The FLAGS trial, a randomized phase III trial, compared S-1, an oral fluoropyrimidine, plus cisplatin (SP) with 5-fluorouracil plus cisplatin (FP) in the first-line treatment for advanced gastric cancer (AGC). The results led to the approval of SP by EMA, and it is now marketed in Europe. The purpose of this analysis was to establish a clinical covariate(s) model using the Predictive Enrichment Strategy Analysis (PESA) identifying patients who benefit from SP.
PESA is a new robust methodology with guidelines by the United States Food and Drug Administration. Consensus-based 15 clinical covariates were selected for PESA and a large cohort with no missing data (FLAGS trial: 889 patients (pts)) was analyzed. The models generated were cross-validated and the results analyzed were validated in the DIGEST trial, a phase III trial comparing SP to FP in diffuse type advanced gastric cancer. From the DIGEST trial, 333 patients and 14 clinical covariates were used in the analysis.
In FLAGS, ECOG Performance status (PS = 1) was the strongest covariate in the enrichment group showing benefit for SP. In the population with PS = 1, the OS in the SP group was significantly longer than the FP group (Hazard Ratio [HR]=0.798, 95%CI = (0.66-0.96) p = 0.0166). Other covariates with high potential to be associated with SP benefit included: diffuse-type histology, positive peritoneal metastases, and the lack of liver metastases. In DIGEST PS = 1 also showed to be most associated with SP benefit. While there was no strong signal from the variables positive peritoneal metastases, and the lack of liver metastases, there appeared to be a signal from the neutrophil variable. In the DIGEST population of diffuse type, patients with PS = 1 and low baseline neutrophil count may benefit from SP.
Presence of PS = 1 was associated with SP benefit in both the FLAGS and DIGEST trial. Although peritoneal and liver metastases resulted in slightly different signals in the trials, further analyses will be done to look at the impact of low baseline neutrophil count on the benefit of SP for PS = 1 and diffuse type histology patients.
Clinical trial identification
FLAGS trial; ClinicalTrials.gov NCT00400179 First received: June 30, 2005 Last updated: March 28, 2012 Last verified: March 2012 DIGEST trial; ClinicalTrials.gov NCT01285557 First received: January 26, 2011 Last updated: October 19, 2016 Last verified: October 2016.
Legal entity responsible for the study
Taiho Pharmaceutical Co,. Ltd.
Taiho Pharmaceutical Co,. Ltd.
M. Takeuchi: Consulting Taiho Pharmaceutical Co., Ltd. Travel, Accommodations, expenses AnGes MG, Inc. M. Takeuchi: Honoraria: Shionogi & Co., Ltd. Consulting or advisory role: Taiho pharmeceutical Co., Ltd.; Hisamitsu Pharmaceutical Co., Inc.; AstraZeneca K.K.; AbbVie Inc. J.A. Ajani: Honoraria: Bristol-Myers Squibb; Five Prime Therapeutics, Inc.; Medscape, LLC.; Celegene, Taiho pharmaceutical Co., Ltd. Research funding Bristol-Myers Squibb; Merck; Taiho pharmaceutical Co., Ltd.; Delta-Fly Pharma, Inc; Gilead Sciences Inc.