Prospective randomized phase III trial comparing FOLFIRINOX and mFOLFOX6 as first-line treatment for patients with disseminated gastric cancer: interim assessment of tolerability and toxicity

Background. The standard approach to the treatment of patients with disseminated gastric and cardioesophageal junction cancer (dGC/CEJC) is the use of two-component chemotherapy regimens (CT). The prognosis of patients with dGC/ CEJC remains extremely unfavorable. In studies of the most popular first-line regimen (mFOLFOX6), median progression-free survival (mPFS) and median overall survival (mOS) rarely exceeded 6 and 11 months. The results of some phase II trials of triple combination FOLFIRINOX in the first line of treatment of patients with dGC/CEJC indicated its high efficacy with controlled toxicity. In November 2019, a prospective randomized phase III trial to study the effectiveness and toxicity of the FOLFIRINOX regimen compared with the mFOLFOX6 doublet in the first line of treatment of patients with dGC/CEJC (ClinicalTrials.gov identifier: NCT04442984) was initiated at the N.N. Blokhin National Medical Research Center of Oncology. The primary endpoint - mPFS. Secondary endpoints included mOR, objective response rate (ORR), tolerability and toxicity. Currently, 304 patients are included in the study.

Objective. Demonstration of the benefit of the mFOLFIRINOX regimen compared with the mFOLFOX6 regimen in terms of PFS.

Methods. The preliminary analysis included 138 patients: 58 in the FOLFIRINOX group (men -58.6%, women - 41.4%; age <65 – 70.7%, ≥65 – 29.3%, ECOG PS 0–1–3,4 and 86.2%, 2 – 10.3%) and 80 patients in the mFOLFOX6 group (men- 60.0% and women – 40.0%, age <65 – 77.5%, ≥65 – 22.5%, ECOG PS 0–1 – 8.8 and 88.8%, 2 – 2.5%).

Results. Hematologic toxicity was the most common. In the FOLFIRINOX group, grades I–II neutropenia was recorded in 29.3% of patients, grades III–IV - in 30%, and febrile neutropenia -in 8.6%. In the group of patients receiving the mFOLFOX6 regimen, grades I–II neutropenia was recorded in 20%, grade III–IV -in 23.8% of cases; febrile neutropenia was not observed. Prescription of granulocyte colony-stimulating factors during triplet treatment was required in 44.8% of patients, which is significantly more often than when using mFOLFOX6 - 13.8% (P<0.05). Among non-hematological types of toxicity, hepatotoxicity was noted in 50% of patients receiving the FOLFIRINOX regimen, and in 33.8% of patients receiving the mFOLFOX6 regimen; the difference was not statistically significant. Compared with the mFOLFOX6 group, patients receiving the FOLFIRINOX regimen had a statistically significantly higher incidence of grades I–II diarrhea (38.0 vs. 10.1%; P<0.05). No statistically significant differences were found for other adverse events (AEs). Toxicity when using the FOLFIRINOX regimen was controlled; we did not note any cases of treatment discontinuation due to AEs.

Conclusion. Comparison of the toxicity of triplet and doublet according to the interim data from a phase III trial indicated acceptable toxicity of the FOLFIRINOX regimen, the possibility of conducting a full first-line chemotherapy in patients with dGC/CEJC without life-threatening complications of treatment. The research is ongoing.