Impact of primary tumor sidedness and sex on prognosis and anti-epidermal growth factor receptor antibody efficacy in BRAF-mutant metastatic colorectal cancer: a pooled analysis of AIO studies FIRE-1, CIOX, FIRE-3, XELAVIRI, and VOLFI

Abstract

Background: Primary tumor (PT) sidedness is an established prognostic marker in metastatic colorectal cancer (mCRC) and has a predictive impact on the efficacy of anti-epidermal growth factor receptor (anti-EGFR) antibody [monoclonal antibody (mAb)] in patients with RAS wild-type mCRC. This investigation focuses on patients with BRAF^V600E-mutated (BRAFmt) mCRC and examines the efficacy of anti-EGFR mAbs in relation to primary tumor sidedness (PTS).

Patient and methods: This pooled analysis was carried out using individual patient data from five randomized studies in the first-line setting of mCRC. The population of interest was limited to patients with BRAFmt mCRC and known PTS. For analysis, treatment was stratified into two groups: those treated with anti-EGFR mAbs and those without. Dichotomous variables, such as overall response rate and objective response rate (ORR), were compared using chi-square or Fisher's exact test. Time-to-event endpoints [progression-free survival (PFS) and overall survival (OS)] were analyzed using the Kaplan-Meier method, log-rank test, and Cox regression. An interaction test was carried out via Cox regression.

Results: A total of 102 patients with BRAFmt mCRC were identified. The type of targeted therapy (anti-EGFR-based versus non-anti-EGFR) did not significantly impact the outcome. However, in patients with left-sided primary tumors, anti-EGFR mAb-based treatment, compared with non-anti-EGFR, was associated with a higher ORR (58% versus 34%; P < 0.01), trended toward improved PFS [hazard ratio (HR) 0.62; 95% confidence interval (CI) 0.34-1.13; P = 0.12], and demonstrated prolonged OS (HR 0.38; 95% CI 0.20-0.72; P < 0.01). In patients with right-sided primary tumors, anti-EGFR-based therapy had no effect on ORR (33% versus 36%; P > 0.99), induced inferior PFS (HR 1.97; 95% CI 1.12-3.47; P = 0.02), and trended toward a worse OS (HR 1.76; 95% CI 0.99-3.13; P = 0.05).

Conclusion: This analysis suggests that PTS has predictive value for the efficacy of anti-EGFR mAb in the first-line treatment of BRAFmt mCRC.

Keywords: BRAF mutation; EGFR antibody; metastatic colorectal cancer; primary tumor location; primary tumor sidedness.

Figure 1

Progression-free survival (PFS) and overall survival (OS) according to primary tumor sidedness and sex in BRAFmt metastatic colorectal cancer (mCRC). (A) PFS according to primary tumor sidedness in BRAFmt mCRC. (B) OS according to primary tumor sidedness in BRAFmt mCRC. (C) PFS in male patients with BRAFmt mCRC according to primary tumor sidedness. (D) OS in male patients with BRAFmt mCRC primary tumor sidedness. (E) PFS in female patients with BRAFmt mCRC according to primary tumor sidedness. (F) OS in female patients with BRAFmt mCRC according to primary tumor sidedness. P values correspond to Cox regression. BRAFmt, BRAF^V600E mutant/RAS wild-type; CI, confidence interval; HR, hazard ratio; OS, overall survival; PT, primary tumor.

Figure 2

Progression-free survival (PFS) and overall survival (OS) in BRAFmt metastatic colorectal cancer (mCRC) cases when treated with or without anti-EGFR. (A) PFS according to treatment with or without anti-EGFR in BRAFmt mCRC. (B) OS according to treatment with or without anti-EGFR in BRAFmt mCRC. P values correspond to Cox regression. BRAFmt, BRAF^V600E mutant/RAS wild-type; CI, confidence interval; EGFR, epidermal growth factor receptor; HR, hazard ratio.

Figure 3

Progression-free survival (PFS) and overall survival (OS) in BRAFmt metastatic colorectal cancer (mCRC) cases according to primary tumor sidedness and treatment with or without anti-EGFR. (A) PFS in left-sided primary tumor (LSPT) according to treatment with or without anti-EGFR in BRAFmt mCRC. (B) OS in LSPT according to treatment with or without anti-EGFR in BRAFmt mCRC. (C) PFS in right-sided primary tumor (RSPT) according to treatment with or without anti-EGFR in BRAFmt mCRC. (D) OS in RSPT according to treatment with or without anti-EGFR in BRAFmt mCRC. P values correspond to Cox regression. BRAFmt, BRAF^V600E mutant/RAS wild-type; CI, confidence interval; EGFR, epidermal growth factor receptor; HR, hazard ratio.