Effectiveness evaluation of combination therapy for specific metastatic colorectal cancer mutation

Abstract

Metastatic colorectal cancer (mCRC) featuring the BRAF V600E mutation is a distinct, aggressive clinical subtype characterized by a poor prognosis and limited benefit from standard chemotherapy. The BRAF V600E mutation drives the constitutive activation of the MAPK pathway, promoting tumor progression and therapeutic resistance. However, advances in targeted treatment strategies that integrate BRAF, MEK, and EGFR inhibitors, as well as immunotherapy, have demonstrated promising improvements in clinical outcomes. However, variability in trial designs, treatment regimens, and patient populations underscores the necessity of systematically synthesizing the available evidence.This study is a systematic review to evaluate the clinical effectiveness of targeted combination therapies compared with standard regimens in patients with BRAF V600E-mutant mCRC. Comprehensive search was conducted in PubMed, the Cochrane Library, ScienceDirect, and Google Scholar for studies published between 2020 and 2025. Eligible studies included clinical trials and observational cohorts that assessed regimens incorporating BRAF, MEK, EGFR, or immunotherapy inhibitors and that reported outcomes in English. Screening and selection adhered to PRISMA guidelines, and data extraction focused on study design, interventions, and efficacy measures.Eleven studies met the inclusion criteria. Combinations of BRAF, MEK, and EGFR inhibition consistenly improved response rates and desease-free progression compared to standard chemotherapy. Some also demonstrated an overall survival benefit. Pivotal trials, including BREAKWATER and SEAMARK, supported the use of these regimens in first-and second-line settings. Exploratory findings suggested that molecular factors, such as microsatellite instability and BRAF allele fraction, may influence treatment response. In conclusion, targeted combination therapy of BRAF V600E-mutant mCRC improves clinical outcomes compared to standard chemotherapy and is acceptable as a primary treatment option based on tumor molecular profiling. Further research is needed to improve patient selection and address therapy resistance.