Safety Of TAS-102 Research Articles

Analysis of neutropenia as a predictive factor of the efficacy of trifluridine-tipiracil treatment.

Trifluridine-tipiracil (TAS-102), an oral cytotoxic agent used in adult patients with refractory metastatic colorectal cancer (mCRC), has been associated with neutropenia (chemotherapy-induced neutropenia) (CIN)). We evaluated the efficacy and safety of TAS-102 in a group of 45 mCRC patients (median age 66 years) in Huelva province, Spain, in a retrospective, multicenter observational study. We showed that the association between TAS-102 and CIN can be used as a predictor of efficacy. 20% (9/45) of patients with an Eastern Cooperative Oncology Group (ECOG) score of 2 had received at least one previous chemotherapy treatment. Overall, 75.5% (34/45) and 28.9% (13/45) had received anti-VEGF and anti-EGFR monoclonal antibodies, respectively. Additionally, 80% (36/45) of patients had received third-line treatment. The mean treatment period, duration of overall survival (OS), and duration of progression-free survival (PFS) were 3.4, 12, and 4 months, respectively. A partial response was seen in 2 patients (4.3%), and disease stabilization was observed in 10 patients (21.3%). Neutropenia was the most frequent grade 3 - 4 toxicity (46.7%; 21/45). Other findings were anemia (77.8%; 35/45), all grades of neutropenia (73.3%; 33/45), and gastrointestinal toxicity (53.3%; 24/45). The dose of TAS-102 needed to be reduced in 68.9% (31/45) of patients, whereas treatment needed to be interrupted in 80% (36/45) of patients. Grade 3 - 4 neutropenia was a positive prognostic factor for OS (p = 0.023). A retrospective evaluation shows that grade 3 - 4 neutropenia is an independent predictor of treatment response and survival in patients undergoing routine treatment for mCRC, but this finding needs confirmation in a prospective study.

Tas-102 for Refractory Metastatic Colorectal Cancer: A Multicenter Retrospective Cohort Study.

Trifluridine/tipiracil (TAS-102) is an oral chemotherapy approved for the treatment of metastatic colorectal cancer. The efficacy and tolerability of TAS-102 were shown in phase II-III clinical trials and in several real-life studies. The elderly and other special subgroups are underrepresented in published literature. We conducted a retrospective multicenter study to assess the effectiveness and safety of TAS-102 in consecutive patients with pretreated mCRC. In particular, we estimated the effectiveness and safety of TAS-102 in elderly patients (aged ≥70, ≥75 and ≥80 years) and in special subgroups, e.g., patients with concomitant heart disease. One hundred and sixty patients were enrolled. In particular, 71 patients (44%) were 70 years of age or older, 50 (31%) were 75 years of age or older, and 23 (14%) were 80 years of age or older. 19 patients (12%) had a concomitant chronic heart disease, three (2%) patients were HIV positive, and one (<1%) patient had a DPYD gene polymorphism. In 115 (72%) cases TAS-102 was administered as a third-line treatment. The median overall survival (OS) in the overall population was 8 months (95% confidence interval [CI], 6-9), while the median progression-free survival (PFS) was 3 months (95% CI, 3-4). No significant age-related reduction in effectiveness was observed in the subpopulations of elderly patients included. The toxicity profile was acceptable in both the whole and subgroups' population. Our study confirms the effectiveness and safety of TAS-102 in patients with pretreated mCRC, suggesting a similar risk-benefit profile in the elderly.

Efficacy and safety of trifluridine/tipiracil plus bevacizumab versus trifluridine/tipiracil monotherapy for refractory metastatic colorectal cancer: A retrospective study.

