Proteinuria with extended VEGF inhibitor therapy in RAS-mutant metastatic colorectal cancer: incidence, interruptions, and exploratory survival analysis

Purpose Vascular endothelial growth factor inhibitors (VEGFIs) are essential for the treatment of metastatic colorectal cancer (mCRC). Given the ineffectiveness of epidermal growth factor receptor inhibitors in managing RAS-mutant mCRC, long-term VEGFI therapy is often required; however, it is associated with an increased risk of proteinuria. As the use of VEGFI in later-line mCRC treatment has become more prevalent, proteinuria has emerged as a critical dose-limiting toxicity. However, its effect on the treatment outcomes remains unclear. This study examined the incidence of proteinuria during extended VEGFI use and its effect on overall survival (OS) in RAS-mutant mCRC. Methods This single-center retrospective study analyzed patients with RAS-mutant stage IV mCRC treated with first-line VEGFIs at Gifu University Hospital. Proteinuria incidence was estimated using the Kaplan–Meier method. OS from a 12-month landmark was compared according to the occurrence of dipstick proteinuria 2+ or greater within the first year using Cox regression. Results Among 185 patients, the Kaplan–Meier cumulative incidence of dipstick proteinuria 2+ or greater was 11%, 37%, and 45% at 1, 2, and 3 years, respectively. Of 123 patients in the 12-month landmark cohort, 13 had early-onset proteinuria. The age- and sex-adjusted HR for subsequent mortality was 1.81 (95% CI 0.84–3.86; p = 0.128). Conclusions Proteinuria accumulated during extended VEGFI therapy. Early-onset proteinuria may be associated with poorer subsequent OS, although the wide confidence interval precludes a definitive conclusion. These findings underscore the importance of careful proteinuria monitoring during long-term VEGFI treatment.