Survival Outcomes in Metastatic Colorectal Cancer Patients with BRAF Mutations Undergoing Targeted Chemotherapy: A Reconstructed Individual Patient Data Meta-Analysis of Randomized Controlled Trials.
7 affiliations
- 1Department of Internal Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, United States. [email protected].
- 2Mayo Clinic School of Graduate Medical Education, Mayo Clinic, Rochester, MN, United States.
- 3Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN, United States.
- 4Department of Internal Medicine, University of Central Florida, Tallahassee, FL, USA.
- 5Sindh Medical College, Jinnah Sindh Medical University, Karachi, Pakistan.
- 6Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan.
- 7Division of Hematology & Oncology, Department of Internal Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, United States.
Abstract
Background
BRAF V600E-mutant metastatic colorectal cancer (mCRC) represents an aggressive molecular subtype associated with poor prognosis and limited response to conventional chemotherapy. Although multiple targeted strategies, including anti-vascular endothelial growth factor (VEGF), anti-epidermal growth factor receptor (EGFR), and BRAF-directed therapies, are used in clinical practice, their comparative effectiveness remains uncertain. We performed a reconstructed individual patient-data (IPD) meta-analysis of randomized controlled trials (RCTs) to evaluate survival outcomes across targeted therapeutic classes in BRAF-mutant mCRC.Methods
A systematic search of PubMed, Embase, Scopus, and Cochrane databases was conducted through July 2025 to identify RCTs reporting survival outcomes for BRAF-mutant mCRC. Kaplan-Meier curves were digitized and IPD reconstructed using established methods. A one-stage meta-analysis using Cox proportional hazards models was performed to estimate pooled overall survival (OS) and progression-free survival (PFS). Models were adjusted for study-level covariates and clustering, with Bonferroni correction applied for multiple comparisons.Results
Eighteen RCTs comprising 11,931 participants were included. Pooled median OS was 22.3 months for BRAF-directed regimens, 17.1 months for VEGF-targeted therapy, and 10.1 months for EGFR-directed therapy across studies evaluating first-line therapy. Across first-line studies, BRAF inhibitor directed regimen was associated with significantly improved OS compared with EGFR inhibition (HR 0.43, 95% CI 0.31-0.60; P < 0.001) and improved PFS (HR 0.47, 95% CI 0.42-0.53; P < 0.001). VEGF inhibition also demonstrated superior OS compared with EGFR inhibition (HR 0.56, 95% CI 0.38-0.81; p < 0.001). EGFR-directed regimen consistently demonstrated the poorest survival outcomes across analyses.Discussion
In this reconstructed IPD meta-analysis, BRAF-directed therapies were associated with the most favourable survival outcomes, whereas EGFR directed regimen demonstrated limited clinical benefit in BRAF-mutant mCRC. These results highlight the importance of biologically aligned pathway-targeted therapy and provide comparative evidence to inform treatment selection in this aggressive molecular subtype.
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BibTeX
@article{kazmi2026survival,
title = {{Survival Outcomes in Metastatic Colorectal Cancer Patients with BRAF Mutations Undergoing Targeted Chemotherapy: A Reconstructed Individual Patient Data Meta-Analysis of Randomized Controlled Trials.}},
author = {Syeda Kanza Kazmi and Muhammad Abdul Rehman and Hanaa Tariq and Aqsa Kabir and Jalib Ahmed and Nelson Shu-Sang S Yee},
journal = {Journal of gastrointestinal cancer},
year = {2026},
month = oct,
doi = {10.1007/s12029-026-01597-6},
url = {https://europepmc.org/article/MED/42957919},
note = {CC BY},
}
RIS
TY - JOUR
TI - Survival Outcomes in Metastatic Colorectal Cancer Patients with BRAF Mutations Undergoing Targeted Chemotherapy: A Reconstructed Individual Patient Data Meta-Analysis of Randomized Controlled Trials.
AU - Syeda Kanza Kazmi
AU - Muhammad Abdul Rehman
AU - Hanaa Tariq
AU - Aqsa Kabir
AU - Jalib Ahmed
AU - Nelson Shu-Sang S Yee
PY - 2026
DA - 2026/10/30
JO - Journal of gastrointestinal cancer
DO - 10.1007/s12029-026-01597-6
UR - https://europepmc.org/article/MED/42957919
AB - Background BRAF V600E-mutant metastatic colorectal cancer (mCRC) represents an aggressive molecular subtype associated with poor prognosis and limited response to conventional chemotherapy. Although multiple targeted strategies, including anti-vascular endothelial growth factor (VEGF), anti-epidermal growth factor receptor (EGFR), and BRAF-directed therapies, are used in clinical practice, their comparative effectiveness remains uncertain. We performed a reconstructed individual patient-data (IPD) meta-analysis of randomized controlled trials (RCTs) to evaluate survival outcomes across targeted therapeutic classes in BRAF-mutant mCRC.Methods A systematic search of PubMed, Embase, Scopus, and Cochrane databases was conducted through July 2025 to identify RCTs reporting survival outcomes for BRAF-mutant mCRC. Kaplan-Meier curves were digitized and IPD reconstructed using established methods. A one-stage meta-analysis using Cox proportional hazards models was performed to estimate pooled overall survival (OS) and progression-free survival (PFS). Models were adjusted for study-level covariates and clustering, with Bonferroni correction applied for multiple comparisons.Results Eighteen RCTs comprising 11,931 participants were included. Pooled median OS was 22.3 months for BRAF-directed regimens, 17.1 months for VEGF-targeted therapy, and 10.1 months for EGFR-directed therapy across studies evaluating first-line therapy. Across first-line studies, BRAF inhibitor directed regimen was associated with significantly improved OS compared with EGFR inhibition (HR 0.43, 95% CI 0.31-0.60; P < 0.001) and improved PFS (HR 0.47, 95% CI 0.42-0.53; P < 0.001). VEGF inhibition also demonstrated superior OS compared with EGFR inhibition (HR 0.56, 95% CI 0.38-0.81; p < 0.001). EGFR-directed regimen consistently demonstrated the poorest survival outcomes across analyses.Discussion In this reconstructed IPD meta-analysis, BRAF-directed therapies were associated with the most favourable survival outcomes, whereas EGFR directed regimen demonstrated limited clinical benefit in BRAF-mutant mCRC. These results highlight the importance of biologically aligned pathway-targeted therapy and provide comparative evidence to inform treatment selection in this aggressive molecular subtype.
SN - 1941-6628
SN - 1941-6636
ER -