e15562 Background: There had been no phase III trial to compare the efficacy between trifluridine/tipiracil (TAS-102) plus bevacizumab (BEV) with TAS-102 monotherapy in refractory metastatic colorectal cancer (mCRC). Our study sought to investigate the efficacy and safety of TAS-102 plus BEV versus TAS-102 monotherapy in these patients. Methods: We retrospectively analyzed the patients with refractory mCRC who received TAS-102 (35 mg/m2 twice daily; day 1–5 and 8–12; every 28 days) with or without BEV (5 mg/kg; day 1,15; every 28 days) between November 2020 and October 2022 in Hunan Cancer Hospital. All patients had previously received at least second-line treatment. The primary endpoint was overall survival (OS). Results: A total of 58 patients received TAS-102 plus BEV, and another 32 patients received TAS-102 monotherapy. With a median follow-up of 4.60 months (range, 0.20–22.80), the median overall survival (mOS) was 10.83 months [95% confidence interval (CI), 10.10–NA] for TAS-102 plus BEV, 7.43months (95% CI, 5.17–NA) for TAS-102 monotherapy. The hazard ratio (HR) was 0.90 (95% CI, 0.42–1.92), P= 0.78. Median progression-free survival (mPFS) was 4.67 months (95% CI, 3.57–7.37) for TAS-102 plus BEV, and 4.30 months (95% CI, 3.03–NA) for TAS-102 monotherapy. The HR was 1.04 (95% CI, 0.54–1.99), P= 0.91. The Cox multivariate regression analysis demonstrated that the patients who received treatment after TAS-102 with or without BEV(HR:0.25;95% CI, 0.09-0.71) and previously undergone Irinotecan (HR:0.23;95% CI, 0.06-0.95) were independent risk factors for OS and the patients who previously received Cetuximab was confirmed to have a significant better PFS(HR:0.17;95% CI, 0.03-0.91). Of the 70 patients who were evaluated, the TAS-102 plus BEV showed higher ORR and DCR than TAS-102 monotherapy, but the difference was not significant (ORR: 12.2% versus 0%; p= 0.16; and DCR: 77.5% versus 61.9%; p= 0.29). The incidence of platelet count decrease (grade ≥3) was significantly higher in the TAS-102 plus BEV group than the TAS-102 monotherapy group (3.00% vs. 0.00%, p = 0.03), whereas other adverse events were comparable between the two groups. Conclusions: Compared with TAS-102 monotherapy, TAS-102 plus BEV seemed to have comparable safety but improved disease control and prognosis in patients with refractory mCRC, although the difference was not significant. Further prospective studies are still needed to confirm our conclusions. [Table: see text]

Efficacy, safety and prognostic factors in patients with refractory metastatic colorectal cancer treated with trifluridine/tipiracil plus bevacizumab in a real-world setting

We evaluated the efficacy and safety of trifluridine/tipiracil (TAS-102) plus bevacizumab in treating refractory metastatic colorectal cancer (mCRC) in a retrospective, observational study. Patients refractory or intolerant to standard therapies received TAS-102 (30–35 mg/m2 twice daily on days 1–5 and days 8–12 every 28 days) plus bevacizumab 5 mg/kg on days 1 and 15. Clinical and pathological characteristics, overall response rate (ORR), disease control rate (DCR), overall survival (OS) and progression-free survival (PFS) data were collected and analysed. Thirty-five patients were treated from July 2019 to October 2021 (median age 64 years). The majority of patients (68.6%) were receiving TAS-102 plus bevacizumab as third-line treatment. Patients received a median of 4 (range 2–15) cycles of treatment. Among 31 patients evaluable for response (88.6%), ORR and DCR were 3.2% and 51.6%, respectively. After a median 11.6 months’ follow-up, median PFS was 4.3 (95% confidence interval [CI] 3.4–5.1) months and median OS was 9.3 (95% CI 6.6–12.1) months. The most common grade 3–4 toxicities were neutropenia, asthenia and nausea/vomiting, and there were no treatment-related deaths. This real-world study confirms the efficacy and safety of TAS-102 plus bevacizumab in patients with refractory mCRC.

Initial experience of TAS-102 chemotherapy in Australian patients with Chemo-refractory metastatic colorectal cancer

For patients with refractory metastatic colorectal cancer (mCRC) treatment with Trifluridine/Tipiracil, also known as TAS-102, improves overall survival. This study aims to investigate the efficacy and safety of TAS-102 in a real-world population from Victoria, Australia. A retrospective analysis of prospectively collected data from the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry was undertaken. The characteristics and outcomes of patients receiving TAS-102 were assessed and compared to those enrolled in the registration study (RECOURSE).Across 13 sites, 107 patients were treated with TAS-102. The median age was 60 years (range: 31-83), compared to 63 for RECOURSE. Comparing registry TAS-102-treated and RECOURSE patients, 75% vs 100% were ECOG performance status 0-1, 74% vs 79% had initiated treatment more than 18 months from diagnosis of metastatic disease and 36% vs 49% were RAS wild-type. Median time on treatment was 10.4 weeks (range: 1.7-32). Median progression-free survival (PFS) was 3.3 months compared to 2 months in RECOURSE, while median overall survival was the same at 7.1 months. Two patients (2.3%) had febrile neutropenia and there were no treatment-related deaths, where TAS-102 dose at treatment initiation was at clinician discretion.TRACC registry patients treated with TAS-102 were younger than those from the RECOURSE trial, with similar overall survival observed. Less strict application of RECIST criteria and less frequent imaging may have contributed to an apparently longer PFS.

