In a phase III trial, investigators are examining if arfolitixorin can supplant leucovorin calcium, a widely used component of combination regimens in patients with metastatic colorectal cancer.
Howard S. Hochster, MD
Can the novel agent arfolitixorin supplant leucovorin calcium, a widely used component of combination regimens for patients with metastatic colorectal cancer (mCRC)? Investigators are seeking to answer that question in a phase III trial now underway.
The AGENT study (NCT03750786) is testing arfolitixorin in combination with 5-fluorouracil (5-FU) and oxaliplatin—or ARFOX, as the experimental regimen is called—versus modified FOLFOX-6 (folinic acid, 5-FU, and oxaliplatin) as first-line therapy for patients with unresectable mCRC. Participants in both arms also will receive bevacizumab (Avastin) (Figure).1
Leucovorin is an active metabolite of the folinic acid that modulates 5-FU, facilitating the cytotoxic agent’s inhibition of thymidylate synthase and subsequent disruption of DNA synthesis and repair, thus promoting tumor cell death.1 However, leucovorin is a pro-drug that needs to be metabolically activated to (6R)-5,10methylenetetrahydrofolic acid (MTHF) to have a therapeutic effect.2
Arfolitixorin is also a folate, and is the biologically active form of MTHF that does not require multistep metabolic activation, which suggests that it could be more effective than leucovorin in combination therapy. AGENT investigators hypothesize that arfolitixorin may also confer benefit to a larger proportion of patients, particularly those who have limited metabolizing capability as a result of low expression of folate-activating genes.1-3
“In the 1980s it was found that 5-FU’s activity can be made a little bit better by giving it with leucovorin. This study is investigating whether or not arfolitixorin can better modulate 5-FU,” Howard S. Hochster, MD, an AGENT investigator, said in an interview with OncologyLive®.
“Arfolitixorin is a more specific compound,” noted Hochster, who is associate director for clinical research and director of gastrointestinal oncology at Rutgers Cancer Institute in New Brunswick, New Jersey. “Hopefully, by using arfolitixorin, we will have more activity for 5-FU and this regimen.”
Investigators are seeking to recruit at least 440 participants at sites in the United States, Canada, Western Europe, and Japan. The primary end point of the parallel-group study is objective response rate (ORR). Secondary end points are progression-free survival (PFS) and duration of response.
Early Signs of Efficacy
Hochster said that the rationale for AGENT derives not only from arfolitixorin’s mechanism of action but also from early-phase study findings that “suggest that [the agent] has a higher response rate and is more active” than leucovorin when given with 5-FU.
Arfolitixorin demonstrated promising activity in initial results from the ongoing phase I/II ISO-CC-005 trial (NCT02244632) presented at the 2018 Gastrointestinal Cancers Symposium. The study assessed the safety and tolerability of the agent at 4 dose levels (30 mg/m2, 60 mg/m2, 120 mg/m2, and 240 mg/m2) with 5-FU alone, with 5-FU plus oxaliplatin in 2 different regimens, with 5-FU plus irinotecan, and with 5-FU plus oxaliplatin plus bevacizumab. Arfolitixorin was administered every 2 weeks for ≥4 cycles of chemotherapy.
At the time of the presentation, 54 patients with mCRC had been treated in the study, which spanned the first to fifth lines of therapy. Arfolitixorin was given every 2 weeks for ≥4 cycles of chemotherapy.
After 8 weeks of treatment, 12 patients were assessed for efficacy. Half of the evaluable patients (6) had a partial response (PR) and 6 had stable disease. All patients (5) who received arfolitixorin at ≥60 mg/m2 with 5-FU and either irinotecan or oxaliplatin had a PR. No tumor progression occurred between week 8 and week 16 for any of the patients in the first line, investigators said. Among all participants, 25 serious adverse events were reported in 16 patients, none of which were considered to be related solely to arfolitixorin.
“For patients with reduced metabolizing capability of leucovorin, arfolitixorin might lead to greater therapeutic effect as well as improved toxicity profile,” investigators said in their conference poster.3
The dose definition part of ISO-CC-005 concluded in March 2018, when investigators selected arfolitixorin at 120 mg/m2 as the continued study dose, according to Isofol Medical AB, a biotechnology company based in Gothenburg, Sweden, that is developing arfolitixorin.4
In January 2019, the company reported new findings from a group of 19 patients with mCRC who were treated in the first-line setting. Almost half (47%; 9 of 19) of these patients showed early tumor shrinkage, which was defined as a reduction of >30% in tumor size from baseline.5
Results from a preliminary response assessment of these patients, released in May 2019, indicated a best ORR of 58% (11 out of 19 patients).6 Best ORR was defined as a reduction of >30% in tumor size from baseline. Patients were treated for 8 to 32 weeks.
Broadening the Treatment Portfolio
Although there have been therapeutic advancements in the mCRC field in recent years, there is a need to further improve outcomes, Hochster said. He noted that median survival with 5-FU with leucovorin was only 1 year when the regimen was introduced.
“With the addition of multiple new drugs, median survival is out to 36 months—to 40 months—but even though patients are living much longer than they did when we just had 5-FU, we still don’t cure a lot of these patients,” Hochster said.
Any improvement to the standard approach that the use of arfolitixorin might yield will “hopefully lead to more tumor shrinkage and more opportunities for cures by surgical resection,” Hochster added.
An interim analysis of ORR and PFS will be performed after 330 patients have been treated for ≥16 weeks. If the findings are positive, the trial could be expanded to include an additional 220 patients, for a total enrollment of 660, Isofol said. The company expects to complete AGENT during 2021.7