ESMO 2016: Dabrafenib/Trametinib/Panitumumab Improves Efficacy in BRAF Mutation–Positive Metastatic Colorectal Cancer
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).
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.
Improved Progression-Free Survival
In the dabrafenib/panitumumab treatment arm, the confirmed complete/partial response rate was 10%, and 80% of patients achieved stable disease. With trametinib/panitumumab, no patients attained complete/partial response, but 53% showed stable disease. However, the 2 agents combined with panitumumab yielded an 18% complete/partial response rate, and 67% of patients showed stable disease.
Median progression-free survival for combined dabrafenib/trametinib/panitumumab has not yet been reached compared with median progression-free survival of 3.4 and 2.8 months demonstrated with dabrafenib/panitumumab and trametinib/panitumumab, respectively.
The safety analysis showed that the most commonly reported adverse events overall were dermatitis acneiform, diarrhea, fatigue, nausea, and rash.
Integrated Biomarker Analysis
Immunohistochemistry done in on-treatment and pretreatment biopsies revealed a reduction in phosphorylated ERK in on-treatment vs pretreatment biopsies. The median phosphorylated ERK reductions were 23% for dabrafenib/panitumumab, 50% for trametinib/panitumumab, and 54% for the triple combination.
Serial circulating tumor DNA analysis also showed reductions in the BRAF V600E–mutant fraction of more than 70% as early as week 4 of treatment in 12 of 14 (86%) patients in the dabrafenib/trametinib/panitumumab arm. This finding corresponds with the partial response achieved by 6 of these 12 patients by week 6.
Conversely, circulating tumor DNA analysis also demonstrated an increased BRAF V600E–mutant fraction in 10 patients upon progression.
Other mutations that were not present at baseline were detected in circulating tumor DNA upon progression. Of the 12 patients showing a best response of complete/partial response or stable disease, 7 (58%) patients had RAS mutations in circulating tumor DNA upon progression that were not detectable at baseline; 3 of these patients developed multiple RAS mutations. In addition, BRAF V600E and RAS mutations were coexpressed in 2 patients at baseline.
Conclusions
Combined dabrafenib/trametinib/panitumumab demonstrated acceptable tolerability and activity in BRAF-mutated metastatic colorectal cancer, according to the authors, who further concluded that integrated biomarker analysis by immunohistochemistry provided evidence of downstream target inhibition. The circulating tumor DNA data suggested that changes in BRAF V600E–mutation frequency may serve as a biomarker and allow for monitoring of both treatment response and disease progression. The investigators explained that preexisting and emergent RAS mutations may represent potential mechanisms of resistance to combination treatment.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