Initial experience of TAS-102 chemotherapy in Australian patients with chemorefractory metastatic colorectal cancer.

71 Background: For patients with refractory metastatic colorectal cancer (mCRC) treatment with Trifluridine/Tipiracil, also known as TAS-102, improves overall survival. In Australia, TAS-102 was initially made available locally through patients self-funding, later via an industry sponsored Medicine Access Program (MAP) and then via the Pharmaceutical Benefits Scheme (PBS). This study aims to investigate the efficacy and safety of TAS-102 in real world Australian population. Methods: A retrospective analysis of prospectively collected data from the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry was undertaken. The characteristics and outcomes of patients receiving TAS-102 were assessed and compared to all TRACC patients and those enrolled in the registration study (RECOURSE). Results: Across 13 sites, 107 patients were treated with TAS-102 (non-PBS n = 27, PBS n = 80), The median number of patients per site was 7 (range: 1-17). The median age was 60 years (range: 31-83), compared to 67 for all TRACC patients and 63 for RECOURSE. Comparing registry TAS-102 and RECOURSE patients, 75% vs 100% were ECOG performance status 0-1, 74% vs 79% had initiated treatment more than 18 months from diagnosis of metastatic disease and 39% vs 49% were RAS wild type. Median time on treatment was 10.4 weeks (range: 1.7-32). Median clinician assessed progression-free survival was 3.3 compared to RECIST defined PFS of 2 months in RECOURSE study, while median overall survival was the same at 7.1 months. Two patients (2.3%) had febrile neutropenia and there were no treatment-related deaths in the real-world series, where TAS102 dose at treatment initiation was at clinician discretion. In the RECOURSE study there was a 4% febrile neutropenia rate and one treatment-related death. Conclusions: TRACC registry patients treated with TAS102 were younger than both TRACC patients overall and those from the RECOURSE trial. Less strict application of RECIST criteria and less frequent imaging may have contributed to an apparently longer PFS. However overall survival outcomes achieved with TAS102 in real world patients were comparable to findings from this pivotal trial with an acceptable rate of major adverse events.

TAS-102 in metastatic colorectal cancer (mCRC): efficacy, tolerability, and quality of life in heavily pretreated elderly patients: a real-life study.

BackgroundTAS-102 is an oral monotherapy, combining trifluridine and tipiracil hydrochloride, indicated for the treatment of pretreated metastatic colorectal cancer (mCRC). The aim of this real-life study is to evaluate the efficacy and safety of TAS-102 in heavily pretreated elderly patients with mCRC whose disease has progressed with standard therapies.MethodsIn this retrospective observational study, we enrolled 50 elderly patients >70 years of age (median age 78 years) with a diagnosis of mCRC who were previously treated or were not considered candidates for treatment with other available therapies. Patients aged >70 years with advanced colorectal cancer and with an ECOG performance status of grade 0 (n=18) or grade 1 (n=32) were included. Overall survival and progression-free survival were the primary endpoints, whereas objective response rate, tolerability, and quality of life were the secondary endpoints.ResultsTreatment with TAS-102 appeared to be well tolerated and side effects were generally mild, achieving disease control and a benefit on quality of life. The median overall survival was 6.7 (95% CI 5.7–11.3) and the median progression-free survival was 2.1 months (95% CI 1.2–3.2), estimated using the Kaplan–Meier method.ConclusionTAS-102 represents a manageable and effective therapeutic opportunity and appeared to be well tolerated with generally mild side effects in elderly patients with mCRC who were heavily pretreated with standard therapies.

Phase I prospective trial of TAS-102 (trifluride and tipiracil) and radioembolization with 90Y resin microspheres for chemo-refractory colorectal liver metastases.

