Efficacy and Safety of Trifluridine/Tipiracil Treatment in Patients With Metastatic Gastric Cancer Who Had Undergone Gastrectomy: Subgroup Analyses of a Randomized Clinical Trial

Abstract

Importance: Trifluridine/tipiracil (FTD/TPI) treatment has shown clinical benefit in patients with pretreated metastatic gastric cancer or gastroesophageal junction cancer (mGC/GEJC). Patients who have undergone gastrectomy constitute a significant proportion of patients with mGC/GEJC.

Objective: To assess the efficacy and safety of FTD/TPI among patients with previously treated mGC/GEJC who had or had not undergone gastrectomy.

Design, setting, and participants: This preplanned subgroup analysis of TAGS (TAS-102 Gastric Study), a phase 3, randomized, placebo-controlled, clinical trial included patients with mGC/GEJC who had received at least 2 previous chemotherapy regimens, and was conducted at 110 academic hospitals in 17 countries in Europe, Asia, and North America, with enrollment between February 24, 2016, and January 5, 2018; the data cutoff was March 31, 2018.

Interventions: Patients were randomized 2:1 to receive oral FTD/TPI 35 mg/m2 twice daily or placebo twice daily with best supportive care on days 1 through 5 and days 8 through 12 of each 28-day treatment cycle.

Main outcomes and measures: The primary end point was overall survival. This subgroup analysis was conducted to examine potential trends and was not powered for statistical significance. Efficacy and safety end points were evaluated in the subgroups.

Results: Of 507 randomized patients (369 [72.8%] male; mean [SD] age, 62.5 [10.5] years), 221 (43.6%) had undergone gastrectomy (147 randomized to FTD/TPI and 74 to placebo) and 286 (56.4%) had not undergone gastrectomy (190 randomized to FTD/TPI and 96 to placebo). In the gastrectomy subgroup, the overall survival hazard ratio (HR) in the FTD/TPI group vs placebo group was 0.57 (95% CI, 0.41-0.79), and the progression-free survival HR was 0.48 (95% CI, 0.35-0.65). In the no gastrectomy subgroup, the overall survival HR in the FTD/TPI group vs placebo group was 0.80 (95% CI, 0.60-1.06), and the progression-free survival HR was 0.65 (95% CI, 0.49-0.85). Among FTD/TPI-treated patients, grade 3 or higher adverse events of any cause occurred in 122 of 145 patients (84.1%) in the gastrectomy subgroup and 145 of 190 (76.3%) in the no gastrectomy subgroup: 64 (44.1%) in the gastrectomy subgroup and 50 (26.3%) in the no gastrectomy subgroup had grade 3 or higher neutropenia, 31 (21.4%) in the gastrectomy subgroup and 33 (17.4%) in the no gastrectomy subgroup had grade 3 or higher anemia, and 21 (14.5%) in the gastrectomy subgroup and 10 (5.3%) in the no gastrectomy subgroup hD grade 3 or higher leukopenia. In the gastrectomy subgroup, 94 (64.8%) had dosing modifications because of adverse events vs 101 (53.2%) in the no gastrectomy subgroup; 15 (10.3%) in the gastrectomy group and 28 (14.7%) in the no gastrectomy group discontinued treatment because of adverse events. Treatment exposure was similar between groups.

Conclusions and relevance: The FTD/TPI treatment was tolerable and provided efficacy benefits among patients with pretreated mGC/GEJC regardless of previous gastrectomy.

