Treatment Settings and Outcomes with Regorafenib and Trifluridine/Tipiracil at Third-Line Treatment and beyond in Metastatic Colorectal Cancer: A Real-World Multicenter Retrospective Study

Abstract

Background: Patients with refractory mCRC rarely undergo third-line or subsequent treatment. This strategy could negatively impact their survival. In this setting, regorafenib (R) and trifluridine/tipiracil (T) are two key new treatment options with statistically significant improvements in overall survival (OS), progression-free survival (PFS), and disease control with different tolerance profiles. This study aimed to retrospectively evaluate the efficacy and safety profiles of these agents in real-world practice.

Materials and methods: In 2012-2022, 866 patients diagnosed with mCRC who received sequential R and T (T/R, n = 146; R/T, n = 116]) or T (n = 325]) or R (n = 279) only were retrospectively recruited from 13 Italian cancer institutes.

Results: The median OS is significantly longer in the R/T group (15.9 months) than in the T/R group (13.9 months) (p = 0.0194). The R/T sequence had a statistically significant advantage in the mPFS, which was 8.8 months with T/R vs. 11.2 months with R/T (p = 0.0005). We did not find significant differences in outcomes between groups receiving T or R only. A total of 582 grade 3/4 toxicities were recorded. The frequency of grade 3/4 hand-foot skin reactions was higher in the R/T sequence compared to the reverse sequence (37.3% vs. 7.4%) (p = 0.01), while grade 3/4 neutropenia was slightly lower in the R/T group than in the T/R group (66.2% vs. 78.2%) (p = 0.13). Toxicities in the non-sequential groups were similar and in line with previous studies.

Conclusions: The R/T sequence resulted in a significantly longer OS and PFS and improved disease control compared with the reverse sequence. R and T given not sequentially have similar impacts on survival. More data are needed to define the best sequence and to explore the efficacy of sequential (T/R or R/T) treatment combined with molecular-targeted drugs.

Keywords: metastatic colorectal cancer; real-world study; regorafenib; third-line therapy; trifluridine/tipiracil.

Figure 1

Study design.

Figure 2

Clinical outcomes in sequential treatment. (A) OS in T/R and R/T groups; (B) PFS in T/R and R/T groups. Abbreviations: OS, overall survival; PFS, progression-free survival; T, trifluridine/tipiracil; R, regorafenib.

Figure 3

Subgroup analysis comparing overall survival between patients in the sequential treatment and in the non-sequential treatment with trifluridine/tipiracil and regorafenib groups stratified by baseline characteristics. Abbreviations: HR, hazard ratio; PS, performance status; T, trifluridine/tipiracil, R, regorafenib; mets, metastases; wt, wild type; mt, mutant type; 95% CI, 95% confidence interval; yrs, years.

Figure 4

Subgroup analysis comparing progression-free survival between patients in the sequential treatment and in the non-sequential treatment with trifluridine/tipiracil and regorafenib groups stratified by baseline characteristics. Abbreviations: HR, hazard ratio; PS, performance status; T, trifluridine/tipiracil, R, regorafenib; mets, metastases; mos, months; wt, wild type; mt, mutant type; 95% CI, 95% confidence interval; yrs, years.

Figure 5

Clinical outcomes in non-sequential treatment. (A) OS in T and R groups; (B) PFS in T and R groups. Abbreviations: OS, overall survival; PFS, progression-free survival; T, trifluridine/tipiracil; R, regorafenib.