110 Background: Clinical efficacy of Yttrium-90 (90Y) radioembolization (TARE) for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC) is limited by extrahepatic disease progression. TAS-102 (trifluride and tipiracil) has overall survival benefit for patients with refractory mCRC and may be a radiosensitizer. We aimed to evaluate the safety of the combination of TAS-102 and 90Y resin TARE in a Phase I dose-escalation trial. Methods: Adult patients with bilobar liver-dominant chemo-refractory mCRC were treated with sequential Y90 resin TARE (body surface area dosimetry) in combination with TAS-102 (20mg/m2, 27mg/m2, and 35mg/m2) in 28-day cycles according to 3+3 dose-escalation design. Beginning with cycle 3, TAS-102 was administered as monotherapy until disease progression or development of intolerable toxicity. Primary objectives were to determine maximum tolerated dose (MTD) of TAS-102, to assess toxicity, and to establish safety of TAS-102 in combination with 90Y TARE. Results: A total of 14 patients (10 women, 4 men) have been treated to date. Among 9 patients enrolled in the dose-escalation phase, no dose limiting toxicities were observed. The MTD of TAS-102 in combination with Y90 was 35mg/m2, which was selected for the dose expansion phase. Severe adverse events (AEs) included: neutropenia (46%); anemia (23%); and thrombocytopenia (8%), which were attributed to TAS-102. All other AEs were mild and transient. At least one follow-up imaging study has been obtained for 13 patients, and 10 patients have completed trial participation. Disease control rate in the liver was 100%. Conclusions: The combination of TAS-102 and 90Y TARE for patients with liver-dominant mCRC is safe and consistently achieved disease control within the liver. Severity and incidence of AEs is within the expected range of TAS-102 and 90Y TARE monotherapy. A dose-expansion phase with planned enrollment of 12 patients is ongoing. Clinical trial information: NCT02602327.

A Trial Protocol of Biweekly TAS-102 and Bevacizumab as Third-Line Chemotherapy for Advanced/Recurrent Colorectal Cancer: A Phase II Multicenter Clinical Trial (The TAS-CC4 Study).

Background: Treatment with TAS-102 has significantly improved the progression-free survival (PFS) and overall survival (OS) of patients with metastatic colorectal cancer (mCRC). Reportedly, the combination of TAS-102 plus bevacizumab extends the median PFS. The present study aimed to confirm the efficacy and safety of TAS-102 plus bevacizumab (biweekly administration) as third-line chemotherapy for patients with mCRC. Methods/Design: This is a single-arm, open-label, prospective, nonrandomized, multicenter phase II trial conducted in Japan. With a threshold and expected PFS of 2.1 and 3.5 months, respectively, the simulation results showed a sample size of 42 with α = 0.05 (both sides) for 90% power, based on the One-Arm Binomial test using the SWOG statistical tool. If the estimated dropout is 7%-8%, the target sample size is estimated to be 45. The TAS-CC4 study regimen comprised 28-day cycles with biweekly oral administration of TAS-102 (35 mg/m2 twice daily on days 1-5 and 15-19 of every 28-day cycle) and bevacizumab (5.0 mg/kg on days 1 and 15). The primary end point is the PFS; secondary end points include response rate (RR), OS, grade ≥3 neutropenia, and genetic alterations (KRAS/BRAF mutations) in the circulating cell-free DNA. Discussion: The present study can contribute to the determination of the effective dosing interval of TAS-102 and bevacizumab in patients with mCRC and is thought to lead to prophylaxis of neutropenia and prolongation of the treatment period.

Efficacy and safety of TAS-102 in refractory metastatic colorectal cancer: a meta-analysis.

BackgroundTAS-102 has been applied to metastatic colorectal cancer (mCRC) patients who had received at least two prior regimens of standard chemotherapy. This meta-analysis is designed to assess the efficacy and safety of TAS-102 in patients with mCRC.MethodsWe searched randomized controlled trials (RCTs) through PubMed, Embase, Web of Science and Cochrane clinical trial databases and clinicaltrial.gov from database initiation to March 2018. The overall survival (OS), progression-free survival (PFS), disease control rate (DCR) and incidence of adverse events were summarized with the use of hazard ratio (HR) or risk ratio (RR).ResultsThree RCTs with 1318 patients were included. Results showed that TAS-102 significantly improved OS (HR 0.70, 95% confidence interval [CI] 0.62–0.79) and PFS (HR 0.46, 95% CI 0.40–0.52) in patients who were intolerant or refractory to fluoropyrimidine, irinotecan and oxaliplatin. The pooled odds ratio of DCR was 4.15 (95% CI 3.18–5.43). Notably, there were significant OS benefits both in patients with KRAS mutation (HR 0.76, 95% CI 0.63–0.92) and those with wild-type KRAS (HR 0.66, 95% CI 0.55–0.79). These benefits were also observed in patients with different numbers of metastatic sites. However, patients with >18 months since the diagnosis of first metastases seemed to have better OS (HR 0.65, 95% CI 0.55–0.77). The most common toxicities associated with TAS-102 were neutropenia (RR 116.51, 95% CI 23.51–577.33), leucopenia (RR 67.70, 95% CI 13.63–336.29), anemia (RR 4.28, 95% CI 2.70–6.79) and diarrhea (RR 5.10, 95% CI 1.40–18.61).ConclusionTAS-102 significantly improves OS, PFS and DCR in refractory mCRC patients with tolerable toxicity. Meanwhile, the OS benefits have nothing to do with KRAS status and the number of metastatic sites.

