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

Abstract

Purpose: 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.

Methods: 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/m² over 2 hours, irinotecan 150 mg/m² over 90 minutes, l-leucovorin 200 mg/m² over 2 hours, each once daily on day 1, and fluorouracil 2,400 mg/m² over 46 hours on days 1-3, every 2 weeks), S-IROX (oxaliplatin 85 mg/m² over 2 hours, irinotecan 150 mg/m² over 90 minutes on day 1, and S-1 80 mg/m²/day administered orally twice daily on days 1-7, every 2 weeks), or nab-paclitaxel (125 mg/m²) + gemcitabine (1,000 mg/m²) on days 1, 8, and 15 every 4 weeks. The primary end point was overall survival (OS).

Results: 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%).

Conclusion: 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.

FIG 1.

Trial profile. mFOLFIRINOX, modified fluorouracil, leucovorin, irinotecan, and oxaliplatin; NSCLC, non–small cell lung cancer; S-IROX, S-1, irinotecan, and oxaliplatin. UGT1A1, uridine diphosphate glucuronosyltransferase 1A1.

FIG 2.

Kaplan-Meier estimates of (A) OS at the planned interim analysis, (B) updated OS, and (C) PFS. Tick marks indicate censored data. HRs are based on a stratified Cox regression model. HR, hazard ratio; mFOLFIRINOX, modified fluorouracil, leucovorin, irinotecan, and oxaliplatin; OS, overall survival; PFS, progression-free survival; S-IROX, S-1, irinotecan, and oxaliplatin.

FIG 3.

Forest plot of overall survival in selected subgroups. The overall hazard ratio is based on a stratified analysis, and subgroup hazard ratios are based on unstratified analyses. CA19-9, carbohydrate antigen 19-9; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; mFOLFIRINOX, modified fluorouracil, leucovorin, irinotecan, and oxaliplatin; S-IROX, S-1, irinotecan, and oxaliplatin.