Triplet Therapy Does Not Improve Survival in Mutant Metastatic Colorectal Cancer

FOLFOXIRI plus anti-VEGF therapy had no survival benefit over doublet chemotherapy for BRAFV600E mutant metastatic colorectal cancer.

Among patients with colorectal cancer (CRC) and a BRAF mutation at amino acid 600 (BRAFV600E), doublet chemotherapy had similar survival outcomes compared with fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) with bevacizumab (BEV) or ramucirumab plus anti-vascular endothelial growth factor (VEGF) triplet therapy. These findings were published in Clinical Colorectal Cancer.

The multicenter, retrospective, registry-based study was conducted by the West Japan Oncology Group. Between 2014 to 2019, patients (N=170) with BRAFV600E CRC who received doublet (n=91) or triplet (n=79) chemotherapy at 33 hospitals in Japan were compared for survival outcomes using an inverse probability of treatment weighting approach.

The study population included 51% men, a median age of 61 (range, 19-83) years, 63% had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0, 74% had metastatic CRC, and 64% had 2 or more metastatic sites. The doublet and triplet groups were well balanced, except that the doublet recipients were older (P =.0022) and more had ECOG PS scores greater than 0 (P =.02). Most of the doublet group (n=57) received FOLFOXIRI plus BEV.

Median progression-free survival (PFS) was 7.8 months among the doublet group and 9.7 months among the triplet group (hazard ratio [HR], 0.82; 95% CI, 0.60-1.13; P =.22). Median overall survival was 17.5 and 18.8 months for the doublet and triplet groups (HR, 0.88; 95% CI, 0.62-1.25; P =.48), respectively.

This real-world retrospective study revealed that the triplet chemotherapy was not superior to the doublet chemotherapy in terms of OS [overall survival] … and PFS [progression-free survival]…

Similar results for PFS (HR, 0.86; 95% CI, 0.69-1.08; P =.20) and overall survival (HR, 0.93; 95% CI, 0.73-1.20; P =.59) were observed in the inverse probability of treatment weighting analysis.

In the subgroup analyses, significant interactions for primary resection status (P =.0015), sex (P =.006), liver metastasis (P =.007), and disease status (P =.04) were observed for PFS, in which triplet therapy was favored among patients without primary resection (HR, 0.52), men (HR, 0.68), with liver metastasis (HR, 0.57), and metastatic CRC (HR, 0.74). For overall survival, a significant sex interaction was observed (P =.04), favoring triplet therapy among men (HR, 0.67).

Any adverse event was reported by 47% of doublet and 65% of triplet therapy recipients. The most common event was neutropenia, occurring among 24% of the doublet and 51% of the triplet therapy groups.

Study limitations include the nonrandomized design, the small sample size, and disparities in treatment periods.

“This real-world retrospective study revealed that the triplet chemotherapy was not superior to the doublet chemotherapy in terms of OS [overall survival] (HR, 0.88; 95% CI, 0.62-1.25; P =.48) and PFS (HR, 0.82; 95% CI, 0.60-1.13; P =.22),” the study authors wrote.

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Shimozaki K, Hirata K, Sato T, et al. WJOG13219G: The efficacy and safety of FOLFOXIRI or doublet plus anti-VEGF therapy in previously untreated BRAFV600E mutant metastatic colorectal cancer: A multi-institutional registry-based study (BRACELET study). Clin Colorectal Cancer. Published online August 11, 2022. doi:10.1016/j.clcc.2022.08.002