P-258 - HGCSG1503: A retrospective cohort study evaluating the safety and efficacy of TAS-102 in patients with metastatic colorectal cancer: Analysis of cases of prior regorafenib

Introduction: The J003 trial and RECOURSE trial revealed the safety and efficacy of TAS-102 for patients with metastatic colorectal cancer (mCRC). In March 2014, TAS-102 was approved in Japan. However, in these pivotal trials, there were few cases in which regorafenib was administered as prior treatments, and also there were few reports on the effectiveness and safety of TAS-102 after administration of regorafenib. Methods: We retrospectively analyzed the clinical data of 411 patients who received TAS-102 in the multi-institutional retrospective study (HGCSG1503). This study was analyzed by CTCAE v4.0 for adverse events (AEs), RECIST v1.1 for response rate (RR)/disease control rate (DCR). To compare patients who received regorafenib before TAS-102 (Prior REG) and those did not receive regorafenib (No prior REG), Fisher’s exact test was used in terms of patient characteristics, AE, RR/DCR, and Log-rank test was used in terms of TTF, PFS and OS. Results: No prior REG and Prior REG were 285 and 126, respectively. The patient’ characteristics between No prior REG and Prior REG were generally balanced except for lung metastasis (56.8% in No prior REG, 67.5% in Prior REG; p = 0.049), prior oxaliplatin administration (95.1% in No prior REG, 99.2% in Prior REG; p = 0.045), prior irinotecan administration (90.5% in No prior REG, 100% in Prior REG; p < 0.001) and patients over 18 months since diagnosis of metastasis (63.2% in No prior REG, 84.1% in Prior REG; p < 0.001). The AEs between No prior REG and Prior REG were also generally balanced. RR/DCR were 0.8/37.5% in No prior REG and 0/36.5% in Prior REG (p = 1.000/0.908). Median PFS was 2.3 months in No prior REG and 2.1 months in Prior REG (HR 1.157, p = 0.185). Median OS was 8.1 months in No prior REG and 5.7 months in Prior REG (HR 1.355, p = 0.007). Conclusion: In this analysis, No prior REG population contained lung metastasis, and short interval from diagnosis of metastasis. The adverse events, detail of administration, RR/DCR, and PFS were no significant difference regardless of the administration history of REG. The OS was significantly extended with No prior REG population. This is presumed because 30% of No prior REG population received REG for post TAS-102 therapy.

Duration of previous treatment as a prognostic factor in metastatic colorectal cancer treated with trifluridine/tipiracil.

We herein describe the findings from the trifluridine/tipiracil (TAS-102) Compassionate Use program in Latvia, set up prior to marketing authorization for the management of pretreated patients with metastatic colorectal cancer (mCRC). The efficacy and safety of TAS-102 in patients with refractory mCRC were evaluated in the phase III trial RECOURSE. A previous report confirmed neutropenia and duration of previous treatment for mCRC as prognostic factors in TAS-102 users. The aim of the present study was to analyze possible prognostic factors, such as neutropenia, in TAS-102 responders. A retrospective analysis of 14 patients who received TAS-102 chemotherapy in two institutions in Latvia (Clinic of Oncology of Pauls Stradins Clinical University Hospital and Oncology Centre of Riga East University Hospital) was performed. Grade 3-4 neutropenia was observed in 28% of the patients. In patients with grade 3-4 neutropenia the median progression-free survival (mPFS) was 7 months, whereas in those without neutropenia the mPFS was 5 months [hazard ratio (HR)=0.24, P=0.033]. In 64% of the patients, the duration of previous treatment was >18 months. In patients treated for >18 months from the start of first-line mCRC treatment the mPFS was 7 months, whereas in those treated for ≤18 months from the start of first-line mCRC treatment the mPFS was 5 months (HR=0.15, P=0.029). Therefore, a longer time from mCRC diagnosis until disease progression may be used to select chemotherapy-refractory mCRC patients for TAS-102 treatment. Furthermore, severe neutropenia may be considered as a surrogate marker for predicting TAS-102 treatment outcomes.

