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A Randomized Phase ...
A Randomized Phase III Study of Arfolitixorin versus Leucovorin with 5-Fluorouracil, Oxaliplatin, and Bevacizumab for First-Line Treatment of Metastatic Colorectal Cancer : The AGENT Trial
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- Tabernero, Josep (author)
- Vall dHebron Hosp Campus, Barcelona 08035, Spain.;IOB Quiron, Inst Oncol VHIO, Barcelona, Spain.;UV UCC, Inst Oncol VHIO, IOB Quiron, Barcelona 08035, Spain.
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- Yoshino, Takayuki (author)
- Natl Canc Ctr Hosp East, Dept Gastroenterol & Gastrointestinal Oncol, Kashiwa, Japan.
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- Stintzing, Sebastian (author)
- Charite Univ Med Berlin, Dept Hematol Oncol & Canc Immunol, Berlin, Germany.
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- de Gramont, Aimery (author)
- Inst Hosp Franco Britannique, Oncol Med, Levallois Perret, France.
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- Gibbs, Peter (author)
- Sunshine Hosp, Western Hlth, Med Oncol, St Albans, Vic, Australia.
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- Jonker, Derek J. (author)
- Univ Ottawa, Ottawa Hosp Res Inst, Ottawa, ON, Canada.
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- Nygren, Peter (author)
- Uppsala universitet,Cancerprecisionsmedicin
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- Papadimitriou, Christos (author)
- Natl & Kapodistrian Univ Athens, Aretaieion Univ Hosp, Oncol Unit, Athens, Greece.
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- Prager, Gerald W. (author)
- Med Univ Wien, Vienna, Austria.
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- Tell, Roger (author)
- Isofol Med AB, Gothenburg, Sweden.
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- Lenz, Heinz-Josef (author)
- Univ Southern Calif, Keck Sch Med, Div Med Oncol & Colorectal Canc, Los Angeles, CA USA.
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Vall dHebron Hosp Campus, Barcelona 08035, Spain;IOB Quiron, Inst Oncol VHIO, Barcelona, Spain.;UV UCC, Inst Oncol VHIO, IOB Quiron, Barcelona 08035, Spain. Natl Canc Ctr Hosp East, Dept Gastroenterol & Gastrointestinal Oncol, Kashiwa, Japan. (creator_code:org_t)
- American Association For Cancer Research (AACR), 2024
- 2024
- English.
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In: Cancer Research Communications. - : American Association For Cancer Research (AACR). - 2767-9764. ; 4:1, s. 28-37
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Abstract
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- Purpose:Suboptimal treatment outcomes with 5-fluorouracil (5-FU)/folate, the standard of care for metastatic colorectal cancer (mCRC), have generated interest in optimizing the folate. Arfolitixorin ([6R]-5,10-methylene-tetrahydrofolate) is an immediately active folate and may improve outcomes over the existing standard of care (leucovorin).Experimental Design:AGENT was a randomized, phase III study (NCT03750786). Patients with mCRC were randomized to arfolitixorin (120 mg/m2 given as two intravenous bolus doses of 60 mg/m2) or leucovorin (400 mg/m2 given as a single intravenous infusion) plus 5-FU, oxaliplatin, and bevacizumab. Assessments were performed every 8 weeks. The primary endpoint was the superiority of arfolitixorin for overall response rate (ORR).Results:Between February 2019 and April 2021, 490 patients were randomized (245 to each arm). After a median follow-up of 266 days, the primary endpoint of superiority for ORR was not achieved (48.2% for arfolitixorin vs. 49.4% for leucovorin, Psuperiority = 0.57). Outcomes were not achieved for median progression-free survival (PFS; 12.8 and 11.6 months, P = 0.38), median duration of response (12.2 and 12.9 months, P = 0.40), and median overall survival (23.8 and 28.0 months, P = 0.78). The proportion of patients with an adverse event of grade ≥3 severity was similar between arms (68.7% and 67.2%, respectively), as was quality of life. BRAF mutations and MTHFD2 expression were both associated with a lower PFS with arfolitixorin.Conclusions:The study failed to demonstrate clinical benefit of arfolitixorin (120 mg/m2) over leucovorin. However, it provides some useful insights from the first-line treatment setting, including the effect of gene expression on outcomes.Significance:This phase III study compared arfolitixorin, a direct-acting folate, with leucovorin in FOLFOX plus bevacizumab in mCRC. Arfolitixorin (120 mg/m2) did not improve the ORR, potentially indicating a suboptimal dose.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
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Tabernero, Josep
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Yoshino, Takayuk ...
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Stintzing, Sebas ...
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de Gramont, Aime ...
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Gibbs, Peter
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Jonker, Derek J.
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Nygren, Peter
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Papadimitriou, C ...
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Prager, Gerald W ...
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Tell, Roger
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Lenz, Heinz-Jose ...
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- MEDICAL AND HEALTH SCIENCES
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Cancer Research ...
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Uppsala University