with panitumumab, dabrafenib, and trametinib (n = 83). Each agent in the combination could be administered at up to the full monotherapy dose.
The trial included integrated biomarker analyses. Tumor biopsies were taken prior to and during treatment and evaluated by immunohistochemistry for phosphorylated ERK. Serial circulating tumor DNA samples were obtained and profiled for mutations in the BRAF, KRAS, NRAS, and PIK3CA genes.
The majority of study participants, 120 patients, had received prior chemotherapy for metastatic colorectal cancer, and 14 were treatment-naive.
In the dabrafenib/panitumumab treatment arm, the confirmed complete/partial response rate wa...