Real-World Activity and Safety of Trifluridine-Tipiracil Plus Bevacizumab Therapy in Patients with Refractory Metastatic Colorectal Cancer

Abstract

Background The combination of trifluridine-tipiracil and bevacizumab was compared with trifluridine-tipiracil monotherapy in a randomized, open-label, phase II trial, resulting in a statistically significant and clinically relevant improvement in progression-free survival (PFS), with tolerable toxicity in patients with refractory metastatic colorectal cancer (mCRC); however, evidence supporting the role of this combination in a real-world setting is limited. Objective The aim of our work was to provide further evidence on the activity and safety of this combination in a real-world series of Western mCRC patients refractory or intolerant to previous therapies. Patient and Methods We conducted a retrospective, observational study of patients with mCRC refractory or intolerant to standard therapies. Patients were treated with trifluridine-tipiracil and bevacizumab. Previous therapy with fluoropyrimidines, irinotecan, oxaliplatin, bevacizumab, aflibercept, regorafenib, and cetuximab or panitumumab (only RAS wild-type) was allowed, as was previous participation in clinical trials. Clinicopathological characteristics, overall response rate (ORR), disease control rate (DCR), overall survival (OS), PFS, and safety data were retrospectively collected and analyzed. Results We recorded 31 patients treated between 1 December 2017 and 30 June 2022. Median age was 69 years (range 38–82 years), 39% were male, 100% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–1, tumor location was left-sided in 77% of cases, 54% had synchronous presentation, 35% were RAS mutant, 3% were BRAF mutant, and 71% underwent primary tumor resection; 64% of patients had liver metastases, 55% had lung metastases, and 23% had peritoneal carcinomatosis. The median number of previous treatment lines was 2 (range 0–5), and 84% of patients received at least one previous anti-angiogenic agent. The ORR and DCR were 3% and 71%, respectively. With a median follow-up of 8 months (range 2–39), median PFS was 6 months (95% confidence interval [CI] 3.1–8.9 months) and median OS was 14 months (95% CI 10.1–17.8 months). Adverse events of any grade were reported in 58% of patients. The most common grade 3–4 toxicities were neutropenia (19%) and anemia (6%); 35% of patients required either dose delays or dose reductions due to toxicity. Granulocyte colony-stimulating factor (G-CSF) prophylaxis was administered either on first or subsequent cycles of treatment in 35% of patients. No treatment-related deaths occurred. Sixty percent of the patients who discontinued treatment eventually received one or more lines of subsequent therapy. Conclusions Our series provides further evidence on the activity and safety of the combination of trifluridine-tipiracil and bevacizumab in a real-world series of Western refractory mCRC patients.

A Systematic Review and Meta-Analysis of Trifluridine/Tipiracil plus Bevacizumab for the Treatment of Metastatic Colorectal Cancer: Evidence from Real-World Series

“…The main types of identified articles leading to exclusion were reviews, guidelines, and editorials. Ten series for potential inclusion in the meta-analysis were identified [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. After evaluation, two of the series were excluded, as they contained, based on the authors, similar centers and dates of study performance, potentially overlapping patients [ 26 , 27 ].…”

“…Among the remaining eight series, six series were from Asia (of which five series were from Japan, where trifluridine/tipiracil was initially developed, and one series from China, Table 1 ) [ 18 , 21 , 22 , 23 , 24 , 25 ]. Two series were from European centers [ 19 , 20 ]. Dates of publication were between 2020 and 2022, and a total of 441 patients were described.…”

“…Regarding efficacy according to line of therapy, one of the two western studies included in the meta-analysis showed that patients with more than three lines of previous therapies had an inferior PFS of 3 months compared to PFS of 8 months in patients with three previous lines of therapy [ 19 ]. This difference was not statistically significant.…”