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.

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). 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). 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. 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.