TAS-102 For Metastatic Colorectal Cancer Research Articles

530P Real-world effectiveness and predictive biomarker analysis of TAS-102+bevacizumab vs. regorafenib vs. TAS-102 in metastatic colorectal cancer: A multicenter cohort study

530P Real-world effectiveness and predictive biomarker analysis of TAS-102+bevacizumab vs. regorafenib vs. TAS-102 in metastatic colorectal cancer: A multicenter cohort study

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.

Development of a Multicriteria Decision Analysis Framework for Evaluating and Positioning Oncologic Treatments in Clinical Practice.

Several frameworks have been developed to define and quantify the value of oncologic therapies and to support decision making; however, they define treatment value mainly in terms of clinical benefit. As part of its mission to improve oncologic care, the ECO Foundation (Excellence and Quality in Oncology) directed this pilot study aimed at developing a reflective multicriteria decision analysis (MCDA)-based framework for evaluating and positioning oncologic drugs in the clinical setting. The framework was developed following Evidence and Value: Impact on Decision-Making methodology, and literature was reviewed to identify relevant criteria. The selected criteria were then presented to a group of experts composed of 9 clinical oncologists who assessed each criterion for inclusion in the framework and suggested modifications in their definition and/or response scale. The framework was tested in 2 case studies (abemaciclib for advanced or metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer and TAS-102 for metastatic colorectal cancer) to validate the proposed framework; this was followed by a discussion of the results. Eight of the 15 criteria presented to the experts were included in the framework: disease severity, unmet needs, comparative efficacy, comparative safety/tolerability, treatment intent, comparative treatment cost, comparative other medical costs, and quality of evidence. Framework validation in 2 drug cases resulted in similar value scores, although they were based on different contributing criteria and resulted in different clinical recommendations. We developed and validated a reflective MCDA framework for the assessment and positioning of oncologic therapies in Spain. Additional work is needed to create a manual for practical decision making in the clinical setting.

Regorafenib Is Associated With Increased Skeletal Muscle Loss Compared to TAS-102 in Metastatic Colorectal Cancer

BackgroundCurrent guidelines of the National Comprehensive Cancer Network and the European Society of Medical Oncology recommend regorafenib or trifluridine/tipiracil (TAS-102) for third-line therapy of metastatic colorectal cancer (mCRC). We evaluated the impact of regorafenib and TAS-102 treatment on skeletal muscle dynamics and sarcopenia. Patients and MethodsThis retrospective analysis was based on unselected, consecutive mCRC patients treated with regorafenib and/or TAS-102 during third or later line of therapy at our tertiary-care cancer center in Salzburg, Austria. The skeletal muscle index (SMI, cm2/m2) and sarcopenia were evaluated from cross-sectional computed tomographic images at the level of the third lumbar vertebra. ResultsBetween January 2013 and April 2018, a total of 45 patients had received regorafenib and/or TAS-102. At initial mCRC diagnosis and at initiation of third-line therapy, 24% and 54% of patients presented with sarcopenia. A statistically significant skeletal muscle loss was observed during regorafenib treatment (median SMI change: −2.75 cm2/m2 [−6.3%]; P < .0001), which was not the case during TAS-102 therapy (−1.5 cm2/m2 [−3.5%]; P = .575). Furthermore, subclassification of patients into 3 groups—normal muscle mass, stable sarcopenia, and new-onset sarcopenia—at initiation of third-line therapy permitted discrimination of overall survival, with 1-year overall survival rates of 61%, 29%, and 16%, respectively (P = .04). ConclusionThe frequency of sarcopenia increases during the course of mCRC and negatively affects survival. In contrast to TAS-102, regorafenib is associated with increased skeletal muscle loss during mCRC treatment and should therefore be used with caution in mCRC patients with preexisting sarcopenia or a history of recent weight loss.

