1616O - Nab-paclitaxel plus gemcitabine versus modified FOLFIRINOX or S-IROX in metastatic or recurrent pancreatic cancer (JCOG1611, GENERATE): A multicentred, randomized, open-label, three-arm, phase II/III trial

Background

Both nab-paclitaxel plus gemcitabine and modified FOLFIRINOX are equivalently recommended as first-line treatment for metastatic pancreatic cancer in patients with good performance status. S-IROX (S-1, irinotecan, and oxaliplatin) showed activity in a phase Ib study in this population. We therefore aimed to compare the efficacy and safety of these three regimens directly.

Methods

This multicentred, randomized, open-label, phase II/III trial was done in 45 centres in Japan. Eligible patients were aged 20–75 years and an Eastern Cooperative Oncology Group performance status of 0 or 1 with pathologically confirmed metastatic or recurrent pancreatic cancer. Patients were randomly assigned (1:1:1) to receive nab-paclitaxel (125 mg/m²) plus gemcitabine (1,000 mg/m²) on days 1, 8, 15, every 4 weeks, modified FOLFIRINOX (oxaliplatin 85 mg/m², irinotecan 150 mg/m², l-leucovorin 200 mg/m², and fluorouracil 2,400 mg/m² on days 1–3, every 2 weeks), or S-IROX (oxaliplatin 85 mg/m², irinotecan 150 mg/m², and S-1 80 mg/m²/day on days 1–7, every 2 weeks). The primary endpoint of the phase III portion was overall survival.

Results

Between Apr 2019, and Mar 2023, 527 patients were enrolled, and 426 patients were analyzed at the planned interim analysis in Mar 2023. The median overall survival was 17.1 months in the nab-paclitaxel plus gemcitabine arm, 14.0 months in the modified FOLFIRINOX arm (HR 1.31, 95% CI 0.97–1.77), and 13.6 months in the S-IROX arm (HR 1.35, 95% CI 1.00–1.82). The predictive probability for achieving superiority at the final analysis was 0.73% for the modified FOLFIRINOX arm and 0.48% for the S-IROX arm. Therefore, the study was terminated for futility. The most common grade 3–4 non-hematological toxicity of anorexia was more frequent in the modified FOLFIRINOX (23.3%) and S-IROX (27.5%) arm than the nab-paclitaxel plus gemcitabine arm (5.0%).

Conclusions

Nab-paclitaxel plus gemcitabine is recommended as the first-line treatment for patients with metastatic or recurrent pancreatic cancer compared to modified FOLFIRINOX or S-IROX.

Clinical trial identification

jRCTs031190009.

Editorial acknowledgement

Legal entity responsible for the study

Japan Clinical Oncology Group (JCOG), Hepatobiliary and Pancreatic Oncology Group (HBPOG).

Funding

Japan Agency for Medical Research and Development; National Cancer Center Research and Development.

