**3.3 Toxicity**

*Multidisciplinary Approach for Colorectal Cancer*

**3. Trifluridine/tipiracil hydrochloride**

regimen is 35 mg/m2

**3.1 Trials**

TAS-102 is a new oral anti-metabolite drug, a 1:0.5 mixture of a thymidine-based nucleoside analog, alpha,alpha,alpha-trifluorothymidine (trifluridine: FTD), and thymidine phosphorylase inhibitor (tipiracil hydrochloride: TPI) [20–23]. FTD inhibits thymidylate synthase (TS), the key enzyme involved in DNA synthesis, whereas trifluridine incorporates into DNA via phosphorylation and initiates DNA fragmentation [20–22]. TPI enhances the exposure to FTD, improves its bioavailability, and increases the durability of response to this agent [24, 25]. Pre-exposure to 5-FU was shown to enhance FTD incorporation into DNA and to increase antitumor activity of this agent, as shown by lesser viability and proliferation of cancer cells [26]. TAS-102 proved to be effective in GI malignancies with inherent or acquired resistance to 5-FU, as well as in 5-FU-sensitive tumors [20, 21]. TAS-102 has recently been approved as the third-line treatment for adults with refractory metastatic colorectal cancer, patients with contraindications to currently available standard chemotherapy and biological therapy in the EU and USA, and individuals with unresectable advanced or recurrent colorectal cancer in Japan. The standard

twice a day on days 1–5 and 8–12 of each 28-day cycle [24, 27].

The efficacy and safety of TAS-102 were a subject of a double-blind randomized

In a randomized double-blind phase III registration trial, TERRA, Asian patients with metastatic colorectal cancer who previously received at least two lines of systemic treatment were randomized in a 2:1 ratio to either TAS-102 or placebo group. The study confirmed the efficacy of TAS-102 in Asian population. Median OS in the TAS-102 arm was significantly longer than in the placebo group (7.8 vs. 7.1 months). Moreover, the TAS-102-treated patients had significantly lower mortality risk and

In a double-blind phase III registration trial, RECOURSE, 800 patients from Europe, North America, and Asia were randomly assigned to receive TAS-102 or placebo. PFS for the TAS-102 and placebo arm was 2.0 and 1.7 months, respectively. Patients from the TAS-102 arm had significantly longer median OS and significantly longer median time to worsening performance status (7.1 and 5.7 months, respectively) than individuals from the placebo arm (5.3 and 4.0 months, respectively). One-year OS rates for the TAS-102 and placebo arm were 27 and 18%, respectively [30]. Those promising results were further confirmed on a subgroup analysis; median OS for TAS-102-treated patients from the USA, Japan, EU, and Spain ranged between 6.5 and 7.8 months as compared with 4.3–6.7 months for the respective placebo arms, whereas median PFS in the TAS-102 and placebo groups amounted to

Genetic polymorphisms in homologous recombination pathway seem to be a predictor of therapeutic response in metastatic colorectal cancer patients treated with TAS-102. According to Suenaga et al., TAS-102-treated patients with a combination of ENT1 rs760370, MATE1 rs2289669, and OCT2 rs316019 single-nucleotide

phase II trial including Japanese patients with metastatic colorectal cancer. The patients were randomized in a 2:1 ratio to either TAS-102 or placebo arm. Median OS in the TAS-102 arm turned out to be longer than in the placebo arm (9.0 vs. 6.6 months). The most common AEs were hematologic toxicities, with grade 3 or 4

of neutropenia found in 50% of TAS-102-treated patients [28].

significantly longer median survival follow-up time [29].

2.0–2.8 and 1.7–1.8 months, respectively [31, 32].

**82**

**3.2 Predictors**

Hematologic toxicities, including leukopenia, neutropenia, and anemia, and gastrointestinal toxicities, such as nausea/vomiting, diarrhea, and the loss of appetite, as well as fatigue of various grade, were the most frequent side effects observed in patients treated with trifluridine/tipiracil [40–45]. The most common grade 3/4 toxicity was myelosuppression (neutropenia, anemia, febrile neutropenia) [46]. In turn, cardiac ischemia seems to be one of the rarest AEs observed during the

therapy with TAS-102, which implies that this agent might constitute a reasonable option for patients with cardiovascular contraindications for 5-FU treatment [47].

Based on available evidence, TAS-102 seems to be a convenient, manageable, and safe agent to be used in daily clinical practice.

According to the data from the RECOURSE and J003 trials, severe AEs (SAEs) occurred in 27.7% of patients treated with TAS-102. In more than 50% of the patients, the toxicity necessitated a delay or interruption of TAS-102 therapy or dose reduction [41]. However, the incidence of SAEs and AEs leading to treatment discontinuation in TAS-102 and placebo arms was essentially similar, and fatal AEs turned out to be more common in the placebo group [41]. Furthermore, in an open-label expanded-access program, TAS-102 had similar safety profiles in older (≥65 years) and younger (<65 years) patients [48].

Finally, the occurrence of AEs had no significant impact on the quality of life and performance status of patients participating in the RECOURSE trial, even in those in whom TAS-102 had to be discontinued because of its toxicity [49].

## **3.4 TAS-102 combined with other anticancer drugs**

In preclinical studies, TAS-102 combined with cytotoxic drugs (oxaliplatin, irinotecan) showed enhanced activity against recurrent and chemo-naïve colorectal cancers [50, 51]. Also, the regimes including TAS-102 and targeted therapies (cetuximab, panitumumab) or antiangiogenic agents (nintedanib, bevacizumab) were shown to be effective against colorectal cancer in preclinical studies [52, 53].

One phase I/II study demonstrated a promising efficacy and moderate toxicity of TAS-102 plus bevacizumab in patients with metastatic and refractory colorectal cancer [54].

The aim of currently ongoing **TR**iflUridine/tipiracil in **S**econd-line s**T**ud**Y** phase II/III study, the results of which will be available in 2022, is to determine DCR, response rate (RR), OS, PFS, safety profile, and time to treatment failure of trifluridine/tipiracil plus bevacizumab and irinotecan, fluoropyrimidine plus bevacizumab as the second-line treatments in patients with metastatic colorectal cancer who failed to respond to the first-line oxaliplatin-based therapy [55].