P2-088 - TAS-102 in metastatic colorectal cancer (mCRC) - predictive and prognostic factors in a European patient population

P2-088 - TAS-102 in metastatic colorectal cancer (mCRC) - predictive and prognostic factors in a European patient population

Trifluridine/Tipiracil (TAS-102) in Refractory Metastatic Colorectal Cancer: A Multicenter Register in the Frame of the Italian Compassionate Use Program.

TAS-102 is indicated for patients with metastatic colorectal cancer (mCRC) previously treated with, or not considered candidates for, available therapies. Given the complete inefficacy in half of patients, the lack of predictive factors, the palliative setting, and the financial and clinical toxicity, optimizing the cost-benefit ratio is crucial. The "ColonLife" nomogram allows an estimate of the 12-week life expectancy of patients with refractory mCRC. We collected data from patients treated at eight Italian centers in the compassionate use program. Baseline characteristics of patients who were or were not progression free at 6 months were compared. The discriminative ability of the ColonLife nomogram was assessed. Among patients who received both TAS-102 and regorafenib, clinical outcomes of the two sequences were compared. This study included 341 patients. Six (2%) and 93 (27%) patients achieved response and disease stabilization, respectively. The median progression-free survival (PFS) was 2.4 months with an estimated 6-month PFS rate of 19%; the median overall survival (OS) was 6.2 months. An Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, normal lactate dehydrogenase (LDH), and a time from the diagnosis of metastatic disease of >18 months were independently associated with higher chances of a patient being progression free at 6 months. The discriminative ability of ColonLife was confirmed. Among 121 patients who received both regorafenib and TAS-102, no differences in first or second PFS or OS were reported between the two sequences. One out of five patients achieves clinical benefit with TAS-102. ECOG PS, LDH, and time from diagnosis of metastatic disease may help to identify these patients. Excluding patients with very short life expectancy appears a reasonable approach. Improving the cost-efficacy ratio of TAS-102 in metastatic colorectal cancer is needed to spare useless toxicities in a definitely palliative setting. Eastern Cooperative Oncology Group performance status, lactate dehydrogenase levels, and time from the diagnosis of metastatic disease may help to identify patients more likely to achieve benefit. Properly designed prognostic tools (i.e., the "ColonLife" nomogram) may enable excluding from further treatments patients with very limited life expectancy.

A Comparison of Regorafenib and TAS-102 for Metastatic Colorectal Cancer: A Systematic Review and Network Meta-analysis

BackgroundRegorafenib and TAS-102 have shown to be superior to placebo in refractory metastatic colorectal cancer. However, no studies have directly compared both drugs. Giving the lack of standard options in this scenario, a systematic review to compare the efficacy and safety of regorafenib and TAS-102 was performed. Materials and MethodsA systematic review using the PubMed, Medline, Embase, Scopus, and Cochrane databases to identify published and unpublished studies up to November 2015 for randomized controlled trials for patients with metastatic colorectal cancer, involving regorafenib or TAS-102, was performed. Data including overall survival, progression-free survival, and toxicity were extracted. Pairwise direct meta-analyses (regorafenib vs. placebo and TAS-102 vs. placebo) and indirect comparison (regorafenib vs. TAS-102) using network meta-analyses methods to preserve randomization were performed using random effects. ResultsThree randomized controlled trials fulfilled eligibility criteria (regorafenib monotherapy for previously treated metastatic colorectal cancer [CORRECT]: an international, multicentre, randomised, pacebo-controlled, phase 3 trial, regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer [CONCUR]: a randomised, double-blind, placebo-controlled, phase 3 trial, and randomized trial of TAS-102 for refractory metastatic colorectal cancer [RECOURSE] trials) involving 1764 patients (regorafenib, 641; TAS-102, 534; placebo, 589). Subgroups of patients (1659) who had not received prior regorafenib or TAS-102 were used to perform meta-analyses for efficacy. In the indirect comparison, no statistically significant differences were observed between regorafenib and TAS-102 in overall survival (hazard ratio, 0.96; 95% confidence interval [CI], 0.57-1.66; P = .91) or progression-free survival (hazard ratio, 0.85; 95% CI, 0.40-1.81; P = .67). However, regorafenib has statistically more all grade any toxicity (risk difference, 0.31; 95% CI, 0.25-0.38; P = .001) compared with TAS-102. Subgroup analysis of adverse events showed a different toxicity profile between both drugs. ConclusionIn this indirect comparison, regorafenib and TAS-102 appeared to have similar efficacy. However, regorafenib was associated with more toxicity compared with TAS-102.