Disclosure

A. Ohba: Financial Interests, Personal, Invited Speaker: Yakult, Ono, Servier, Taiho, Eisai; Financial Interests, Personal, Advisory Board: Zymeworks; Financial Interests, Institutional, Local PI: Ono, Chugai, Novartis. M. Ozaka: Financial Interests, Personal, Invited Speaker: Taiho, Yaklut, MSD, Incyte, Ono, Bayer, Servier. T. Okusaka: Financial Interests, Personal, Advisory Board: AstraZeneca, Chugai Pharma, Daiichi Sankyo, Eisai, Fujifilm Toyama Chemical, Incyte, Nihon Servier, Ono Pharmaceutical; Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai Pharma, Eisai, Eli Lilly, Incyte, Johnson & Johnson, Nihon Servier, Ono Pharmaceutical, Yakut Honsha; Financial Interests, Institutional, Local PI: AstraZeneca, Bristol Myers Squibb, Chugai Pharma, Dainippon Sumitomo Pharma, Eisai, Incyte, MSD, Novartis; Financial Interests, Personal, Steering Committee Member: AstraZeneca, Bristol Myers Squibb. S. Kobayashi: Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical, Bayer Yakuhin, Eisai Pharmaceutical, Yakult Honsha, Servier Japan, GSK, Chugai Pharmaceutical, Eli Lilly Japan, Takeda Pharmaceutical, Otsuka Pharmaceutical, AstraZeneca; Financial Interests, Personal, Advisory Board: Zymeworks. M. Ikeda: Financial Interests, Personal, Advisory Board: AstraZeneca, Chugai, Eli Lilly Japan, Eisai, Nihon Servier, Novartis, MSD; Financial Interests, Personal, Invited Speaker: AstraZeneca, Bayer, Bristol Myers Squibb, Chugai, Eli Lilly Japan, Eisai, Nihon Servier, Novartis, Taiho, Yakult, Teijin Pharma, AbbVie, Abbott Japan, Fujifilm Toyama Chemical, Incyte Biosciences Japan, Takeda, Ono, MSD, Taisho Pharmaceutical, Nippon Kayaku, Guardant Health Japan; Financial Interests, Institutional, Coordinating PI: Bayer, Bristol Myers Squibb, Eisai, AstraZeneca, Eli Lilly Japan, Chugai Pharmaceutical, MSD, Ono, Novartis, J-Pharma, Pfizer, Chiome Bioscience, Nihon Servier, Delta-Fly Pharma, Syneos Health, Merus .N.V., Merck, Boehringer Ingelheim, Invitae; Financial Interests, Personal, Steering Committee Member: Chugai, Nihon Servier, Takeda, Novartis. K. Sugimori: Financial Interests, Personal, Advisory Role: J-MIT; Financial Interests, Institutional, Research Grant: Taiho Pharmaceutical CO., LTD., Otsuka Pharmaceutical CO., LTD. N. Sasahira: Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical, Eisai, Chugai Pharmaceutical, Takeda Pharmaceutical, AstraZeneca; Financial Interests, Institutional, Funding: Taiho Pharmaceutical, Chugai Pharmaceutical, Daiichi Sankyo, Shionogi, Teijin Pharma. K. Ikezawa: Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical, Yakult Honsha, Ono Pharmaceutical, MSD, Myriad Genetics, Asahi Kasei Pharma, Incyte Biosciences Japan; Financial Interests, Institutional, Research Grant: ASKA Pharmaceutical. N. Okano: Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical, Eli Lilly Japan, Eisai, Bayer Yakuhin, Chugai Pharma, Ono Pharmaceutical, Takeda, Daiichi Sankyo, AstraZeneca. N. Mizuno: Financial Interests, Personal, Invited Speaker: Yakult Honsha, AstraZeneca, Novartis, Fujifilm Toyama Chemical, Taiho Pharmaceutical; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Institutional, Local PI: MSD, Incyte, Ono Pharmaceutical, Seagen; Financial Interests, Institutional, Coordinating PI: Novartis. M. Furukawa: Financial Interests, Institutional, Local PI: Nobelpharma, Incyte Corporation, Astellas, Merck, MSD, Eisai, Ono, J-Pharma, Yakult, Servier, Taiho, Chugai, Daiichi Sankyo, Otsuka; Financial Interests, Personal, Invited Speaker: Yakult, Ono, Servier, Daiichi Sankyo, Taiho, Chugai, AstraZeneca. J. Furuse: Financial Interests, Personal, Invited Speaker: Ono, Bayer, Eisai, Eli Lilly Japan, MSD, Yakult Honsha, Chugai Pharma, Novartis Pharma, AstraZeneca, Pfizer, Takeda, Taiho Pharmaceutical, Sanofi, Mylan EPD, EA Pharma, Kyowa Hakko Kirin, Daiichi Sankyo, Teijin pharma, Servier Japan, Incy; Financial Interests, Personal, Advisory Board: Fuji film, Mundipharma, Onco Therapy Science, Merck Bio, Ono Pharmaceutical, MSD, Taiho Pharmaceutical, Chugai Pharma, Astellas, AstraZeneca, Takara bio, Delta-Fly-Pharma, Incyte Japan; Financial Interests, Institutional, Research Grant: Ono Pharmaceutical, MSD, Merck Bio, J-Pharma, Taiho Pharmaceutical, Takeda, Chugai Pharma, AstraZeneca, Yakult Honsha, Eisai, Daiichi Sankyo, Mochida, Sanofi, Sumitomo Dainippon Bayer, Astellas, Incyte Japan; Financial Interests, Personal, Steering Committee Member: Merck Bio, Ono, MSD, Taiho Pharmaceutical, Astellas, AstraZeneca, Incyte Japan. M. Ueno: Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai, Incyte, MSD, Nihon Servier, Ono Pharmaceutical, Taiho Pharmaceutical, Daiichi Sankyo, Takeda Pharmaceutical; Financial Interests, Personal, Advisory Board: Nippon Boehringer Ingelheim; Financial Interests, Institutional, Local PI: Chugai, Astellas Pharma, AstraZeneca, DFP, Daiichi Sankyo, Eisai, Incyte, MSD, Merck Biopharma, Ono, Novartis, Taiho Pharmaceutical. All other authors have declared no conflicts of interest.