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EClinicalMedicine Apr 2024Trifluridine-tipiracil has shown a survival benefit compared with placebo in patients with chemorefractory metastatic esophago-gastric adenocarcinoma. We aimed to...
BACKGROUND
Trifluridine-tipiracil has shown a survival benefit compared with placebo in patients with chemorefractory metastatic esophago-gastric adenocarcinoma. We aimed to compare the efficacy of trifluridine-tipiracil plus bevacizumab vs trifluridine-tipiracil monotherapy in pre-treated patients with metastatic esophago-gastric adenocarcinoma.
METHODS
This investigator-initiated, open-label, randomized trial enrolled patients with metastatic esophago-gastric adenocarcinoma. The main inclusion criteria were patients with pre-treated metastatic esophago-gastric adenocarcinoma, and WHO performance status 0 or 1. Participants were randomly assigned (1:1) to receive oral trifluridine-tipiracil (35 mg/m twice daily on days 1-5 and 8-12 every 28 days) alone or combined with bevacizumab (5 mg/kg on days 1 and 15) until progression, unacceptable toxicity, or patient decision to withdraw. Randomisation was stratified by sex and treatment line. The primary endpoint was investigator-evaluated progression-free survival. All analyses were based on intention to treat. This trial is registered with EudraCT, 2018-004845-18.
FINDINGS
From Oct 1, 2019, to Sept 30, 2021, 103 patients were enrolled and randomly assigned to trifluridine-tipiracil (n = 53) or trifluridine-tipiracil plus bevacizumab (n = 50). The clinical cut-off date was March 1st, 2023, after a median follow-up of 36.6 months. Median progression-free survival was 3.1 months (95% CI 2.0-4.3) in the trifluridine-tipiracil group vs 3.9 months (3.0-6.3) in the trifluridine-tipiracil plus bevacizumab group (hazard ratio 0.68, 95% CI 0.46-1.02; p = 0.058). The most frequent grade 3 or worse adverse event was neutropenia, observed in 26 (49%) patients in the trifluridine-tipiracil group vs 23 patients (46%) in the trifluridine-tipiracil plus bevacizumab group. At least one hospitalization was observed in 21 patients (40%) in the trifluridine-tipiracil group and 22 patients (44%) in the trifluridine-tipiracil plus bevacizumab group. No deaths were deemed treatment related.
INTERPRETATION
In patients with pre-treated metastatic esophago-gastric cancer, trifluridine-tipiracil plus bevacizumab, compared to trifluridine-tipiracil monotherapy, did not significantly prolong progression-free survival. The combination of trifluridine-tipiracil with bevacizumab was well tolerated without increase in severe neutropenia and no new safety signals.
FUNDING
Servier, Roche.
PubMed: 38495525
DOI: 10.1016/j.eclinm.2024.102521 -
JCO Global Oncology Mar 2024Metastatic colorectal cancer (mCRC) is a significant global health burden. This retrospective study compared the effectiveness of trifluridine/tipiracil (FTD/TPI),... (Comparative Study)
Comparative Study
Efficacy of Chemotherapy Rechallenge Versus Regorafenib or Trifluridine/Tipiracil in Third-Line Setting of Metastatic Colorectal Cancer: A Multicenter Retrospective Comparative Study.
PURPOSE
Metastatic colorectal cancer (mCRC) is a significant global health burden. This retrospective study compared the effectiveness of trifluridine/tipiracil (FTD/TPI), regorafenib, and chemotherapy rechallenge for third-line mCRC treatment.
MATERIALS AND METHODS
We reviewed the medical records of 132 patients with mCRC treated with regorafenib, FTD/TPI, or a rechallenge with the initial chemotherapy regimen in a third-line setting from four different institutions. The primary end point was progression-free survival (PFS). Secondary end points were objective response rate and overall survival (OS) across the three treatment approaches.