153P - Retrospective analysis of TAS-102 for metastatic colorectal cancer

153P - Retrospective analysis of TAS-102 for metastatic colorectal cancer

Efficacy and safety of regorafenib compared to TAS-102 for metastatic colorectal cancer: A systematic review and network meta-analysis.

735 Background: Recent studies have shown regorafenib and TAS-102 (TAS) to be superior to placebo (P) in refractory metastatic colorectal cancer (mCRC). However, no studies have directly compared both drugs. Giving the lack of therapeutic options for these patients,, a systematic review to compare the efficacy and safety of regorafenib compared with TAS was performed, using indirect comparison methods. Methods: A systematic review using PubMed, Medline, Embase, Scopus and Cochrane database to identify published and unpublished studies up to November 2015 for randomized controlled trials (RCTs) for patients with metastatic colorectal cancer, involving regorafenib or TAS was performed. Data including overall survival (OS), progression-free survival (PFS) and toxicity were extracted. Pairwise direct meta-analyses (regorafenib versus placebo and TAS versus placebo) and indirect comparison (regorafenib versus TAS) using network meta-analyses methods (R package “netmeta”) to preserve randomization were performed using random effects. Results: 914 citations were initially identified among which 3 RCTs fulfilled eligibility criteria (CORRECT, CONCUR and RECOURSE trials) involving 1.764 patients (regorafenib: 641, TAS: 534, Placebo: 589). Subgroups of patients (1.659) who had not received prior regorafenib or TAS-102 were used to performed meta-analyses for efficacy. In indirect comparison, there were no statically differences observed between regorafenib and TAS-102 in overall survival (HR 0.96 95% CI 0.56-1.55 p = 0.082) and progression-free survival (HR HR 0.85 95% CI 0.40-1.80 p = 0.0182). In addition, there were no differences in objective response rate and disease control between both drugs. However, regorafenib has statistically more all grade toxicity (risk difference (RD) 0.31 CI 0.25-0.38 p = 0.001) and toxicity grade 3-5 (RD 0.22 CI 0.13-0.31 p &lt; 0.001) compared to TAS. Conclusions: In this indirect comparison, regorafenib and TAS appeared to have similar efficacy. However, regorafenib has more toxicity compared to TAS. Post-approval real world data focusing on the comparative toxicity of regorafenib and TAS is warranted.

Interstitial pneumonia in a patient treated with TAS-102 for metastatic colorectal cancer: a case report

BackgroundTAS-102, a new treatment option for patients with metastatic colorectal cancer that is refractory or intolerant to standard therapies, has been improving survival with acceptable tolerability and adverse events. Adverse hematological events associated with TAS-102 treatment were extensively profiled in the RECOURSE trial, but pulmonary toxicities associated with TAS-102 therapy are distinctly uncommon. In a recent early post-marketing phase vigilance on TAS-102 in Japan, seven cases of pulmonary disease were reported, but patient follow-up in this study was incomplete. Here, we present the first case of interstitial lung disease occurring in association with TAS-102 treatment.Case presentationA 57-year-old Japanese man who had previously received two standard treatments was admitted in 2014, at which time we administered TAS-102 (110 mg/day) as a third-line chemotherapy. He was safely treated with TAS-102 for the first planned cycle; however, approximately 4 days after receiving the second cycle of TAS-102, he complained of high fever and subsequent dyspnea with severe hypoxemia and went to the emergency room. A chest X-ray revealed diffuse coarse reticular shadows with ground-glass opacity on both lungs. Furthermore, a chest computed tomography scan showed thickening of the bronchovascular bundles with extensive ground-glass opacification and pleural effusions in both lung fields.In addition, a peripheral blood lymphocyte stimulation test with TAS-102 showed higher values compared with control samples. Consequently, we suspected drug-induced interstitial pneumonia, and discontinued treatment. Our patient was given an initial administration of high-dose methylprednisolone (1000 mg/day) for 3 days and oxygen. Our patient was discharged with oral prednisolone (20 mg/day) and improved symptomatically and radiologically.ConclusionsThese findings suggest that interstitial pneumonia is a rare complication of TAS-102 chemotherapy, but the possibility of interstitial pneumonia should always be considered when a patient presents with a respiratory disorder while undergoing TAS-102 systemic chemotherapy.Prompt discontinuation of TAS-102 and treatment with high-dosage corticosteroids is needed to avoid exacerbating respiratory symptoms.

