Elsevier

The Lancet Oncology

Volume 19, Issue 11, November 2018, Pages 1437-1448
The Lancet Oncology

Articles
Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial

https://doi.org/10.1016/S1470-2045(18)30739-3Get rights and content

Summary

Background

Trifluridine/tipiracil showed activity and was well tolerated in a phase 2 study of pretreated patients with advanced gastric cancer done in Japan. We investigated whether the treatment was efficacious compared with placebo in a global population.

Methods

TAGS was a randomised, double-blind, placebo-controlled, phase 3 trial done in 110 academic hospitals in 17 countries. Patients aged 18 years or older with histologically confirmed, non-resectable, metastatic gastric adenocarcinoma (including adenocarcinoma of the gastroesophageal junction) as defined by the American Joint Committee on Cancer staging classification (7th edition) who had received at least two previous chemotherapy regimens and had experienced radiological disease progression were eligible for inclusion. Patients were randomly assigned (2:1) via dynamic randomisation from a centralised interactive voice-response system to receive either oral trifluridine/tipiracil (35 mg/m2 twice daily on days 1–5 and days 8–12 every 28 days) plus best supportive care or placebo plus best supportive care. Participants were allocated to groups by study-site personnel. Randomisation was stratified by region (Japan vs rest of world), ECOG performance status (0 vs 1), and previous treatment with ramucirumab (yes vs no). Both patients and investigators were masked to treatment allocation. The primary endpoint was overall survival. Efficacy was assessed in the intention-to-treat population and safety in all patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov, number NCT02500043. The trial, including follow-up of all participants, has been completed.

Findings

Between Feb 24, 2016, and Jan 5, 2018, 507 patients were enrolled and randomly assigned, 337 to the trifluridine/tipiracil group and 170 to the placebo group. Median overall survival was 5·7 months (95% CI 4·8–6·2) in the trifluridine/tipiracil group and 3·6 months (3·1–4·1) in the placebo group (hazard ratio 0·69 [95% CI 0·56–0·85]; one-sided p=0·00029, two-sided p=0·00058). Grade 3 or worse adverse events of any cause occurred in 267 (80%) patients in the trifluridine/tipiracil group and 97 (58%) in the placebo group. The most frequent grade 3 or worse adverse events of any cause were neutropenia (n=114 [34%]) and anaemia (n=64 [19%]) in the trifluridine/tipiracil group and abdominal pain (n=15 [9%]) and general deterioration of physical health (n=15 [9%]) in the placebo group. Serious adverse events of any cause were reported in 143 (43%) patients in the trifluridine/tipiracil group and 70 (42%) in the placebo group. One treatment-related death was reported in each group (because of cardiopulmonary arrest in the trifluridine/tipiracil group and because of toxic hepatitis in the placebo group).

Interpretation

Trifluridine/tipiracil significantly improved overall survival compared with placebo and was well tolerated in this heavily pretreated population of patients with advanced gastric cancer. Trifluridine/tipiracil could be a new treatment option in this population who represent a high unmet medical need.

Funding

Taiho Oncology and Taiho Pharmaceutical.

Introduction

Gastric cancer is the fifth most common cancer worldwide and the third most common cause of cancer-related death.1 Most patients with gastric cancer present with advanced or metastatic disease, for which palliative systemic treatment is the only therapeutic option.2 Combinations of a fluoropyrimidine (eg, fluorouracil, capecitabine, or S-1), a platinum agent, and a taxane (eg, docetaxel) are usually recommended as first-line treatment in patients with HER2-negative tumours, whereas combinations of a fluoropyrimidine, a platinum agent, and trastuzumab (an anti-HER2 antibody) are usually recommended as first-line treatment for patients with HER2-positive tumours.3, 4, 5 However, these treatments have low efficacy, and median overall survival is roughly 1 year in both HER2-positive and HER2-negative disease.6, 7 Recommended second-line treatments include taxanes, irinotecan, and the VEGFR-2 inhibitor ramucirumab.3, 4, 5 As of June 30, 2015 (when the initial study protocol for our trial was finalised), no third-line treatments had been approved globally for advanced or metastatic gastric cancer (although apatinib had been approved in China in 2014).3, 4, 8