RESULTS
Twenty-nine patients received chemotherapy rechallenge, and 103 received FTD/TPI or regorafenib. Patients' characteristics were comparable, except for a lower number of left-sided primaries and wild-type tumors in the FTD/TPI-regorafenib group. The median PFS for the entire group was 3.0 months, and the median OS was 13.7 months. Chemotherapy rechallenge has resulted in a median PFS of 3.1 months and a median OS of 21.2 months, compared with 2.9 months (PFS) and 12.6 months (OS) for the FTD/TPI-regorafenib group. Multivariate analyses identified male sex and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1 as independent prognostic factors for better PFS, whereas chemotherapy rechallenge, localized stage at diagnosis, and an ECOG PS of 0-1 were significant prognostic factors for better OS.
CONCLUSION
This study suggests that chemotherapy rechallenge may provide a survival benefit in the third-line treatment of mCRC. However, patient characteristics, such as sex and ECOG PS, should also be considered in treatment decisions. Further prospective studies are required to confirm our findings.
Topics: Humans; Male; Colorectal Neoplasms; Frontotemporal Dementia; Phenylurea Compounds; Pyridines; Pyrrolidines; Retrospective Studies; Thymine; Trifluridine; Female
PubMed: 38484194
DOI: 10.1200/GO.23.00461 -
ESMO Open Mar 2024In metastatic colorectal cancer (mCRC), KRAS mutations are often associated with poorer survival; however, the prognostic impact of specific point mutations is unclear.... (Randomized Controlled Trial)
Randomized Controlled Trial
Impact of KRAS mutations on survival with trifluridine/tipiracil plus bevacizumab in patients with refractory metastatic colorectal cancer: post hoc analysis of the phase III SUNLIGHT trial.
BACKGROUND
In metastatic colorectal cancer (mCRC), KRAS mutations are often associated with poorer survival; however, the prognostic impact of specific point mutations is unclear. In the phase III SUNLIGHT trial, trifluridine/tipiracil (FTD/TPI) plus bevacizumab significantly improved overall survival (OS) versus FTD/TPI alone. We assessed the impact of KRAS mutational status on OS in SUNLIGHT.
PATIENTS AND METHODS
In the global, open-label, randomized, phase III SUNLIGHT trial, adults with mCRC who had received no more than two prior chemotherapy regimens were randomized 1 : 1 to receive FTD/TPI alone or FTD/TPI plus bevacizumab. In this post hoc analysis, OS was assessed according to the presence or absence of a KRAS mutation in the overall population and in patients with RAS-mutated tumors.
RESULTS
Overall, 450 patients were analyzed, including 302 patients in the RAS mutation subgroup (214 with a KRAS mutation and 88 with a non-KRASRAS mutation). In the overall population, similar OS outcomes were observed in patients with and without a KRAS mutation [median 8.3 and 9.2 months, respectively; hazard ratio (HR) 1.09, 95% confidence interval (CI) 0.87-1.4]. Similar OS outcomes were also observed in the subgroup analysis of patients with a KRAS mutation versus those with a non-KRASRAS mutation (HR 1.03, 95% CI 0.76-1.4). FTD/TPI plus bevacizumab improved OS compared with FTD/TPI alone irrespective of KRAS mutational status. Among patients with a KRAS mutation, the median OS was 9.4 months with FTD/TPI plus bevacizumab versus 7.2 months with FTD/TPI alone (HR 0.67, 95% CI 0.48-0.93), and in patients without a KRAS mutation, the median OS was 11.3 versus 7.1 months, respectively (HR 0.59, 95% CI 0.43-0.81).
CONCLUSIONS
The presence of a KRAS mutation had no detrimental effect on OS among patients treated in SUNLIGHT. The benefit of FTD/TPI plus bevacizumab over FTD/TPI alone was confirmed independently of KRAS status.
Topics: Adult; Humans; Bevacizumab; Proto-Oncogene Proteins p21(ras); Colorectal Neoplasms; Uracil; Trifluridine; Frontotemporal Dementia; Colonic Neoplasms; Mutation; Pyrrolidines; Thymine
PubMed: 38471240
DOI: 10.1016/j.esmoop.2024.102945 -
Targeted Oncology Mar 2024Non-inferiority of trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) to irinotecan/fluoropyrimidine plus BEV in metastatic colorectal cancer was investigated in...
