Efficacy of liposomal irinotecan + 5-FU/LV vs. S-1 in gemcitabine-refractory metastatic pancreatic cancer: a real-world study using inverse probability of treatment weighting.

Background: S-1 monotherapy had previously been widely used as a second-line treatment for pancreatic cancer (PC) after gemcitabine-based chemotherapy mainly in Japan. Based on the results of the NAPOLI-1 trial, the recommended second-line therapy is now liposomal irinotecan plus fluorouracil/folinic acid (nal-IRI + 5-FU/LV). However, there have been no studies comparing nal-IRI + 5-FU/LV therapy with S-1 monotherapy.
Methods: The main objective of this study was to compare overall survival (OS) in patients treated with nal-IRI + 5-FU/LV and those treated with S-1 monotherapy as second-line treatments, using the inverse probability of treatment weighting (IPTW) method. This study was conducted in 31 institutions participating in Japan Oncology Network in Hepatobiliary and Pancreas. To minimize potential biases due to the retrospective design, IPTW analysis was performed with multiple imputation, and imputed IPTW-adjusted hazard ratios and corresponding 95% confidence intervals (CIs) were estimated using a Cox proportional hazards model and combined into pooled estimates.
Results: A total of 463 metastatic PC patients were enrolled in this study (257 in the S-1 monotherapy group and 206 in the nal-IRI + 5-FU/LV group). The median OS was 7.50 months (95% CI 4.18-12.69 months) in the nal-IRI + 5-FU/LV group and 5.72 months (95% CI 2.76-10.79 months) in the S-1 monotherapy group. In the IPTW-adjusted Cox proportional hazards model, nal-IRI + 5-FU/LV was associated with a significant OS benefit (pooled IPTW-adjusted hazard ratio, 0.779; 95% CI 0.399-0.941; p = 0.025).
Conclusion: These findings support the use of nal-IRI + 5-FU/LV as standard second-line treatment for PC patients after gemcitabine-based chemotherapy.
Competing Interests: Declarations. Conflict of interest: Hiroshi Imaoka has received research funding from Ono Pharmaceutical, Servier, Novartis, and Boehringer Ingelheim; and honoraria from Servier and Novartis. Masafumi Ikeda has received research funding from AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Chugai, Chiome Bioscience, Delta-Fly Pharma, Eisai, Eli Lilly Japan, Invitae, MSD, J-Pharma, Merck biopharma, Merus N.V., Novartis, Servier, Ono Pharmaceutical, Pfizer, and Syneos Health; and honoraria from AbbVie, AstraZeneca, Chugai Pharmaceutical, Eisai, Eli Lilly Japan, Fujifilm Toyama Chemical, Guardant Health Japan, Incyte Biosciences Japan, MSD, Servier, Novartis, Nippon Kayaku, Ono Pharmaceutical, Taisho Pharmaceutical, Teijin, Takeda, Taiho Pharmaceutical, and Yakult Honsha; and is a member of advisory board for AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, MSD, and Servier. Satoshi Kobayashi has received honoraria from AstraZeneca, Eli Lilly, Boston Scientific, Taiho, Daiichi Sankyo, and Yakult Honsha. Yasuyuki Kawamoto has received research funding from Takeda. Noritoshi Kobayashi has received research funding from Novartis; and honoraria from Novartis, Teijin Pharma, Teijin Healthcare, EA Pharma, Ono Pharmaceutical, Taiho Pharmaceutical, Yakult Honsha, MSD, and PD Radiopharma (successor to the radiopharmaceutical business of Fujifilm Toyama Chemical). Naohiro Okano has received honoraria from AstraZeneca. Kumiko Umemoto has received honoraria from Chugai Pharmaceutical, Taiho Pharmaceutical, Novartis and Yakult Honsha. Ayumu Hosokawa has received honoraria from Ono Pharmaceutical and Daiichi Sankyo. Hiroyuki Okuyama has received honoraria from Novartis and AstraZeneca. Satoshi Shimizu has received research funding from AstraZeneca, Incyte, Delta-Fly Pharma, and Servier. Chigusa Morizane has received research funding from Eisai, Yakult Honsha, Ono Pharmaceutical, Taiho Pharmaceutical, J-Pharma, AstraZeneca, Merck, Daiichi Sankyo, Boehringer Ingelheim, Eisai, Daiichi Sankyo RD Novare, Labcorp, Hitachi, and MSD; and honoraria from Novartis, Yakult Honsha, Servier, Taiho Pharmaceutical, Eisai, MSD, AstraZeneca, TORAY, Guardant, and Myriad Genetics; and is a member of advisory board for Yakult Honsha, MSD, Servier, Boehringer Ingelheim, Taiho, Novartis, AstraZeneca, MSD, Servier, and Merck. Makoto Ueno has received research funding from Astellas Pharma, AstraZeneca, Chiome Bioscience, Chugai Pharmaceutical, DFP, Eisai, Incyte, J-pharma, MSD, Novartis, Novocure, Ono Pharmaceutical, Taiho Pharmaceutical, Boehringer Ingelheim, and Servier; and honoraria from AstraZeneca, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Incyte, J-pharma, MSD, Servier, Ono Pharmaceutical, Taiho Pharmaceutical, Takeda Pharmaceutical, Boehringer Ingelheim, and Yakult Honsha. The other authors have no conflict of interest.
(© 2025. The Author(s).)