A retrospective cohort study evaluating the safety and efficacy of TAS-102 in patients with metastatic colorectal cancer (HGCSG1503): Analysis of cases of prior regorafenib.

832 Background: The J003 trial and RECOURSE trial revealed the safety and efficacy of TAS-102 for patients with metastatic colorectal cancer (mCRC). In March 2014, TAS-102 was approved in Japan. However, in these pivotal trials, there were few cases in which regorafenib was administered as prior treatments, and also there were few reports on the effectiveness and safety of TAS-102 after administration of regorafenib. Methods: We retrospectively analyzed the clinical data of 126 patients who received TAS-102 after administration of regorafenib in the multi-institutional retrospective study (HGCSG1503). This study was analyzed by CTCAE v4.0 for adverse events (AEs), RECIST v1.1 for response rate (RR)/disease control rate (DCR), and Kaplan-Meier method for progression free survival (PFS) and overall survival (OS). Results: Patients characteristics were as follows; male/female 75/51, median age 66.5 (range 38-84), ECOG PS (0/1/2/3) 48/64/12/2, KRAS Exon2 wild/mutant 64/60 (2 patients; KRAS Exon2 was not tested). The initial starting dose was 70 mg/m2 (n = 100, 79.4%) and reduced dose (n = 26, 20.6%). Dose reductions were required in 30 patients (30.9%). The common ≥grade 3 AEs were neutrophil count decreased (45.1%), white blood cell decreased (34.9%), and anemia (28.6%). RR and DCR were 0% and 36.5%, respectively. Median PFS and OS were 2.1 and 5.7 months. In the analysis on the relationship between ECOG PS 0-1 and PS 2-3, median PFS was 2.2 vs. 1.4 months (HR 2.187, p = 0.008), and MST was 6.5 vs. 2.7 months (HR 2.424, p = 0.002). Conclusions: In this analysis, TAS-102 after administration of regorafenib in the real-world clinical practice showed similar efficacy and safety to the pivotal clinical trials, except for patients with PS 2-3. Clinical trial information: 000020551.

Safety for trifluridine/tipiracil (TAS-102) with bevacizumab combination in patients with refractory metastatic colorectal cancer in real-world clinical practice: The single-institutional experience.

865 Background: Trifluridine/tipiracil (TAS-102) is an oral combination therapy approved for the treatment of patients with metastatic colorectal cancer (mCRC). Phase 1/2 C-TASK FORCE study of TAS-102 plus bevacizumab for patients with refractory mCRC demonstrated a promising efficacy results with mild toxicity profile (Kuboki Y, et al. Lancet Oncology, 2017). The retrospective single-institutional study is aiming to investigate safety of TAS-102 plus bevacizumab for patients with refractory mCRC in real-world clinical practice. Methods: MCRC patients who were refractory or intolerant to a fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF therapy, and anti-EGFR therapy (if wild-type RAS) and consecutively received TAS-102 plus bevacizumab between January 2016 and June 2017, were analyzed. Adverse events (AEs) were assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0. Results: A total of 33 patients were identified for safety analysis. Patient characteristics were as follows; male/female, 19/14; median age, 59.0 (range 38-81); ECOG Performance Status of 0/1, 21/12; and All wild/ RAS mutant/ BRAF mutant/ unknown, 16/15/1/1. Six patients had received prior regorafenib. The relative dose intensities of TAS-102 and bevacizumab were 87% and 79%, respectively. Grade 3 or higher hematological and non-hematological AEs were follows; leucopenia, 33%; neutropenia, 42%; anemia, 9%; and proteinuria, 12%. There were no febrile neutropenia or treatment-related death. G-CSF was given in 8 patients (24%), while intravenous antibiotics was in one patient. There were four patients with emergency admission, and out of these, the two patients had intestinal perforation, and perianal abscess, which were regarded as treatment-associated; ultimately these AEs were fully recovered. Conclusions: Our findings suggested safety for TAS-102 plus bevacizumab combination in real-world clinical practice is consistent with those in clinical trial setting.

