**3.1 Trials**

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

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

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

## **3.2 Predictors**

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

**83**

**3.3 Toxicity**

*Further Therapeutic Options in Heavily Pretreated Colorectal Cancer Patients*

significantly longer OS and PFS in TAS-102-treated patients [34].

G3 or G4 neutropenia after introduction of this agent [37].

confirmed in a meta-analysis conducted by Chen et al. [39].

the KRAS status, as well as with patients' age and ethnicity [31].

factors turned out to be a predictor of therapeutic response [30].

polymorphisms of genes involved in trifluridine metabolism and thymidine phosphorylase inhibitor excretion had significantly longer PFS and OS [33]. Also, single-nucleotide polymorphisms of genes involved in homologous recombination, such as ATM and XRCC3, could be predictive and prognostic markers in metastatic colorectal cancer treated with TAS-102. The TAS-102-treated patients who carried any G allele in ATM rs609429 polymorphism had significantly longer OS and nonsignificantly longer PFS than carriers of the C/C variant. Also, the presence of any A allele in XRCC3 rs861539 polymorphism was shown to be associated with

Patients with ≥grade 2 chemotherapy-induced neutropenia (absolute neutrophil

median PFS (3.0 vs. 2.4 months) and OS (14.0 vs. 5.6 months) than those without the neutropenia. The presence of neutropenia at 1 month of TAS-102 treatment and higher baseline CEA levels were identified as independent predictors of OS [35]. In another study, grade 3 or 4 CIN-1-month was shown to be associated with longer PFS than grade 0-2 CIN-1-month (4.3 vs. 2.0 months). Moreover, G3 or G4 neutropenia during the first cycle of TAS-102 therapy turned out to be associated with significantly higher DCR (72.2%) than grade 0–2 neutropenia (72.2 vs. 30.9%) [36]. Finally, a significant association was found between baseline creatinine clearance rate of less than 57.1 mL/min prior to TAS-102 administration and the incidence of

Also, longer time elapsed since the onset of the first-line therapy to disease progression (more than 18 months) seems to be a predictor of better response to TAS-102 therapy. In one study, median PFS in TAS-102-treated patients with the time to progression exceeding 18 months was longer than in those who received the first-line therapy ≤18 months before (7 vs. 5 months) [38]. These findings were later

Kwakman et al. identified KRAS-wild type tumor, good performance status (PS0 or PS1), and normal serum levels of lactate dehydrogenase and alkaline phosphatase as independent predictors of better response to TAS-102 treatment. All these factors correlated positively with longer OS. Patients with KRAS-wild type tumors had longer median OS than those with KRAS-mutated malignancies (6.9 vs. 4.9 months), and median OS in persons with ECOG PS0–1 turned out to be longer than in individuals with worse performance status (5.9 vs. 3.2 months) [40]. However, in a meta-analysis involving the data of 1318 patients who received TAS-102, OS was significantly longer than in the study mentioned above, regardless the KRAS mutation status. Furthermore, the treatment response was not influenced by the number of metastatic sites (1, 2, or more) [39]. Also, in a subgroup analysis of patients participating in the RECOURSE trial, neither OS nor PFS correlated with

ECOG performance status (PS0 or PS1), the number of metastatic sites (1 or 2), and the time elapsed since the diagnosis of the first metastasis (18 months or longer) were identified as prognostic factors in the RECOURSE trial; however, none of those

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

) at 1 month (CIN-1-month) of TAS-102 therapy had longer

*DOI: http://dx.doi.org/10.5772/intechopen.85027*

count <1500/mm3

## *Further Therapeutic Options in Heavily Pretreated Colorectal Cancer Patients DOI: http://dx.doi.org/10.5772/intechopen.85027*

polymorphisms of genes involved in trifluridine metabolism and thymidine phosphorylase inhibitor excretion had significantly longer PFS and OS [33]. Also, single-nucleotide polymorphisms of genes involved in homologous recombination, such as ATM and XRCC3, could be predictive and prognostic markers in metastatic colorectal cancer treated with TAS-102. The TAS-102-treated patients who carried any G allele in ATM rs609429 polymorphism had significantly longer OS and nonsignificantly longer PFS than carriers of the C/C variant. Also, the presence of any A allele in XRCC3 rs861539 polymorphism was shown to be associated with significantly longer OS and PFS in TAS-102-treated patients [34].

Patients with ≥grade 2 chemotherapy-induced neutropenia (absolute neutrophil count <1500/mm3 ) at 1 month (CIN-1-month) of TAS-102 therapy had longer median PFS (3.0 vs. 2.4 months) and OS (14.0 vs. 5.6 months) than those without the neutropenia. The presence of neutropenia at 1 month of TAS-102 treatment and higher baseline CEA levels were identified as independent predictors of OS [35]. In another study, grade 3 or 4 CIN-1-month was shown to be associated with longer PFS than grade 0-2 CIN-1-month (4.3 vs. 2.0 months). Moreover, G3 or G4 neutropenia during the first cycle of TAS-102 therapy turned out to be associated with significantly higher DCR (72.2%) than grade 0–2 neutropenia (72.2 vs. 30.9%) [36]. Finally, a significant association was found between baseline creatinine clearance rate of less than 57.1 mL/min prior to TAS-102 administration and the incidence of G3 or G4 neutropenia after introduction of this agent [37].

Also, longer time elapsed since the onset of the first-line therapy to disease progression (more than 18 months) seems to be a predictor of better response to TAS-102 therapy. In one study, median PFS in TAS-102-treated patients with the time to progression exceeding 18 months was longer than in those who received the first-line therapy ≤18 months before (7 vs. 5 months) [38]. These findings were later confirmed in a meta-analysis conducted by Chen et al. [39].

Kwakman et al. identified KRAS-wild type tumor, good performance status (PS0 or PS1), and normal serum levels of lactate dehydrogenase and alkaline phosphatase as independent predictors of better response to TAS-102 treatment. All these factors correlated positively with longer OS. Patients with KRAS-wild type tumors had longer median OS than those with KRAS-mutated malignancies (6.9 vs. 4.9 months), and median OS in persons with ECOG PS0–1 turned out to be longer than in individuals with worse performance status (5.9 vs. 3.2 months) [40]. However, in a meta-analysis involving the data of 1318 patients who received TAS-102, OS was significantly longer than in the study mentioned above, regardless the KRAS mutation status. Furthermore, the treatment response was not influenced by the number of metastatic sites (1, 2, or more) [39]. Also, in a subgroup analysis of patients participating in the RECOURSE trial, neither OS nor PFS correlated with the KRAS status, as well as with patients' age and ethnicity [31].

ECOG performance status (PS0 or PS1), the number of metastatic sites (1 or 2), and the time elapsed since the diagnosis of the first metastasis (18 months or longer) were identified as prognostic factors in the RECOURSE trial; however, none of those factors turned out to be a predictor of therapeutic response [30].
