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Neutropenia and survival outcomes in metastatic colorectal cancer patients treated with trifluridine/tipiracil in the RECOURSE and J003 trials.

ABSTRACT: BACKGROUND:The phase II J003 (N = 169) and phase III RECOURSE (N = 800) trials demonstrated a significant improvement in survival with trifluridine (FTD)/tipiracil (TPI) versus placebo in patients with refractory metastatic colorectal cancer. This post hoc analysis investigated pharmacokinetic data of FTD/TPI exposure and pharmacodynamic markers, such as chemotherapy-induced neutropenia (CIN) and clinical outcomes. PATIENTS AND METHODS:A total of 210 patients from RECOURSE were enrolled in this substudy. A limited sampling approach was used, with three pharmacokinetic samples drawn on day 12 of cycle 1. Patients were categorized as being above or below the median area under the plasma concentration-time curve (AUC) for FTD and TPI. We conducted a post hoc analysis using the entire RECOURSE population to determine the correlations between CIN and clinical outcome. We then carried out a similar analysis on the J003 trial to validate the results. RESULTS:In the RECOURSE subset, patients in the high FTD AUC group had a significantly increased CIN risk. Analyses of the entire population demonstrated that FTD/TPI-treated patients with CIN of any grade in cycles 1 and 2 had significantly longer median overall survival (OS) and progression-free survival (PFS) than patients who did not develop CIN and patients in the placebo group. Patients who required an FTD/TPI treatment delay had increased OS and PFS versus those in the placebo group and those who did not develop CIN. Similar results were obtained in the J003 cohort. CONCLUSIONS:In RECOURSE, patients with higher FTD drug exposure had an increased CIN risk. FTD/TPI-treated patients who developed CIN had improved OS and PFS versus those in the placebo group and those who did not develop CIN. Similar findings were reported in the J003 cohort, thus validating the RECOURSE results. The occurrence of CIN may be a useful predictor of treatment outcomes for FTD/TPI-treated patients. CLINICALTRIALS. GOV IDENTIFIER:NCT01607957 (RECOURSE). JAPAN PHARMACEUTICAL INFORMATION CENTER NUMBER:JapicCTI-090880 (J003).

SUBMITTER: Yoshino T

PROVIDER: S-EPMC7491979 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Neutropenia and survival outcomes in metastatic colorectal cancer patients treated with trifluridine/tipiracil in the RECOURSE and J003 trials.

Yoshino T T Cleary J M JM Van Cutsem E E Mayer R J RJ Ohtsu A A Shinozaki E E Falcone A A Yamazaki K K Nishina T T Garcia-Carbonero R R Komatsu Y Y Baba H H Argilés G G Tsuji A A Sobrero A A Yamaguchi K K Peeters M M Muro K K Zaniboni A A Sugimoto N N Shimada Y Y Tsuji Y Y Hochster H S HS Moriwaki T T Tran B B Esaki T T Hamada C C Tanase T T Benedetti F F Makris L L Yamashita F F Lenz H-J HJ

Annals of oncology : official journal of the European Society for Medical Oncology 20200101 1

<h4>Background</h4>The phase II J003 (N = 169) and phase III RECOURSE (N = 800) trials demonstrated a significant improvement in survival with trifluridine (FTD)/tipiracil (TPI) versus placebo in patients with refractory metastatic colorectal cancer. This post hoc analysis investigated pharmacokinetic data of FTD/TPI exposure and pharmacodynamic markers, such as chemotherapy-induced neutropenia (CIN) and clinical outcomes.<h4>Patients and methods</h4>A total of 210 patients from RECOURSE were en ...[more]

PMID: 31912801

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Project description:BACKGROUND:The choice of treatment in patients with metastatic colorectal cancer (mCRC) is generally influenced by tumour and patient characteristics, treatment efficacy and tolerability, and quality of life. Better patient selection might lead to improved outcomes. METHODS:This post hoc exploratory analysis examined the effect of prognostic factors on outcomes in the Randomized, Double-blind, Phase 3 Study of trifluridine tipiracil (FTD/TPI) plus Best Supportive Care (BSC) versus Placebo plus BSC in Patients with mCRC Refractory to Standard Chemotherapies (RECOURSE) trial. Patients were redivided by prognosis into two subgroups: those with <3 metastatic sites at randomisation (low tumour burden) and ?18 months from diagnosis of metastatic disease to randomisation (indolent disease) were included in the good prognostic characteristics (GPC) subgroup; the remaining patients were considered to have poor prognostic characteristics (PPC). RESULTS:GPC patients (n=386) had improved outcome versus PPC patients (n=414) in both the trifluridine/tipiracil and placebo arms. GPC patients receiving trifluridine/tipiracil (n=261) had an improved median overall survival (9.3 vs 5.3 months; HR (95% CI) 0.46 (0.37 to 0.57), p<0.0001) and progression-free survival (3.3 vs 1.9 months; HR (95% CI) 0.56 (0.46 to 0.67), p<0.0001) than PPC patients receiving trifluridine/tipiracil (n=273). Improvements in survival were irrespective of age, Eastern Cooperative Oncology Group Performance Status (ECOG PS), KRAS mutational status, and site of metastases at randomisation. In the trifluridine/tipiracil arm, time to deterioration of ECOG PS to ?2 and proportion of patients with PS=0-1 discontinuing treatment were longer for GPC than for PPC patients (7.8 vs 4.2 months and 89.1% vs 78.4%, respectively). CONCLUSION:Low tumour burden and indolent disease were factors of good prognosis in late-line mCRC, with patients experiencing longer progression-free survival and greater overall survival.