BACKGROUND
Non-inferiority of trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) to irinotecan/fluoropyrimidine plus BEV in metastatic colorectal cancer was investigated in the phase III TRUSTY study, and we conducted a phase II study of FOLFIRI (5-FU+leucovorin+irinotecan) plus zib-aflibercept (AFL) after FTD/TPI plus BEV. However, the TRUSTY study failed during the recruitment of our patients.
OBJECTIVE
We present the findings of a phase II study on the efficacy of FOLFIRI plus zib-aflibercept (AFL) after FTD/TPI plus BEV, including clinical results with plasma biomarker analyses.
METHODS
This was a multicenter, single-arm, phase II study in patients with metastatic colorectal cancer refractory or intolerant to oxaliplatin, fluoropyrimidine, BEV, and FTD/TPI. The primary endpoint was progression-free survival. Fifteen plasma angiogenesis-associated biomarkers were analyzed using a Luminex multiplex assay U-kit.
RESULTS
Between January 2020 and May 2022, 26 patients (median age, 68 years) from 15 sites were enrolled. The median progression-free survival was 4.9 months (85% confidence interval, 3.4 month-not estimated). The overall response and disease control rates were 8% and 62%, respectively. The median levels of vascular endothelial growth factor-A and placental growth factor, both targets of AFL, were below the measurable limit of 30 pg/mL and 16 pg/mL, respectively. Patients were divided into two groups at the median levels of baseline biomarkers. The progression-free survival did not differ between high and low expressers of placental growth factor (p = 0.7), while it tended to be shorter in those with high levels of osteopontin (p = 0.05), angiopoietin-2 (p = 0.07), and tissue inhibitor of matrix metalloproteinases-1 (p = 0.1).
CONCLUSIONS
This study did not meet the primary endpoint. Hence, FOLFIRI plus AFL should not be used after FTD/TPI plus BEV for metastatic colorectal cancer. Further studies are needed to determine factors not targeted by AFL that may affect the efficacy of the treatment.
CLINICAL TRIAL REGISTRATION
jRCTs041190100.
Topics: Aged; Female; Humans; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers; Colonic Neoplasms; Colorectal Neoplasms; Frontotemporal Dementia; Irinotecan; Leucovorin; Placenta Growth Factor; Pyrrolidines; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Thymine; Trifluridine; Vascular Endothelial Growth Factor A
PubMed: 38427280
DOI: 10.1007/s11523-024-01043-2 -
Clinical & Translational Oncology :... Jun 2024The optimal drug regimen and sequence are still unknown for patients with metastatic colorectal cancer (mCRC) who are candidates for third-line (3L) or subsequent...
PURPOSE
The optimal drug regimen and sequence are still unknown for patients with metastatic colorectal cancer (mCRC) who are candidates for third-line (3L) or subsequent treatment. The aim of this study is to know the opinion of experts on the most appropriate treatment options for mCRC in 3L and to clarify certain clinical decisions in Spain.
METHODS
Using a modified Delphi method, a group of experts discussed the treatment in 3L of patients with mCRC and developed a questionnaire with 21 items divided into 5 sections.
RESULTS
After 2 rounds, the 67 panelists consulted agreed on 17 items (81%). They considered that the main objective of 3L is to equally increase survival and improve patients' quality of life (QoL), but preferably the QoL. It was agreed that patients with mCRC in 3L prefer to receive active versus symptomatic treatment. Panelists considered trifluridine/tipiracil (FTD/TPI) to be the best oral treatment available to them in 3L. In patients with MSI-H or dMMR and BRAF V600E, the panelists mostly prefer targeted treatments. Panelists agreed the use of a therapeutic sequence that not only increases outcomes but also allows patients to be treated later. Finally, it was agreed that FTD/TPI has a mechanism of action that allows it to be used in patients refractory to previous treatment with 5-fluorouracil.
