Sequential Treatment with Regorafenib and Trifluridine/Tipiracil ± Bevacizumab in Refractory Metastatic Colorectal Cancer in Community Clinical Practice in the USA

Abstract

Background: Regorafenib (R) and Trifluridine/Tipiracil ± bevacizumab (T) are approved for treating refractory metastatic colorectal cancer (mCRC) but their optimal sequence is unclear. This study describes the characteristics/clinical outcomes of patients with mCRC in U.S. clinical practice treated sequentially with R-T or T-R. Methods: A retrospective cohort study of 818 patients treated with R-T or T-R between January 2015 and November 2022 was conducted using an electronic health record-derived database. The primary objective was to describe the demographic/clinical characteristics and biomarker status of patients treated with R-T or T-R, stratified by treatment line/age. Secondary objectives were to evaluate/estimate the frequency of neutropenia and myelosuppression-related treatments, the number/type of subsequent therapies, time to treatment discontinuation (TTD), and overall survival (OS). Results: Baseline characteristics were similar among patients who received R-T (n = 393) or T-R (n = 425). Lower rates of moderate/severe neutropenia (26%/12% vs. 32%/16%) and granulocyte colony-stimulating factor/erythropoietin use (22% vs. 24%) were observed with R-T versus T-R. The median TTD was 8.7 months and 8.5 months with R-T versus 8.1 months and 7.9 months with T-R as third- and fourth-line treatment, respectively. The median OS was 13.1 months and 11.6 months with R-T versus 11.5 months and 10.3 months with T-R as third- and fourth-line treatment, respectively. Conclusions: This study did not show a statistically significant difference in OS with R-T versus T-R. Although limited by its retrospective nature, the study suggested R-T may be preferable to T-R given the observed reduction in neutropenia/myelosuppression-related treatments.

Keywords: Regorafenib; TAS-102; Trifluridine/Tipiracil; colorectal cancer; community practice; metastatic; real world; refractory; sequence.

Figure 1

Study schema. GIST: gastrointestinal stromal tumor, HCC: hepatocellular carcinoma, mCRC: metastatic colorectal cancer, R: Regorafenib, T: TAS-102 ± bevacizumab.

Figure 2

OS for R-T and T-R in third-line patients. * Adjusted for age, gender, ECOG PS, KRAS mutation status, prior targeted treatments (anti-EGFR or bevacizumab), stage at initial diagnosis, tumor sidedness, and site of metastasis. HRs (Cox proportional hazards model) are for exploratory purposes only (baseline not balanced). OS was calculated from the index date to the date of death due to any cause; patients who were alive at the data cut-off date were censored at the last confirmed activity date. CI: confidence interval, ECOG PS: Eastern Cooperative Oncology Group performance status, EGFR: epidermal growth factor receptor, HR: hazard ratio, IQR: interquartile range, KM: Kaplan–Meier, OS: overall survival, R: Regorafenib, T: TAS-102 ± bevacizumab.

Figure 3

OS for R-T and T-R in fourth-line patients. * Adjusted for age, gender, ECOG PS, KRAS mutation status, prior targeted treatments (anti-EGFR or bevacizumab), stage at initial diagnosis, tumor sidedness, and site of metastasis. HRs (Cox proportional hazards model) are for exploratory purposes only (baseline not balanced). OS was calculated from the index date to the date of death due to any cause; patients who were alive at the data cut-off date were censored at the last confirmed activity date. CI: confidence interval, ECOG PS: Eastern Cooperative Oncology Group performance status, EGFR: epidermal growth factor receptor, HR: hazard ratio, IQR: interquartile range, KM: Kaplan–Meier, OS: overall survival, R: Regorafenib, T: TAS-102 ± bevacizumab.

Figure 4

Time to discontinuation for R-T and T-R in third-line patients. * Adjusted for age, gender, ECOG PS, KRAS mutation status, prior targeted treatments (anti-EGFR or bevacizumab), stage at initial diagnosis, tumor sidedness, and site of metastasis. HRs (Cox proportional hazards model) are for exploratory purposes only (baseline not balanced). CI: confidence interval, ECOG PS: Eastern Cooperative Oncology Group performance status, EGFR: epidermal growth factor receptor, HR: hazard ratio, IQR: interquartile range, KM: Kaplan–Meier, R: Regorafenib, T: TAS-102 ± bevacizumab.

Figure 5

Time to discontinuation for R-T and T-R in fourth-line patients. * Adjusted for age, gender, ECOG PS, KRAS mutation status, prior targeted treatments (anti-EGFR or bevacizumab), stage at initial diagnosis, tumor sidedness, and site of metastasis. HRs (Cox proportional hazards model) are for exploratory purposes only (baseline not balanced). CI: confidence interval, ECOG PS: Eastern Cooperative Oncology Group performance status, EGFR: epidermal growth factor receptor, HR: hazard ratio, IQR: interquartile range, KM: Kaplan–Meier, R: Regorafenib, T: TAS-102 ± bevacizumab.

Figure 6

Median OS (A) and time to discontinuation (B) (months [95% CI]) across subgroups of patients treated with R-T or T-R. * HR adjusted for index line, age, gender, ECOG PS, KRAS mutation status, prior anti-EGFR, prior bevacizumab, stage at initial diagnosis, tumor sidedness, and site of metastasis. 3L: third line, 4L: fourth line, BEV: bevacizumab, CI: confidence interval; ECOG PS: Eastern Cooperative Oncology Group performance status, EGFR: epidermal growth factor receptor, HR: hazard ratio, OS: overall survival, R: Regorafenib, T: TAS-102 ± bevacizumab, TTD: time to treatment discontinuation, WT: wild type.