Fruquintinib or Regorafenib? A Weighted Toxicity Score Analysis to Facilitate Better Discussions on Toxicity and Benefits in Later-line Colorectal Cancer Treatment

Background: Regorafenib and fruquintinib are key treatment options for later-line therapy in metastatic colorectal cancer. In the absence of direct comparative studies, treatment selection frequently depends on safety profiles. The weighted toxicity score (WTS) was developed to summarize overall toxicity within a single arm of a randomized clinical trial, facilitating toxicity-benefit evaluations. Material and methods: In this analysis, WTS was applied to the CORRECT and FRESCO-2 trials. Adverse events (AEs) from both studies were analyzed, and toxicity burden was assessed by comparing WTS differences between trial arms. AEs were classified as either measurable or symptomatic, resulting in the calculation of measurable-WTS (M-WTS) and symptomatic-WTS (S-WTS). For a deeper characterization of treatment-attributable toxicities between the drugs, 3 additional metrics were employed: attributable fraction, which quantifies the proportion of each toxicity rate attributable to the study drug, risk difference, and toxicity incidence rate ratio (TIRR), which measures the frequency of each AE adjusted for toxicity likely related to the underlying disease. Results: After adjustment for placebo-related toxicity, fruquintinib and regorafenib increased the toxicity burden by 97.8% and 85.1%, respectively. Regorafenib was associated with a greater increase in symptomatic toxicity, while fruquintinib was linked to a greater increase in measurable toxicities. Comparative TIRR analysis demonstrated that regorafenib was associated with a higher risk of dysphonia, oral mucositis, weight loss, and fever. In contrast, fruquintinib exceeded regorafenib in the risk of hand-foot skin reaction, transaminase elevation, constipation, and hypertension. Conclusion: These findings may support clinicians in making more informed treatment decisions by distinguishing between drug-related toxicity and cancer-related effects.