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Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study
A. Dasari, S. Lonardi, R. Garcia-Carbonero, E. Elez, T. Yoshino, A. Sobrero, J. Yao, P. García-Alfonso, J. Kocsis, A. Cubillo Gracian, A. Sartore-Bianchi, T. Satoh, V. Randrian, J. Tomasek, G. Chong, AS. Paulson, T. Masuishi, J. Jones, T. Csőszi,...
Language English Country England, Great Britain
Document type Randomized Controlled Trial, Clinical Trial, Phase III, Multicenter Study, Journal Article
NLK
ProQuest Central
from 1992-01-04 to 3 months ago
Nursing & Allied Health Database (ProQuest)
from 1992-01-04 to 3 months ago
Health & Medicine (ProQuest)
from 1992-01-04 to 3 months ago
Family Health Database (ProQuest)
from 1992-01-04 to 3 months ago
Psychology Database (ProQuest)
from 1992-01-04 to 3 months ago
Health Management Database (ProQuest)
from 1992-01-04 to 3 months ago
Public Health Database (ProQuest)
from 1992-01-04 to 3 months ago
- MeSH
- Double-Blind Method MeSH
- Colorectal Neoplasms * MeSH
- Quality of Life MeSH
- Humans MeSH
- Rectal Neoplasms * drug therapy MeSH
- Colonic Neoplasms * MeSH
- Antineoplastic Combined Chemotherapy Protocols adverse effects MeSH
- Trifluridine adverse effects MeSH
- Vascular Endothelial Growth Factor A MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase III MeSH
- Multicenter Study MeSH
- Randomized Controlled Trial MeSH
BACKGROUND: There is a paucity of effective systemic therapy options for patients with advanced, chemotherapy-refractory colorectal cancer. We aimed to evaluate the efficacy and safety of fruquintinib, a highly selective and potent oral inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3, in patients with heavily pretreated metastatic colorectal cancer. METHODS: We conducted an international, randomised, double-blind, placebo-controlled, phase 3 study (FRESCO-2) at 124 hospitals and cancer centres across 14 countries. We included patients aged 18 years or older (≥20 years in Japan) with histologically or cytologically documented metastatic colorectal adenocarcinoma who had received all current standard approved cytotoxic and targeted therapies and progressed on or were intolerant to trifluridine-tipiracil or regorafenib, or both. Eligible patients were randomly assigned (2:1) to receive fruquintinib (5 mg capsule) or matched placebo orally once daily on days 1-21 in 28-day cycles, plus best supportive care. Stratification factors were previous trifluridine-tipiracil or regorafenib, or both, RAS mutation status, and duration of metastatic disease. Patients, investigators, study site personnel, and sponsors, except for selected sponsor pharmacovigilance personnel, were masked to study group assignments. The primary endpoint was overall survival, defined as the time from randomisation to death from any cause. A non-binding futility analysis was done when approximately one-third of the expected overall survival events had occurred. Final analysis occurred after 480 overall survival events. This study is registered with ClinicalTrials.gov, NCT04322539, and EudraCT, 2020-000158-88, and is ongoing but not recruiting. FINDINGS: Between Aug 12, 2020, and Dec 2, 2021, 934 patients were assessed for eligibility and 691 were enrolled and randomly assigned to receive fruquintinib (n=461) or placebo (n=230). Patients had received a median of 4 lines (IQR 3-6) of previous systemic therapy for metastatic disease, and 502 (73%) of 691 patients had received more than 3 lines. Median overall survival was 7·4 months (95% CI 6·7-8·2) in the fruquintinib group versus 4·8 months (4·0-5·8) in the placebo group (hazard ratio 0·66, 95% CI 0·55-0·80; p<0·0001). Grade 3 or worse adverse events occurred in 286 (63%) of 456 patients who received fruquintinib and 116 (50%) of 230 who received placebo; the most common grade 3 or worse adverse events in the fruquintinib group included hypertension (n=62 [14%]), asthenia (n=35 [8%]), and hand-foot syndrome (n=29 [6%]). There was one treatment-related death in each group (intestinal perforation in the fruquintinib group and cardiac arrest in the placebo group). INTERPRETATION: Fruquintinib treatment resulted in a significant and clinically meaningful benefit in overall survival compared with placebo in patients with refractory metastatic colorectal cancer. These data support the use of fruquintinib as a global treatment option for patients with refractory metastatic colorectal cancer. Ongoing analysis of the quality of life data will further establish the clinical benefit of fruquintinib in this patient population. FUNDING: HUTCHMED.