Trial registration: ClinicalTrials.gov identifier: NCT02500043.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Ilson reported receiving grants and advisory role support from Amgen Inc, Astellas, AstraZeneca, Bayer AG, Bristol-Myers Squibb, Eli Lilly & Company, Merck & Company Inc, Pieris Pharmaceuticals, F Hoffman-LaRoche Limited, and Taiho Oncology outside the submitted work. Dr Tabernero reported receiving advisory role support from Array Biopharma, AstraZeneca, Bayer AG, Biocartis, Boehringer Ingelheim, Chugai Pharma, Foundation Medicine, Genentech Inc, Genmab A/S, F Hoffman-LaRoche Limited, HalioDX SAS, Halozyme, Imugene Limited, Inflection Biosciences, Ipsen Pharma, Eli Lilly & Company, Merck Sharp and Dohme Corporation, Menarini Group, Merck Serono, Merrimack, Merus, Molecular Partners, Novartis, Peptomyc, Pfizer, Pharmacyclics, ProteoDesign SL, Rafael Pharmaceuticals, Roche Diagnostics, Sanofi, Seattle Genetics, Servier, Symphogen, Taiho Pharmaceutical, and VCN Biosciences outside the submitted work. Dr Van Cutsem reported receiving grants and personal fees from Servier during the conduct of the study; receiving grants from Amgen Inc, Bayer AG, Boehringer Ingelheim, Bristol-Myers Squibb Company, Celgene, Ipsen, Eli Lilly & Company, Merck Sharp and Dohme Corporation, Merck KGaA, Novartis AG, and Roche; and receiving personal fees from Astellas, AstraZeneca, Bayer AG, Bristol-Myers Squibb, Celgene, Eli Lilly & Company, Merck Sharp and Dohme Corporation, Merck KGaA, Novartis, and Roche outside the submitted work. Dr Thuss-Patience reported receiving nonfinancial support from Roche; receiving personal fees and nonfinancial support from Bristol-Myers Squibb Company; and receiving personal fees from Eli Lilly & Company, Merck Darmstadt, Merck Sharp and Dohme Corporation, Nordic, and Pfizer outside the submitted work. Dr Beretta reported receiving grants from Taiho Pharmaceutical during the conduct of the study. Dr Alsina reported receiving personal fees and consultancy support from Servier and Bristol-Myers Squibb; personal fees from Amgen, Eli Lilly & Company, Merck Sharp & Dohme Corporation, and Roche/Genentech; travel, accommodations, and expenses from Amgen Inc, Eli Lilly & Company, and Roche/Genentech; and participating in the speakers’ bureau for Amgen Inc, Bristol-Myers Squibb Company, Eli Lilly & Company, Merck Sharp and Dohme Corporation, Roche/Genentech, and Servier. Dr George reported having a consulting or advisory role at Bayer, Bristol-Myers Squibb Company, Celgene, Cook Medical, Exelixis, Foundation Medicine, Merrimack, Ipsen, Taiho Pharmaceutical, and Terumo; receiving honoraria from Newlink Genetics; and receiving research funding from Boehringer Ingelheim, CeGaT GmbH, Celgene, Eisai, Foundation Medicine, Roche/Genentech, Roche, and Taiho Pharmaceutical. Dr Catenacci reported having a consulting or advisory role at Amgen Inc, Astellas, Bristol-Myers Squibb Company, Roche/Genentech, Eli Lilly & Company, Merck & Company Inc, and Taiho Pharmaceutical; participating in the speakers’ bureau for Foundation Medicine and Guardant Health; and receiving honoraria from Amgen Inc, Bristol-Myers Squibb Company, Foundation Medicine, Genmab A/S, Roche/Genentech, Gritstone Oncology, Guardant Health, Five Prime Therapeutics, Eli Lilly & Company, Merck & Company Inc, NantWorks, OncoPlex Diagnostics, and Taiho Pharmaceutical. Dr McGuigan reported being employed at Taiho Oncology. Dr Makris reported being a paid statistical consultant at Taiho Oncology. Dr Doi reported having a consulting or advisory role at Amgen Inc, Chugai Pharma, Daiichi Sankyo, Kyowa Hakko Kirin, Eli Lilly & Company Japan, Merck Sharp and Dohme Corporation, Sumitomo Dainippon Pharma, and Taiho Pharmaceutical and receiving research funding from Abbvie, Astellas, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Chugai Pharma, Daiichi Sankyo, Janssen, Kyowa Hakko Kirin, Eli Lilly & Company Japan, Merck Serono, Merck Sharp and Dohme Corporation, Novartis, Pfizer, Quintiles, Sumitomo Group, Taiho Pharmaceutical, and Takeda. Dr Shitara reported having a consulting or advisory role at Astellas, Bristol-Myers Squibb, Eli Lilly & Company, Ono Pharmaceutical, Pfizer, and Takeda; receiving honoraria from Abbvie, Novartis, and Yakult Pharmaceutical; and reported receiving research funding from Chugai Pharma, Daiichi Sankyo, Eli Lilly & Company, Merck Sharp and Dohme Corporation, Ono Pharmaceutical, Sumitomo Dainippon Pharma, and Taiho Pharmaceutical. No other conflicts are reported.

Figures

Figure 1.. Patient Enrollment Flowchart

Figure 2.. Subgroup Analysis of Overall Survival Among Patients Who Had or Had Not Undergone Gastrectomy

Prespecified multivariate subgroup analysis of overall survival in the TAGS (TAS-102 Gastric Study) trial based on previous gastrectomy. This figure is adapted with permission of Elsevier Science and Technology Journals, from Shitara K et al. Trifluridine/tipiracil vs placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2018;19:1437-1448; permission conveyed through Copyright Clearance Center, Inc.

Figure 3.. Overall Survival and Progression-Free Survival Among Patients Who Had or Had Not Undergone Gastrectomy

HR indicates hazard ratio.