TAS-102 plus bevacizumab for patients with metastatic colorectal cancer refractory to standard therapies (C-TASK FORCE): an investigator-initiated, open-label, single-arm, multicentre, phase 1/2 study

In patients with heavily treated metastatic colorectal cancer, TAS-102-a combination of trifluridine and tipiracil-has shown a significant overall survival benefit compared with placebo. In preclinical models, TAS-102 plus bevacizumab has shown enhanced activity against colorectal cancer xenografts compared with that for either drug alone. In this phase 1/2 study, we assessed the activity and safety of TAS-102 plus bevacizumab. We did this investigator-initiated, open-label, single-arm, multicentre, phase 1/2 trial of TAS-102 plus bevacizumab in four cancer centres in Japan. Eligible patients were aged 20 years or older; had histologically confirmed unresectable, metastatic colorectal adenocarcinoma; were refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF therapy, and anti-EGFR therapy (for tumours with wild-type KRAS); and had no previous treatment with regorafenib. Patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1. Using a dose de-escalation design in phase 1, the recommended phase 2 dose (RP2D) was determined for TAS-102 (35 mg/m2 given orally twice daily on days 1-5 and 8-12 in a 28-day cycle for level 1) plus bevacizumab (5 mg/kg, administered by intravenous infusion for 30 min every 2 weeks). In phase 2, patients received the RP2D. The primary endpoint was centrally assessed progression-free survival at 16 weeks, analysed in the first 21 patients to be enrolled and treated with the RP2D who had at least one imaging assessment. This study is completed and registered with the University Hospital Medical Information Network, number UMIN000012883. Between Feb 25, 2014, and July 23, 2014, we enrolled 25 patients with metastatic colorectal cancer: six patients in phase 1 and 19 patients in phase 2. The six patients who received TAS-102 at level 1 experienced no dose-limiting toxicities and this was deemed the RP2D. Nine of 21 patients who received the RP2D did not have a centrally assessed progression event; 16-week progression-free survival was 42·9% (80% CI 27·8-59·0). The most common grade 3 or worse adverse events as assessed in all 25 patients were neutropenia (18 [72%] patients), leucopenia (11 [44%]), anaemia (four [16%]), febrile neutropenia (four [16%]), and thrombocytopenia (three [12%]). Treatment-related serious adverse events were reported in three (12%) patients. No treatment-related deaths occurred. TAS-102 plus bevacizumab has promising activity with manageable safety, suggesting that this combination might become a potential treatment option for patients with metastatic colorectal cancer in a refractory setting. Taiho Pharmaceutical.

Regorafenib Versus Trifluridine/Tipiracil for Refractory Metastatic Colorectal Cancer: A Retrospective Comparison

BackgroundRegorafenib and trifluridine/tipiracil (TAS-102) both prolong survival for patients with refractory metastatic colorectal cancer. However, it is unclear which drug should be administered first. Materials and MethodsWe retrospectively evaluated the data from patients who had received regorafenib or TAS-102 at 2 institutions from May 2013 to March 2015. The inclusion criteria were disease refractory or intolerant to fluoropyrimidines, oxaliplatin, irinotecan, anti-vascular endothelial growth factor antibodies, and anti-epidermal growth factor receptor (EGFR) antibodies (if KRAS exon 2 wild-type), and no previous treatment with regorafenib or TAS-102. ResultsA total of 146 and 54 patients received regorafenib and TAS-102, respectively. The baseline characteristics were similar between the 2 groups, except for a history of irinotecan and anti-EGFR therapy and high alkaline phosphatase levels. The median progression-free survival and overall survival were 2.1 months and 6.7 months, respectively, with regorafenib and 2.1 months and 6.5 months, respectively, with TAS-102 (progression-free survival hazard ratio 1.20, P = .27; overall survival hazard ratio, 1.01, P = .97). The analysis of overall survival for patients after the approval of TAS-102 in Japan was similar to the overall survival for the entire population. The frequency of hand–foot syndrome and increased aspartate aminotransferase, alanine aminotransferase, and bilirubin levels was higher and the frequency of neutropenia, leukopenia, anemia, nausea, and febrile neutropenia was lower with regorafenib than with TAS-102. No remarkable differences were found in the efficacy and safety of TAS-102 between patients with and without previous regorafenib and vice versa. ConclusionRegorafenib and TAS-102 had similar efficacy but resulted in different toxicities, which could guide the agent choice.

