Previous publications of the FLAGS and the DIGEST trials have shown that S-1/Cisplatin (CS) had a similar overall survival (OS) compared to 5-fluorouracil/cisplatin (CF) in patients with advanced gastric cancer (AGC) (Ajani JA et al, Eur J Cancer 2013. Ajani JA et al, Ann Oncol 2017). Although a co-enrichable population (Eastern Cooperative Oncology Group performance status (ECOG PS) 1) that respond favorably to CS compared to CF was identified with predictive enrichment strategy analysis by the FLAGS and the DIGEST trials respectively (Takeuchi et al, ESMO 2017), a more enrichable population may exist. Here we report the result of a meta-enrichment analysis assessing whether such a population exists.
To overcome differences in baseline characteristics of the FLAGS and the DIGEST a meta-enrichment analysis was performed after combining the data from the two trials. Since the treatment effect is consistent in the FLAGS and the DIGEST trial, meta-enrichment analysis allows for the combination of the two datasets and identify a robust subgroup of high response patients. Eleven clinicopathological factors were selected and a high response enrichable population was determined. It must be noted that although peritoneal metastases was included in the previous analysis as a clinicopathological factor, it was removed from this analysis due to inconsistent date readings between the individual and the central review committee.
The efficacy of the combined data set of 1365 patients (n = 1019 from FLAGS and n = 346 from DIGEST) were analyzed. A total of 683 patients (n = 374 from CS, n = 309 from CF) were identified as the high response enrichable population. High response patients were classified as patients with ECOG PS1, more than two metastatic sites and low Neutrophil-Lymphocyte ratio (log(NL ratio)) In the high response enrichable population, the median OS in the CS group was 241 days compared to 210 days in the CF group (Hazard ratio 0.776 ; 95% Confidence interval 0.658 to 0.915 ; P value 0.004).
Through meta-enrichment analysis, a higher response enrichable population to CS was identified. This statistically robust analysis indicated that for selected patients with AGC, CS is more beneficial compared to CF.
Clinical trial identification
FLAGS trial: NCT00400179. First received: June 30, 2005. Last updated: April 23, 2012. Last verified: March 2012. DIGEST trial: NCT01285557. First received: January 28, 2011. Last updated: October 21, 2016. Last verified: October 2016.
Legal entity responsible for the study
Taiho Pharmaceutical Co., Ltd.
Taiho Pharmaceutical Co., Ltd.
M. Takeuchi: Honoraria: Shionogi & Co., Ltd.; Consulting or advisory role: Taiho pharmeceutical Co., Ltd., Hisamitsu Pharmaceutical Co. Inc., AstraZeneca K.K., AbbVie Inc. M. Takeuchi: Consulting: Taiho Pharmaceutical Co., Ltd.; Travel, accommodations, expenses: AnGes MG, Inc. H.W.M. van Laarhoven: Consultant: Celgene, Lilly, Nordic; Unrestricted research funding: Bayer, BMS, Celgene, Lilly, Merck Serono, MSD, Nordic, Roche. P. Pfeiffer: Research Funding: Taiho pharmeceutical Co., Ltd. J.A. Ajani: Honoraria: Bristol-Myers Squibb, Five Prime Therapeutics, Inc., Medscape, LLC., Celgene, Taiho Pharmaceutical Co., Ltd., Eli Lilly and Company, Merck KGaA; Research funding: Bristol-Myers Squibb, Merck, Taiho Pharmaceutical Co., Ltd., Delta‐Fly Pharma, Inc., Gilead Sciences Inc. All other authors have declared no conflicts of interest.