Research in context

Evidence before this study

We searched PubMed without language restrictions on July 14, 2018, with the terms “advanced gastric cancer”, “metastatic gastric cancer”, “advanced gastroesophageal cancer”, and “metastatic gastroesophageal cancer” (and synonyms) combined with “later-line”, “third-line”, or “salvage therapy” for reports published between Jan 1, 2012, and Dec 31, 2015. As of June 30, 2015, when our study protocol was finalised, no third-line treatments had been approved globally for advanced or metastatic gastric cancer (although apatinib had been approved in China in 2014), and no international guidelines provided recommendations for such treatment.

Added value of this study

Treatment options are few for patients with heavily pretreated metastatic gastric cancer. To the best of our knowledge, ours is the first randomised, controlled trial with any approved treatment to be done in this population. Compared with placebo, trifluridine/tipiracil was associated with significant improvements in overall survival and had a manageable safety profile.

Implications of all the available evidence

Trifluridine/tipiracil could be a new treatment option for patients with heavily pretreated advanced gastric cancer after progression on, or intolerance to, two or more previous lines of chemotherapy, including a fluoropyrimidine, a platinum agent, a taxane or irinotecan (or both), and an anti-HER2 therapy (in patients with HER2-positive disease). In view of trifluridine/tipiracil's efficacy and tolerability, future research exploring the treatment in novel combination regimens could be warranted.

Trifluridine/tipiracil (TAS-102) is a novel oral cytotoxic chemotherapy consisting of a thymidine-based nucleoside analogue, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil. Trifluridine/tipiracil has a unique mechanism of action in which trifluridine is incorporated into DNA, resulting in DNA dysfunction,9, 10, 11 and tipiracil blocks trifluridine degradation by thymidine phosphorylase, increasing trifluridine bioavailability.12 Trifluridine/tipiracil was approved in Japan, the EU, the USA, and other countries for the treatment of patients with metastatic colorectal cancer refractory to standard therapies on the basis of results from the phase 3 RECOURSE trial.13 Trifluridine/tipiracil also had promising efficacy and acceptable tolerability in a phase 2 study14 (EPOC1201) in Japanese patients with advanced gastric cancer who had received one or more previous lines of chemotherapy. In EPOC1201, median overall survival was 8·7 months (95% CI 5·7–14·9), and investigator-determined disease control was noted in 19 (66%) of 29 patients. We did a phase 3 randomised controlled trial to assess the efficacy and safety of trifluridine/tipiracil in patients with metastatic gastric cancer who had previously received at least two regimens for advanced disease.

Section snippets

Study design and participants

TAGS was a randomised, double-blind, multinational, placebo-controlled, phase 3 trial done at 110 academic hospitals in 17 countries (Belarus, Belgium, Czech Republic, France, Germany, Ireland, Israel, Italy, Japan, Poland, Portugal, Romania, Russia, Spain, Turkey, the UK, and the USA). Eligible patients were aged 18 years or older (20 years or older in Japan) and had histologically confirmed, non-resectable, metastatic gastric adenocarcinoma (including adenocarcinoma of the gastroesophageal

Results

Between Feb 24, 2016, and Jan 5, 2018, 507 patients were enrolled and randomly assigned to the trifluridine/tipiracil group (n=337) and the placebo group (n=170; figure 1). 503 patients received at least one dose of study treatment, 335 in the trifluridine/tipiracil group and 168 in the placebo group (safety analysis population). In the trifluridine/tipiracil group, one patient had a protocol violation and one patient died before treatment started, and in the placebo group two patients withdrew

Discussion

In the randomised, double-blind, placebo-controlled TAGS trial, trifluridine/tipiracil was associated with significantly longer overall survival compared with placebo in patients with heavily pretreated gastric cancer. Compared with placebo, trifluridine/tipiracil was also associated with significant improvements in progression-free survival, the proportion of patients achieving disease control, and time to deterioration of ECOG performance status. Thus, trifluridine/tipiracil could represent a

Data sharing

Data generated or analysed during this study are on file with Taiho Oncology and Taiho Pharmaceutical, and are not publicly available. Inquiries about data access should be sent to [email protected].

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