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
- Author(s)
- Tabernero, J; Yoshino, T; Stintzing, S; de Gramont, A; Gibbs, P; Jonker, D; Nygren, P; Papadimitriou, CA; Prager, GW; Tell, R; Lenz, HJ;
- Journal Title
- Cancer Research Communications
- Publication Type
- epub ahead of print
- Abstract
- PURPOSE: Suboptimal treatment outcomes with 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 IV bolus doses of 60 mg/m2) or leucovorin (400 mg/m2 given as a single IV 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 versus 49.4% for leucovorin, P for superiority = 0.57). Outcomes were not achieved for median PFS (12.8 and 11.6 months, P = 0.38), median DoR (12.2 and 12.9 months, P = 0.40) and median OS (23.8 and 28.0 months, P = 0.78). The proportion of patients with an AE 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.
- Publisher
- AACR
- Research Division(s)
- Personalised Oncology
- PubMed ID
- 38059497
- Publisher's Version
- https://doi.org/10.1158/2767-9764.Crc-23-0361
- Open Access at Publisher's Site
https://doi.org/10.1158/2767-9764.CRC-23-0361- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2023-12-13 10:26:53
Last Modified: 2023-12-13 10:39:29