Dataset Information

Safety and efficacy of trifluridine/tipiracil in previously treated metastatic colorectal cancer: final results from the phase IIIb single-arm PRECONNECT study by duration of therapy.

ABSTRACT:

Background

PRECONNECT was an international, phase IIIb trial evaluating the safety and efficacy of trifluridine/tipiracil (FTD/TPI) for metastatic colorectal cancer (mCRC).

Methods

Patients with mCRC received FTD/TPI 35 mg/m² twice-daily on days 1-5 and 8-12 of each 28-day cycle for third- or later-line treatment.

Primary endpoint

safety and time to deterioration of Eastern Cooperative Oncology Group performance status [ECOG PS] to ≥2). Secondary endpoints included progression-free survival (PFS). Potential prognostic factors for PFS were explored.

Results

Of 914 patients, 69% completed 0-3, 24% completed 4-7, and 7% completed ≥8 cycles of FTD/TPI. Drug-related grade ≥ 3 adverse events included neutropenia (38.1%), anaemia (7.2%) and asthenia (3.4%). Median [95% CI] time to ECOG PS deterioration was 8.7 [8.1-not calculable] months and increased with duration of treatment (DoT). Median PFS was 2.8 [2.7-3.0] months and increased with duration of treatment DoT. Prognostic factors associated with longer PFS included time since diagnosis of first metastasis, number of metastatic sites, baseline ECOG PS, presence/absence of liver metastasis or previous regorafenib treatment, and laboratory variables.

Conclusions

No new safety concerns for FTD/TPI were identified and PFS increased with DoT. These data provide confidence for the use of FTD/TPI, including the use of multiple cycles, in routine practice.

Trial registration

EudraCT Number: 2016-002311-18; registered 19/09/2016. https://clinicaltrials.gov/ct2/show/NCT03306394 ; registered 11/10/2017.

SUBMITTER: Taieb J

PROVIDER: S-EPMC9881327 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Safety and efficacy of trifluridine/tipiracil in previously treated metastatic colorectal cancer: final results from the phase IIIb single-arm PRECONNECT study by duration of therapy.

Taieb Julien J Price Timothy T Vidot Loïck L Chevallier Bénédicte B Wyrwicz Lucjan L Bachet Jean-Baptiste JB

BMC cancer 20230127 1

<h4>Background</h4>PRECONNECT was an international, phase IIIb trial evaluating the safety and efficacy of trifluridine/tipiracil (FTD/TPI) for metastatic colorectal cancer (mCRC).<h4>Methods</h4>Patients with mCRC received FTD/TPI 35 mg/m<sup>2</sup> twice-daily on days 1-5 and 8-12 of each 28-day cycle for third- or later-line treatment.<h4>Primary endpoint</h4>safety and time to deterioration of Eastern Cooperative Oncology Group performance status [ECOG PS] to ≥2). Secondary endpoints includ ...[more]

PMID: 36707808

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Project description:BackgroundEffective later-line chemotherapy treatment options are scarce for patients with metastatic breast cancer (MBC). Trifluridine-tipiracil has shown survival benefit in heavily pre-treated patients with metastatic colorectal and in gastric cancer refractory to a fluoropyrimidine. This study aimed to investigate the efficacy of trifluridine-tipiracil in a Western population of previously treated patients with oestrogen receptor (ER+), HER2- MBC to facilitate further optimization of this treatment strategy.MethodsAdult patients at least 18 years old diagnosed with hormone receptor positive, HER2- receptor negative MBC with a performance status of 0 or 1 who have been treated with capecitabine in the metastatic setting and up to two other lines of chemotherapy, including a taxane, were enrolled in this single-arm, multicentre, phase 2 study in the Netherlands. The participants received trifluridine-tipiracil 35 mg/m2 orally twice a day on days 1-5 and days 8-12 during a 28-day cycle until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was the disease control rate (DCR) at 8 weeks, defined as the percentage of patients that had stable disease, partial response or complete response according to RECIST 1.1, in all patients that received at least one dose of trifluridine-tipiracil and met the key eligibility criteria defined a priori. Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and quality of life and were performed in all patients that received at least one dose of trifluridine-tipiracil. The primary endpoint was considered met, justifying further research of this treatment regimen, if the lower boundary of the 80% confidence interval (CI) exceeded 30%. The study was registered within ClinicalTrials.gov (NCT04489173) and is closed for inclusion.FindingsFifty female patients were enrolled from September 2020 to July 2023, with a median of 3 (IQR, 2-3) previous endocrine therapy lines and 2 (IQR, 2-3) chemotherapy lines for MBC. The DCR rate at 8 weeks was 64.0% (n = 32, 95% CI: 50.1-75.9%; 80% CI: 55.0-72.1%), thereby meeting the primary endpoint of this study. At data cutoff (January 8, 2024), the median follow-up time was 18.2 months (IQR, 13.1-25.1 months). The median PFS was 5.4 months (95% CI: 2.0-7.2 months) and the median OS 14.0 months (95% CI: 8.8-17.8 months). The safety profile of trifluridine-tipiracil aligned with expected toxicities and included leukopenia (n = 36, 69%), neutropenia (n = 43, 83%), and fatigue (n = 43, 83%). The most common grade 3-4 AEs were primarily haematological disorders and included neutropenia (n = 38, 73%), leukopenia (n = 15, 29%) and anaemia (n = 6, 12%). The most common SAEs (any grade) with a possible relationship with trifluridine-tipiracil included anaemia (n = 2) and vomiting (n = 2). No treatment-related deaths occurred. Quality of life scores remained stable throughout the treatment.InterpretationTrifluridine-tipiracil demonstrated promising efficacy in heavily pre-treated patients with MBC, despite prior exposure to a fluoropyrimidine. Clinically, this suggests that trifluridine-tipiracil holds potential as a viable oral later-line treatment option with a manageable toxicity profile while maintaining quality of life. Preparations for a phase 3 trial are underway.FundingServier, France.

Project description:BackgroundThe 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 methodsA 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.ResultsIn 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.ConclusionsIn 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 identifierNCT01607957 (RECOURSE).Japan pharmaceutical information center numberJapicCTI-090880 (J003).

Dataset Information

Safety and efficacy of trifluridine/tipiracil in previously treated metastatic colorectal cancer: final results from the phase IIIb single-arm PRECONNECT study by duration of therapy.

Background

Methods

Primary endpoint

Results

Conclusions

Trial registration

Publications

Safety and efficacy of trifluridine/tipiracil in previously treated metastatic colorectal cancer: final results from the phase IIIb single-arm PRECONNECT study by duration of therapy.

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