Efficacy of trifluridine and tipiracil (TAS-102) versus placebo, with supportive care, in a randomized, controlled trial of patients with metastatic colorectal cancer from Spain: results of a subgroup analysis of the phase 3 RECOURSE trial

PurposeTAS-102 is a combination of the thymidine-based nucleoside analog trifluridine and the thymidine phosphorylase inhibitor tipiracil. Efficacy and safety of TAS-102 in patients with metastatic colorectal cancer (mCRC) refractory or intolerant to standard therapies were evaluated in the phase 3 RECOURSE trial. Results of RECOURSE demonstrated significant improvement in overall survival (OS) and progression-free survival (PFS) with TAS-102 versus placebo [hazard ratio (HR) = 0.68 and 0.48 for OS and PFS, respectively; both P < 0.001]. The current analysis evaluates efficacy and safety of TAS-102 in the RECOURSE Spanish subgroup.MethodsPrimary and key secondary endpoints were evaluated in a post hoc analysis of the RECOURSE Spanish subgroup, using univariate and multivariate analyses. Safety and tolerability were reported with descriptive statistics.ResultsThe RECOURSE Spanish subgroup included 112 patients (mean age 61 years, 62 % male). Median OS was 6.8 months in the TAS-102 group (n = 80) versus 4.6 months in the placebo group (n = 32) [HR = 0.47; 95 % confidence interval (CI): 0.28–0.78; P = 0.0032). Median PFS was 2.0 months in the TAS-102 group and 1.7 months in the placebo group (HR = 0.47; 95 % CI: 0.30–0.74; P = 0.001). Eighty (100 %) TAS-102 versus 31 (96.9 %) placebo patients had adverse events (AEs). The most common drug-related ≥Grade 3 AE was neutropenia (40 % TAS-102 versus 0 % placebo). There was 1 (1.3 %) case of febrile neutropenia in the TAS-102 group versus none in the placebo group.ConclusionsIn the RECOURSE Spanish subgroup, TAS-102 was associated with significantly improved OS and PFS versus placebo, consistent with the overall RECOURSE population. No new safety signals were identified.ClinicalTrials.gov study numberNCT01607957

Efficacy and safety results in patients with impaired renal and hepatic function in the RECOURSE trial.

3547Background: TAS-102 contains an antineoplastic nucleoside, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil, at a molar ratio of 1:0.5. The efficacy and safety of TAS-102 in pat...

Supportive treatment for hematologic toxicities in the phase 3 RECOURSE trial of TAS-102 vs placebo with best supportive care in patients with metastatic colorectal cancer.

e15021Background: TAS-102 is comprised of an antineoplastic thymidine-based nucleoside analog, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil. Efficacy and safety of TAS-102 in pa...

TAS-102 versus placebo (PBO) in patients (pts) ≥65 years (y) with metastatic colorectal cancer (mCRC): An age-based analysis of the recourse trial.

638 Background: TAS-102 is comprised of an antineoplastic thymidine-based nucleoside analog, trifluridine, and the thymidine phosphorylase inhibitor, tipiracil hydrochloride, at a molar ratio of 1:0.5 (weight ratio, 1:0.471). Efficacy and safety of TAS-102 in pts with mCRC refractory to standard therapies were evaluated in the RECOURSE trial; enrollment criteria included ≥2 prior lines of standard chemotherapy. Primary results of RECOURSE demonstrated a significant improvement in overall survival (OS) (TAS-102 7.1 mo vs PBO 5.3 mo; HR=0.68; P&lt;0.0001) and progression-free survival (PFS) (HR=0.48; P&lt;0.0001). Methods: This prespecified analysis compared the efficacy and safety of TAS-102 vs PBO in pts ≥65 y and &lt;65 y with mCRC. A retrospective analysis of pts ≥75 y was also performed. Results: Of 800 randomized pts, 352 (44.0%) were ≥65 y and 60 (7.5%) were ≥75 y. Median OS in pts ≥65 y was 7.0 mo with TAS-102 vs 4.6 mo with PBO (HR=0.62, 95% CI: 0.48-0.80, P=0.0002). PFS HR was 0.41 (95% CI: 0.32-0.52, P&lt;0.0001) for pts ≥65 y, also favoring TAS-102. In pts ≥65 y, disease control rate (complete or partial response or stable disease) was 48.7% with TAS-102 vs 15.5% with PBO. An age-related difference in overall incidence of adverse events (AEs) was not observed in either treatment arm. Treatment-related AEs, ≥ Grade 3 AEs, and severe AEs were generally more common in pts ≥65 y than in pts &lt;65 y (Table). Mean drug exposure was similar among pts ≥65 y and ≥75 y, as was overall safety profile. Conclusions: Significant improvements in OS and PFS were observed in pts ≥65 y who received TAS-102 vs PBO, with a mild increase in toxicity. Pts ≥65 y and &lt;65 y showed a generally favorable safety profile. A significant increase in toxicity in pts ≥75 y was not apparent vs the overall ≥65 y population. Clinical trial information: NCT01607957. [Table: see text]