Project description:BACKGROUND:In the phase III RECOURSE trial, trifluridine/tipiracil (TAS-102) extended overall survival (OS) and progression-free survival (PFS) with an acceptable toxicity profile in patients with metastatic colorectal cancer refractory or intolerant to standard therapies. The present analysis investigated the efficacy and safety of trifluridine/tipiracil in RECOURSE subgroups. METHODS:Primary and key secondary end-points were evaluated using a Cox proportional hazards model in prespecified subgroups, including geographical subregion (United States of America [USA], European Union [EU], Japan), age (<65 years, ?65 years) and v-Ki-ras2 Kirsten rat sarcoma 2 viral oncogene homologue (KRAS) status (wild type, mutant). Safety and tolerability were reported with descriptive statistics. RESULTS:Eight-hundred patients were enrolled: USA, n = 99; EU, n = 403; Japan, n = 266. Patients aged ?65 years and those with mutant KRAS tumours comprised 44% and 51% of all patients in the subregions, respectively. Final OS analysis (including 89% of events, compared with 72% in the initial analysis) confirmed the survival benefit associated with trifluridine/tipiracil, with a hazard ratio (HR) of 0.69 (95% confidence interval [CI] 0.59-0.81; P = 0.0001). Median OS in the three regions was 6.5-7.8 months in the trifluridine/tipiracil arm and 4.3-6.7 months in the placebo arm (USA: HR 0.56; 95% CI 0.34-0.94; P = 0.0277; EU: HR 0.62; 95% CI 0.48-0.80; P = 0.0002; Japan: HR 0.75; 95% CI 0.57-1.00; P = 0.0470). Median PFS was 2.0-2.8 months for trifluridine/tipiracil and 1.7-1.8 months for placebo; HRs favoured trifluridine/tipiracil in all regions. Similar clinical benefits of trifluridine/tipiracil were observed in elderly patients and in those with mutant KRAS tumours. There were no marked differences among subregions in terms of safety and tolerability. CONCLUSIONS:Trifluridine/tipiracil was effective in all subgroups, regardless of age, geographical origin or KRAS status. This trial is registered with ClinicalTrials.gov: NCT01607957.

Project description:BackgroundThe outcome of patients with refractory metastatic colorectal cancer (mCRC) treated with trifluridine/tipiracil (FTD/TPI) beyond the second-line has not been studied in Saudi Arabia. Therefore, this multicenter retrospective analysis was conducted to evaluate the efficacy of FTD/TPI.MethodsThis multicenter retrospective analysis included five centers in Saudi Arabia. FTD/TPI was administered to all the patients beyond the oxaliplatin- and irinotecan-based chemotherapy regimens. The electronic medical records were reviewed, and progression-free survival (PFS) and overall survival (OS) were determined.ResultsThe study included 100 patients with a mean age of 55.4 ± 11.8 years. The overall response to FTD/TPI was 4%. The median PFS was 4 months (95% confidence interval (CI) 3.487-4.513), and the median OS was 11 months (95% CI, 9.226-12.771). In a Cox regression analysis of the independent predictors for PFS, advanced stage of the disease (P = 0.037; HR, 2.614; and CI, 1.102-7.524), presence of lymph node metastasis (P = 0.018; HR, 3.664; and 95% CI, 1.187-8.650), and >2 metastatic sites (P = 0.020; HR, 1.723; and 95% CI, 1.089-2.727) were independent factors predicting disease progression. The Cox regression analysis confirmed that age ≥ 55 years (P = 0.046; HR, 1.667; and 95%, 1.097-3.100), advanced disease stage (P = 0.044; HR, 1.283; and 95% CI, 1.035-2.940), prior use of adjuvant chemotherapy (P = 0.037; HR, 0.892; and 95% CI, 0.481-0.994), liver metastasis (P = 0.025; HR, 2.015; and 95% CI, 1.091-3.720), >2 metastatic sites (P = 0.038; HR, 1.248; and 95% CI, 1.036-1.846), development of neutropenia after receiving first cycle of FTD/TPI (P = 0.042; HR, 1.505; and 95% CI, 1.064-2.167), and increased number of FTD/TPI cycles (P = 0.002; HR, 0.769; and 95% CI, 0.664-0.891) were independent variables for OS.ConclusionTreatment with FTD/TPI is feasible and effective in daily clinical practice in Saudi Arabian patients. The risk of progression increased with advanced disease stage, lymph node metastasis, bone metastasis, and metastasis to >2 sites. Age ≥ 55 years, advanced disease stage, liver metastasis, metastasis to >2 sites, neutropenia after the first cycle of FTD/TPI, and increased number of FTD/TPI cycles were independent factors predicting mortality.

Dataset Information

Neutropenia and survival outcomes in metastatic colorectal cancer patients treated with trifluridine/tipiracil in the RECOURSE and J003 trials.

Publications

Neutropenia and survival outcomes in metastatic colorectal cancer patients treated with trifluridine/tipiracil in the RECOURSE and J003 trials.

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