PD-010 Association between chemotherapy-induced neutropenia at 1-month and overall survival in patients receiving TAS-102 for metastatic colorectal cancer

PD-010 Association between chemotherapy-induced neutropenia at 1-month and overall survival in patients receiving TAS-102 for metastatic colorectal cancer

Effect of regorafenib and TAS-102 in metastatic colorectal cancer (mCRC) patients on survival in salvage line with different toxicity profile.

763 Background: In the CORRECT study, regorafenib has survival benefits in patients with metastatic colorectal cancer (mCRC) in salvage line. In the J-003 and RECOURSE study, TAS-102 has also survival benefit in them, too. But no randomized study is existed about the comparison between regorafenib and TAS-102. So we retrospectively compared the efficacy and toxicity of regorafenib and TAS-102 in patients with mCRC for salvage line in our hospital. Methods: The selection criteria were pathologically proven mCRC; 20 years or older; had a previous treatment history of two or more regimens of standard chemotherapy; no prior regorafenib and TAS-102 therapy; performance status 0-1; able to oral intake; and adequate organ functions. The patients in regorafenib group, regorafenib 160mg/body was given orally once daily for 21days followed by a 7-day rest. In TAS-102 group, TAS-102 35mg/m2 was given orally twice daily 5 days of treatment followed by a 2-day rest period, and then a 14-day rest period. Results: The analysis covered 51 patients over the period from October 2009 to June 2015.The median age was 67 years (range 33-79); 29 males and 22 females; PS 0/1 score 19/32; 23 patients were treated regorafenib and 28 patients were treated TAS-102.Progression-free survival and overall survival were 2.6 and 10.6 months with regorafenib and 3.2 and 9.7 months with TAS-102 (no significant difference). The rate of grade 3-4 toxicity were hypertension (35%), hand-foot syndrome(35%), AST/ALT increased(12%) in regorafenib group, and leucopenia (15%), neutropenia (35%), anemia(10%) in TAS-102 group. There was no treatment death in both groups. Conclusions: Both regorafenib and TAS-102 give mCRC patients survival benefit in salvage line with different toxicity profile.

A novel antimetabolite: TAS-102 for metastatic colorectal cancer

ABSTRACTTAS-102 is a new oral anti-tumor drug, composed of a thymidine-based nucleoside analog (trifluridine: FTD) and a thymidine phosphorylase inhibitor (tipiracil hydrochloride: TPI). TAS-102 has been shown to significantly improve overall survival and progression-free survival in patients with refractory metastatic colorectal cancer (mCRC) in placebo-controlled randomized phase II and III trials. The current review summarizes mechanisms of action, pharmacokinetics/dynamics and preclinical and clinical data of TAS-102 in colorectal cancer. TAS-102 is a new salvage-line treatment option for patients with mCRC. TAS-102 is well tolerated and has great potential in future clinical drug combination therapies.

2113 Initial safety survey report from early post-marketing phase vigilance (EPPV) on TAS-102 for metastatic colorectal cancer (mCRC)

2113 Initial safety survey report from early post-marketing phase vigilance (EPPV) on TAS-102 for metastatic colorectal cancer (mCRC)