Prognostic factors and outcome measures after BRAF-directed targeted therapy of unresectable metastatic BRAF colorectal cancer: a study cohort-level analysis.

BRAF mutation in metastatic colorectal cancer (mCRC) is associated with a poor prognosis. BRAF inhibitors (BRAFi) plus EGFR inhibitors + / - MEK inhibitors regimens prolonged overall survival (OS), but prognosis remains heterogeneous and intermediate endpoints' reliability after BRAFi-based regimens has been poorly evaluated. The purpose of the study is to investigate the relationship of baseline variables and intermediate endpoints with OS in studies of BRAFi-based regimens. A literature search was conducted to identify clinical trials reporting the outcome of mCRC patients receiving a BRAFi-based regimen. The relationship of each baseline variable and of the intermediate endpoints with OS was calculated by linear regression, separately for the most frequently reported of variables and for progression-free survival (PFS), objective response rate (ORR), or disease control rate (DCR). Finally, the effect of the prognostic baseline variables on the relationship of intermediate endpoints with OS was evaluated. Twelve articles (17 study cohorts) were eligible, and seven variables were reported in at least 15 study cohorts. Older age and microsatellite instability-high (MSI) status were inversely related to longer survival, with MSI maintaining its prognostic effect even in the cohorts receiving BRAFi plus EGFR inhibitor (adjusted R = 0.317; β =  - 0.239; p-value = 0.033). All intermediate endpoints showed a significant relationship with OS. After adjusting for MSI, the relationship of DCR with OS significantly improved, whereas the changes in the relationship of ORR and PFS with OS were not significant.