Proton Pump Inhibitor Use and the Efficacy of Capecitabine and Fluorouracil in Metastatic Colorectal Cancer: A Post Hoc Analysis of the AXEPT Randomised Phase III Trial

Background: Concomitant use of proton pump inhibitors (PPIs) with capecitabine was suggested to be associated with poor outcomes in gastrointestinal cancers. We analysed the differential impact of PPI use on capecitabine and fluorouracil using the dataset from the AXEPT trial, a phase III randomised trial that demonstrated the non-inferiority of modified XELIRI (mXELIRI; capecitabine plus irinotecan) with FOLFIRI (leucovorin, fluorouracil, and irinotecan), both either with or without bevacizumab in patients with metastatic colorectal cancer.Methods: Out of the per-protocol set (n=620), patients with information on concomitant medications (n=482) were included in this post-hoc analysis. PPI use was defined as concomitant exposure of capecitabine and the use of any PPI for 20% or more of the study period. The treatment-by-PPI-use interaction was examined after adjusting for stratification factors.Findings: Of the 482 patients, 49 (10·1%) used PPI. Among the PPI users, the mXELIRI group tended to have poorer overall survival (adjusted hazard ratio [aHR], 1·83; 95% confidence interval [CI], 0·96–3·48; p=0·064) compared with the FOLFIRI group. In contrast, among the non-users, the overall survival of the mXELIRI group was significantly better than that of the FOLFIRI group (aHR, 0·76; 95% CI, 0·61–0·95; p=0·016). Similarly, a trend of worse progression-free survival with mXELIRI compared with FOLFIRI was observed in PPI users but not in non-users. Treatment-by-PPI-use interaction was significant for overall survival (p=0·012) and progression-free survival (p=0·042). No significant interactions were found between treatment and drug use in terms of time-to-treatment failure, overall response rate, disease control rate, and grade 3–4 toxicities.Interpretation: The significant interaction between PPI use and the type of fluoropyrimidine in terms of overall and progression-free survival suggests that fluorouracil could be a more favourable option than capecitabine for patients with metastatic colorectal cancer using PPIs.Trial Registration: This study was registered with Clinicaltrials.gov, number NCT01996306.Funding Statement: Chugai Pharmaceutical and F Hoffmann-La Roche.Declaration of Interests: Dr SY Kim reported research funding from Roche/Genentech. S Morita reported honoraria from AstraZeneca KK, Bristol-Myers Squibb, Chugai Pharmaceutical, Eisai, Lilly, Merck Sharp & Dohme, Nippon Boehringer Ingelheim Co. Ltd, Ono Pharmaceutical, Pfizer, and Taiho Pharmaceutical; research funding from Nippon Boehringer Ingelheim Co. Ltd. J Sakamoto reported honoraria from Chugai Pharmaceutical and Nihon Karaku Co. Ltd; consulting or advisory role for Olympus Medical Systems and Takeda. K Muro reported honoraria from Bayer, Chugai Pharmaceutical, Lilly, Merck Serono, Ono Pharmaceutical, Sanofi, Taiho Pharmaceutical, Takeda, and Yakult Honsha; research funding from Daiichi Sankyo, Gilead Sciences, Kyowa Hakko Kirin, Mediscience Planning, Merck Serono, MSD, Ono Pharmaceutical, Parexel International, Pfizer, Sanofi, Shionogi, Solasia Pharmaceutical, and Sumitomo Dainippon. Dr R Xu reported honoraria from Merck KGaA and Roche. Dr TW Kim reported research funding from Astrazeneca, Merck Serono, and Sanofi. Drs JS Lee, J Kang, and Y Park reported no conflicts of interest to disclose.Ethics Approval Statement: The AXEPT trial was conducted in accordance with the tenets of the Declaration of Helsinki and Good Clinical Practice. The study protocol was approved by the institutional review boards or independent ethics committees of all participating institutions, and written informed consent was obtained from all participants.