CONCLUSION
The experts agreed with most of the proposed items on 3L treatment of mCRC, prioritizing therapeutic options that increase survival and preserve QoL, while facilitating the possibility that patients can continue to be treated later.
Topics: Humans; Colorectal Neoplasms; Delphi Technique; Quality of Life; Antineoplastic Combined Chemotherapy Protocols; Consensus; Pyrrolidines; Trifluridine; Thymine; Surveys and Questionnaires; Neoplasm Metastasis; Proto-Oncogene Proteins B-raf; Spain
PubMed: 38411748
DOI: 10.1007/s12094-023-03369-1 -
Advances in Therapy Apr 2024This literature review and exploratory network meta-analysis (NMA) aimed to compare the clinical effectiveness and tolerability of selective internal radiation therapy... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
This literature review and exploratory network meta-analysis (NMA) aimed to compare the clinical effectiveness and tolerability of selective internal radiation therapy (SIRT) using yttrium-90 (Y-90) resin microspheres, regorafenib (REG), trifluridine-tipiracil (TFD/TPI), and best supportive care (BSC) in adult patients with chemotherapy-refractory or chemotherapy-intolerant metastatic colorectal cancer (mCRC).
METHODS
In light of recently published data, the literature was searched to complement and update a review published in 2018. Studies up to December 2022 comparing two or more of the treatments and reporting overall survival (OS), progression-free survival (PFS), or incidence of adverse events (AE) were included. The NMA compared hazard ratios (HRs) for OS and PFS using Markov chain Monte Carlo techniques.
RESULTS
Fifteen studies were included, with eight studies added (none addressing SIRT). All active treatments improved OS in relation to BSC. SIRT had the longest OS among all treatments, although without statistically significant differences (HR [95% credible interval] for SIRT, 0.48 [0.27, 0.87]; TFD/TPI, 0.62 [0.46, 0.83]; REG, 0.78 [0.57, 1.05]) in a fixed effects model. Information regarding SIRT was insufficient for PFS analysis, and TFD/TPI was the best intervention (HR 2.26 [1.6, 3.18]). One SIRT study reported radioembolization-induced liver disease in > 10% of the sample; this was symptomatically managed. Non-haematological AEs (hand-foot skin reaction, fatigue, diarrhoea, hypertension, rash or desquamation) were more common with REG, while haematological events (neutropoenia, leukopenia, and anaemia) were more common with TFD/TPI.
CONCLUSION
Current evidence supports SIRT treatment in patients with chemotherapy-refractory or chemotherapy-intolerant mCRC compared to newer oral agents, with comparable OS and low incidence of AEs.
Topics: Adult; Humans; Yttrium Radioisotopes; Colorectal Neoplasms; Network Meta-Analysis; Microspheres; Colonic Neoplasms; Pyrrolidines; Antineoplastic Combined Chemotherapy Protocols; Phenylurea Compounds; Pyridines
PubMed: 38407790
DOI: 10.1007/s12325-024-02800-5 -
The Oncologist May 2024We performed a systematic literature review to identify and summarize data from studies reporting clinical efficacy and safety outcomes for trifluridine/tipiracil...
