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
Akihiro Ohba, Masato Ozaka, Junki Mizusawa, Takuji Okusaka, Satoshi Kobayashi, Taro Yamashita, Masafumi Ikeda, Ichiro Yasuda, Kazuya Sugimori, Naoki Sasahira, Kenji Ikezawa, Ikuya Miki, Naohiro Okano, Nobumasa Mizuno, Masayuki Furukawa, Hirofumi Shirakawa, Y. Sano, Hiroshi Katayama, Junji Furuse, Makoto Ueno, Keiya Okamura, Yoshito Komatsu, Akio Katanuma, Michiaki Unno, Hirofumi Shirakawa, Hironori Yamaguchi, Satoshi Shimizu, Masafumi Ikeda, Hiroshi Ishii, Naoya Kato, Takuji Okusaka, Fumio Nagashima, Takao Itoi, Yasushi Kojima, Hidekazu Kuramochi, Naoki Sasahira, Keiji Sano, Shinichiro Takahashi, Yu Sunakawa, Makoto Ueno, Yusuke Kumamoto, Kazuya Sugimori, Kazuhiko Shioji, Ichiro Yasuda, Taro Yamashita, Kunihiro Tsuji, Kentaro Yamazaki, Kazuo Hara, Etsuro Hatano, Hidetoshi Eguchi, Masatoshi Kudo, Kazuyoshi Ohkawa, Kunihito Gotoh, Sohei Satoi, Kazutoshi Tobimatsu, Seiko Hirono, Ikuya Miki, Masayuki Kitano, Hiroaki Nagano, Akinori Asagi, Takehiro Okabayashi, Masayuki Furukawa, Nao Fujimori, Kazuhiko Nakao, Akio Ido
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/m 2 over 2 hours, irinotecan 150 mg/m 2 over 90 minutes, l-leucovorin 200 mg/m 2 over 2 hours, each once daily on day 1, and fluorouracil 2,400 mg/m 2 over 46 hours on days 1-3, every 2 weeks), S-IROX (oxaliplatin 85 mg/m 2 over 2 hours, irinotecan 150 mg/m 2 over 90 minutes on day 1, and S-1 80 mg/m 2 /day administered orally twice daily on days 1-7, every 2 weeks), or nab-paclitaxel (125 mg/m 2 ) + gemcitabine (1,000 mg/m 2 ) 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.