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

<jats:sec> <jats:title>PURPOSE</jats:title> <jats:p>Modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) and nab-paclitaxel + gemcitabine are recommended as first-line treatments for metastatic pancreatic cancer. S-1, irinotecan, and oxaliplatin (S-IROX) demonstrated activity in a phase Ib trial in this population. Therefore, these three regimens were directly compared.</jats:p> </jats:sec> <jats:sec> <jats:title>METHODS</jats:title> <jats:p> This randomized phase II/III trial was performed at 45 centers in Japan. Eligible patients age 20-75 years with an Eastern Cooperative Oncology Group performance status of 0 or 1 and pathologically confirmed metastatic or recurrent pancreatic cancer were randomly assigned (1:1:1) to receive mFOLFIRINOX (oxaliplatin 85 mg/m <jats:sup>2</jats:sup> over 2 hours, irinotecan 150 mg/m <jats:sup>2</jats:sup> over 90 minutes, l-leucovorin 200 mg/m <jats:sup>2</jats:sup> over 2 hours, each once daily on day 1, and fluorouracil 2,400 mg/m <jats:sup>2</jats:sup> over 46 hours on days 1-3, every 2 weeks), S-IROX (oxaliplatin 85 mg/m <jats:sup>2</jats:sup> over 2 hours, irinotecan 150 mg/m <jats:sup>2</jats:sup> over 90 minutes on day 1, and S-1 80 mg/m <jats:sup>2</jats:sup> /day administered orally twice daily on days 1-7, every 2 weeks), or nab-paclitaxel (125 mg/m <jats:sup>2</jats:sup> ) + gemcitabine (1,000 mg/m <jats:sup>2</jats:sup> ) on days 1, 8, and 15 every 4 weeks. The primary end point was overall survival (OS). </jats:p> </jats:sec> <jats:sec> <jats:title>RESULTS</jats:title> <jats:p>A total of 527 patients were enrolled, with 426 included in the planned interim analysis. The median OS was 14.0 months (hazard ratio [HR], 1.31 [95% CI, 0.97 to 1.77]) and 13.6 months (HR, 1.35 [95% CI, 1.00 to 1.82]) in the mFOLFIRINOX and S-IROX groups, respectively, as compared with 17.1 months in the nab-paclitaxel + gemcitabine group. The predictive probability of achieving superiority in the final analysis was <1% in both groups. Thus, the trial was terminated owing to its futility. Grade 3 to 4 anorexia was more frequent in the mFOLFIRINOX (23.3%) and S-IROX (27.5%) groups than in the nab-paclitaxel + gemcitabine group (5.0%).</jats:p> </jats:sec> <jats:sec> <jats:title>CONCLUSION</jats:title> <jats:p>Neither mFOLFIRINOX nor S-IROX appeared to be superior compared with nab-paclitaxel + gemcitabine as the first-line treatment for metastatic or recurrent pancreatic cancer.</jats:p> </jats:sec>