Asklepios Tumorzentrum Hamburg Department of Oncology and Hematology AK Altona Hamburg Germany
Békés Megyei Központi Kórház Pándy Kálmán Tagkórház Megyei Onkológiai Központ Gyula Hungary
Department of Clinical Oncology Aichi Cancer Center Hospital Aichi Japan
Department of Complex Oncology Care Masaryk Memorial Cancer Institute Brno Czech Republic
Department of Hepato Gastroenterology CHU Poitiers Université de Poitiers Poitiers France
Department of Medical Oncology Azienda Ospedaliera San Martino Genoa Italy
Department of Medical Oncology Centre Georges François Leclerc Dijon France
Department of Medical Oncology West German Cancer Center University Hospital Essen Essen Germany
Department of Medicine University of Michigan Ann Arbor MI USA
Department of Oncology and Hemato Oncology Università degli Studi di Milano Milan Italy
Department of Oncology CHU UCL Namur Site Godinne Yvoir Belgium
Department of Oncoradiology Bács Kiskun Megyei Oktatókórház Kecskemét Hungary
Division Hematology and Oncology Vanderbilt Ingram Cancer Center Nashville TN USA
Division of Hematology and Medical Oncology Mayo Clinic Cancer Center Jacksonville FL USA
Grande Ospedale Metropolitano Niguarda Milan Italy
Hetényi Géza Kórház Onkológiai Központ Szolnok Hungary
HUTCHMED International Corporation Florham Park NJ USA
Medical Oncology Unit 1 Veneto Institute of Oncology IOV IRCCS Padua Padua Italy
Olivia Newton John Cancer Wellness and Research Centre Austin Hospital Melbourne VIC Australia
Oncology and Haematology Clinic North Estonia Medical Centre Tallinn Estonia
Oncology Department Hospital Universitario 12 de Octubre lmas12 UCM Madrid Spain
Palliative and Supportive Care Center Osaka University Hospital Osaka Japan
Rutgers Cancer Institute of New Jersey New Brunswick NJ USA
Texas Oncology Baylor Charles A Sammons Cancer Center US Oncology Research Dallas TX USA
University Hospitals Gasthuisberg Leuven and KU Leuven Leuven Belgium
University of Chicago Biological Sciences Division Chicago IL USA
References provided by Crossref.org
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- $a BACKGROUND: There is a paucity of effective systemic therapy options for patients with advanced, chemotherapy-refractory colorectal cancer. We aimed to evaluate the efficacy and safety of fruquintinib, a highly selective and potent oral inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3, in patients with heavily pretreated metastatic colorectal cancer. METHODS: We conducted an international, randomised, double-blind, placebo-controlled, phase 3 study (FRESCO-2) at 124 hospitals and cancer centres across 14 countries. We included patients aged 18 years or older (≥20 years in Japan) with histologically or cytologically documented metastatic colorectal adenocarcinoma who had received all current standard approved cytotoxic and targeted therapies and progressed on or were intolerant to trifluridine-tipiracil or regorafenib, or both. Eligible patients were randomly assigned (2:1) to receive fruquintinib (5 mg capsule) or matched placebo orally once daily on days 1-21 in 28-day cycles, plus best supportive care. Stratification factors were previous trifluridine-tipiracil or regorafenib, or both, RAS mutation status, and duration of metastatic disease. Patients, investigators, study site personnel, and sponsors, except for selected sponsor pharmacovigilance personnel, were masked to study group assignments. The primary endpoint was overall survival, defined as the time from randomisation to death from any cause. A non-binding futility analysis was done when approximately one-third of the expected overall survival events had occurred. Final analysis occurred after 480 overall survival events. This study is registered with ClinicalTrials.gov, NCT04322539, and EudraCT, 2020-000158-88, and is ongoing but not recruiting. FINDINGS: Between Aug 12, 2020, and Dec 2, 2021, 934 patients were assessed for eligibility and 691 were enrolled and randomly assigned to receive fruquintinib (n=461) or placebo (n=230). Patients had received a median of 4 lines (IQR 3-6) of previous systemic therapy for metastatic disease, and 502 (73%) of 691 patients had received more than 3 lines. Median overall survival was 7·4 months (95% CI 6·7-8·2) in the fruquintinib group versus 4·8 months (4·0-5·8) in the placebo group (hazard ratio 0·66, 95% CI 0·55-0·80; p<0·0001). Grade 3 or worse adverse events occurred in 286 (63%) of 456 patients who received fruquintinib and 116 (50%) of 230 who received placebo; the most common grade 3 or worse adverse events in the fruquintinib group included hypertension (n=62 [14%]), asthenia (n=35 [8%]), and hand-foot syndrome (n=29 [6%]). There was one treatment-related death in each group (intestinal perforation in the fruquintinib group and cardiac arrest in the placebo group). INTERPRETATION: Fruquintinib treatment resulted in a significant and clinically meaningful benefit in overall survival compared with placebo in patients with refractory metastatic colorectal cancer. These data support the use of fruquintinib as a global treatment option for patients with refractory metastatic colorectal cancer. Ongoing analysis of the quality of life data will further establish the clinical benefit of fruquintinib in this patient population. FUNDING: HUTCHMED.
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