First-Line mFOLFIRINOX, S-IROX Fail to Improve Survival Among Patients With Recurrent or Metastatic Pancreatic Cancer

Results from the phase 2/3 GENERATE study demonstrated that neither mFOLFIRINOX nor S-IROX improved survival results compared to nab-paclitaxel plus gemcitabine among patients with recurrent or metastatic pancreatic cancer in the first-line setting. 

“Both [mFOLFIRINOX] and nab-paclitaxel [plus] gemcitabine are recommended first-line treatments for metastatic pancreatic cancer; however, no direct comparison has been conducted,” stated Akihiro Ohba, MD, Shizuoka Cancer Center, Shizuoka, Japan, and coauthors. Here, researchers “directly compared these two treatments, along with [S-IROX].”

In this multicenter, open-label study, 426 patients were randomized on a 1-to-1-to-1 basis to receive either 85 mg/m² of oxaliplatin plus 150 mg/m² of irinotecan and 200 mg/m² of I-leucovorin once daily on day 1 of each cycle with 2400 mg/m² of fluorouracil on days 1 through 3 of each cycle once every 2 weeks (mFOLFIRINOX; n = 171), 85 mg/m² of oxaliplatin plus 150 mg/m² of irinotecan and 80 mg/m²/day of S-1 twice daily on days 1 through 7 of each cycle once every 2 weeks (S-IROX; n = 174), or nab-paclitaxel plus gemcitabine (n = 174) until disease progression or unacceptable toxicity. The primary end point was overall survival (OS). 

At analysis, median OS was 14 months in the mFOLFIRINOX arm, 13.6 months in the S-IROX arm, and 17.1 months in the nab-paclitaxel plus gemcitabine arm. The predictive probability of achieving superiority was < 1% in both treatment arms and the study was terminated. Grade 3/4 neutropenia was more frequently reported in the mFOLFIRINOX (23.3%) and S-IROX (27.5%) arms compared to the nab-paclitaxel plus gemcitabine arm (5%). One treatment-related death occurred in the S-IROX arm. 

As Dr Ohba et al concluded, “mFOLFIRINOX or S-IROX did not appear to show superiority compared with nab-paclitaxel [plus] gemcitabine as the first-line treatment for metastatic or recurrent pancreatic cancer.” 

“This study provides continued support for doublet regimens (gemcitabine/nab-paclitaxel) for untreated metastatic pancreatic cancer with a good performance status,” added Journal of Clinical Oncology associate editor Eileen O’Reilly, MD, Memorial Sloan Kettering Cancer Center, New York, New York. “However, the field clearly needs to move beyond chemotherapy alone and biomarker-based selection is urgently needed in this disease.” 

Source: 

Ohba A, Ozaka M, Mizusawa J, et al. Modified fluorouracil, leucovorin, irinotecan, and oxaliplatin or S-1, irinotecan, and oxaliplatin Versus nab-paclitaxel + gemcitabine in metastatic or recurrent pancreatic cancer (GENERATE, JCOG1611): A randomized, open-label, phase II/III trial. J Clin Oncol. Published online: July 28, 2025. doi: 10.1200/JCO.24.00936