We performed a systematic literature review to identify and summarize data from studies reporting clinical efficacy and safety outcomes for trifluridine/tipiracil (FTD/TPI) combined with other antineoplastic agents in advanced cancers, including metastatic colorectal cancer (mCRC). We conducted a systematic search on May 29, 2021, for studies reporting one or more efficacy or safety outcome with FTD/TPI-containing combinations. Our search yielded 1378 publications, with 38 records meeting selection criteria: 35 studies of FTD/TPI-containing combinations in mCRC (31 studies second line or later) and 3 studies in other tumor types. FTD/TPI plus bevacizumab was extensively studied, including 19 studies in chemorefractory mCRC. Median overall survival ranged 8.6-14.4 months and median progression-free survival 3.7-6.8 months with FTD/TPI plus bevacizumab in refractory mCRC. Based on one randomized and several retrospective studies, FTD/TPI plus bevacizumab was associated with improved outcomes compared with FTD/TPI monotherapy. FTD/TPI combinations with chemotherapy or other targeted agents were reported in small early-phase studies; preliminary data indicated higher antitumor activity for certain combinations. Overall, no safety concerns existed with FTD/TPI combinations; most common grade ≥ 3 adverse event was neutropenia, ranging 5%-100% across all studies. In studies comparing FTD/TPI combinations with monotherapy, grade ≥ 3 neutropenia appeared more frequently with combinations (29%-67%) vs. monotherapy (5%-41%). Discontinuation rates due to adverse events ranged 0%-11% for FTD/TPI plus bevacizumab and 0%-17% with other combinations. This systematic review supports feasibility and safety of FTD/TPI plus bevacizumab in refractory mCRC. Data on non-bevacizumab FTD/TPI combinations remain preliminary and need further validation.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Drug Combinations; Pyrrolidines; Thymine; Trifluridine
PubMed: 38366864
DOI: 10.1093/oncolo/oyae007 -
International Medical Case Reports... 2024We report a case of a 62-year-old male who was diagnosed with advanced rectal cancer. The attending gastro-enterologist initiated chemotherapy using capecitabine plus...
We report a case of a 62-year-old male who was diagnosed with advanced rectal cancer. The attending gastro-enterologist initiated chemotherapy using capecitabine plus oxaliplatin and bevacizumab; however, this treatment regimen was discontinued, as the patient developed a skin rash. Once the skin rash improved, chemotherapy was re-initiated using a combination of trifluridine and tipiracil hydrochloride (TAS-102). The patient developed high fever and dyspnea 2 months after initiation of TAS-102. Chest high-resolution computed tomography showed bilateral diffuse ground glass opacities in all lung lobes with traction bronchiectasis. At this time, the gastro-enterologist consulted our department. The patient was put on non-invasive positive pressure ventilation due to worsening respiratory symptoms. The patient was suspected to develop TAS-102-induced interstitial pneumonia based on positive TAS-102 drug-induced lymphocyte stimulation test. The patient's respiratory symptoms and radiological findings improved after corticosteroid treatment. The corticosteroid dose was gradually decreased by 5 mg. Thereafter, chemotherapy was re-initiated using different anti-cancer agents.
PubMed: 38344468
DOI: 10.2147/IMCRJ.S444330 -
Therapeutic Advances in Medical Oncology 2024Recent trials have reported a median overall survival (OS) of 11-17 months in patients with advanced gastric cancer (AGC). However, it is unclear how recently approved...
BACKGROUND
Recent trials have reported a median overall survival (OS) of 11-17 months in patients with advanced gastric cancer (AGC). However, it is unclear how recently approved drugs contribute to patient prognosis.
OBJECTIVES
We aimed to evaluate the characteristics and survival in patients with AGC over the past 15 years.
DESIGN
Retrospective study.
METHODS
We evaluated data of 1355 patients with AGC who received first-line chemotherapy between January 2005 and March 2019 at a single institution. We compared the characteristics and survival rates across four periods: January 2005-December 2007 (period A), January 2008-February 2011 (period B), March 2011-May 2015 (period C), and June 2015-March 2019 (period D). The median follow-up duration was 13.1 months, with 312, 333, 393, and 317 patients in periods A, B, C, and D, respectively.
RESULTS
There were no significant differences in patient characteristics between the four periods, except for the proportion of patients who underwent prior gastrectomy and human epidermal growth factor receptor 2 (HER2) testing. Patients in period D had significantly longer OS than those in period A [median: 15.7 12.4 months; adjusted hazard ratio (aHR): 0.79; = 0.02]. The mean OS in patients with liver metastasis (LM) in period D was remarkably longer than that in patients in period A (median: 19.3 12.4 months; aHR: 0.61; < 0.01), while that in patients with peritoneal metastasis showed limited improvement.
CONCLUSION
Clinical strategy changes, including gastrectomy, HER2 testing, and approval of new drugs, may be associated with improved OS in patients with AGC. In the last 4 years, a remarkable improvement has been observed in patients with LM.
PubMed: 38344409
DOI: 10.1177/17588359241229428