Redefining the Use of Regorafenib and Trifluridine/Tipiracil Without Bevacizumab in Refractory Metastatic Colorectal Cancer: Findings from the ReTrITA Study

Abstract

Background: Regorafenib (R) and trifluridine/tipiracil (T) are approved treatments for metastatic colorectal cancer (mCRC) in refractory cases. However, the optimal sequencing of these agents is unknown. The ReTrITA study planned to assess the real-world efficacy of R and T, administered either sequentially or as monotherapy, in a large Italian multicentre population. Methods: This retrospective observational analysis comprised 1156 mCRC patients treated between 2012 and 2023 at 17 Italian cancer centres. Patients were divided into four groups: sequential T/R (n = 261), sequential R/T (n = 155), R monotherapy (n = 313), and T monotherapy (n = 427). The primary objectives were overall survival (OS) and progression-free survival (PFS), with secondary goals being disease control rate, objective response rate, and treatment-related toxicity. Results: The monotherapy cohorts showed no significant difference in OS (R: 5.0 months; T: 5.9 months; p = 0.8371) or PFS (R: 3.2 months; T: 3.3 months; p = 0.6531). Compared to T/R, the sequential R/T group had significantly better outcomes: median OS was 16.6 vs. 12.6 months (HR = 0.67; p = 0.0004), and median PFS was 11.5 vs. 8.5 months (HR = 0.60; p < 0.0001). The survival advantage of R/T was consistent across clinical subgroups. The toxicity profiles were comparable with known safety data, with a lower prevalence of neutropenia reported in the R/T sequence. Conclusions: ReTrITA confirms the efficacy of R and T as monotherapies and provides compelling real-world evidence that the R/T sequence improves survival in refractory mCRC. These findings support a regorafenib-first approach in patients who are eligible, and they emphasise the need for future research into combination strategies and comparisons with newer drugs such as fruquintinib.

Keywords: metastatic colorectal cancer; real-world evidence; regorafenib; sequencing; survival; toxicity; trifluridine/tipiracil.

Figure 1

ReTrITA study design. Abbreviations: T, trifluridine/tipiracil; R, regorafenib.

Figure 2

Kaplan–Meier overall survival (OS) graphs showing the differences between treating patients with metastatic colorectal cancer (mCRC) in the ReTrITA study sequentially with trifluridine/tipiracil followed by regorafenib (T/R) versus regorafenib followed by trifluridine/tipiracil (R/T).

Figure 3

Progression-free survival (PFS) curves comparing sequential T/R and R/T treatments using the Kaplan–Meier method.

Figure 4

Kaplan–Meier curves for overall survival (OS), comparing the cohorts receiving monotherapy.

Figure 5

Kaplan–Meier analysis of the monotherapy cohorts’ progression-free survival (PFS).

Figure 6

A forest plot showing subgroup analyses for overall survival (OS) and progression-free survival (PFS) in metastatic colorectal cancer patients treated with sequential T/R versus R/T. Statistically significant p-values are reported in bold. Abbreviations: OS, overall survival; PFS, progression-free survival; HR, hazard ratio; PS, performance status; T, trifluridine/tipiracil; R, regorafenib; CI, confidence interval; and n, number. The bold numbers in the table indicate statistically significant p-values.

Figure 7

A forest plot showing subgroup analyses for overall survival (OS) and progression-free survival (PFS) for patients receiving non-sequential trifluridine/tipiracil (T) or regorafenib (R) in the ReTrITA study. Statistically significant p-values are reported in bold. Abbreviations: OS, overall survival; PFS, progression-free survival; HR, hazard ratio; PS, performance status; T, trifluridine/tipiracil; R, regorafenib; CI, confidence interval; and n, number. The bold numbers in the table indicate statistically significant p-values.