Safety and activity of trifluridine/tipiracil and ramucirumab in previously treated advanced gastric cancer: an open-label, single-arm, phase 2 trial

Lancet Gastroenterol Hepatol. 2021 Mar;6(3):209-217. doi: 10.1016/S2468-1253(20)30396-4. Epub 2021 Jan 26.


Background: Findings of preclinical and clinical trials in colorectal cancer have shown promising antitumour effects of the co-formulation trifluridine/tipiracil and VEGF inhibition. We aimed to investigate the safety and activity of trifluridine/tipiracil and ramucirumab for previously treated advanced gastric cancer.

Methods: We did an open-label, single-arm, two-cohort, phase 2 study at eight centres in Japan. We enrolled patients with unresectable advanced gastric cancer or gastro-oesophageal junction adenocarcinoma. Cohort A included patients previously treated with one line of chemotherapy without ramucirumab and cohort B included patients previously treated with two to four lines of chemotherapy, including ramucirumab. Patients received trifluridine/tipiracil (35 mg/m2) orally twice daily on days 1-5 and days 8-12 of each 28-day treatment cycle, plus intravenous ramucirumab (8 mg/kg) on days 1 and 15. The primary endpoint was the disease control rate, assessed by investigators and defined as the proportion of patients with a confirmed best overall response, according to Response Evaluation Criteria in Solid Tumors version 1.1. This trial is registered on JapicCTI (JapicCTI-194596) and is ongoing but not recruiting.

Findings: Between April 8 and Oct 11, 2019, 64 patients were enrolled and included in the safety and activity analyses, 33 in cohort A and 31 in cohort B. In cohort A, the disease control rate was 85% (95% CI 68-95; 28 of 33 patients) and in cohort B it was 77% (59-90; 24 of 31 patients). Common treatment-related adverse events of grade 3 or worse were neutrophil count decreased (27 [82%] in cohort A and 23 [74%] in cohort B), white blood cell count decreased (eight [24%] and seven [23%]), and platelet count decreased (eight [24%] and four [13%]). Serious treatment-related adverse events were recorded in three patients in cohort A (fatigue and neutrophil count decreased; large intestine perforation; and febrile neutropenia, platelet count decreased, and anaemia). No patients in cohort B had a serious treatment-related adverse event, and no treatment-related deaths were reported in either cohort.

Interpretation: Trifluridine/tipiracil and ramucirumab showed an acceptable safety profile and clinical activity in patients with previously treated advanced gastric cancer regardless of previous ramucirumab exposure.

Funding: Taiho Pharmaceutical and Eli Lilly.

Publication types

  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Administration, Intravenous
  • Aged
  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Antibodies, Monoclonal, Humanized / adverse effects
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Case-Control Studies
  • Drug Combinations
  • Esophageal Neoplasms / drug therapy
  • Female
  • Humans
  • Japan / epidemiology
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Progression-Free Survival
  • Pyrrolidines / administration & dosage
  • Pyrrolidines / adverse effects
  • Pyrrolidines / therapeutic use*
  • Ramucirumab
  • Safety
  • Stomach Neoplasms / drug therapy*
  • Thymine / administration & dosage
  • Thymine / adverse effects
  • Thymine / therapeutic use*
  • Trifluridine / administration & dosage
  • Trifluridine / adverse effects
  • Trifluridine / therapeutic use*


  • Antibodies, Monoclonal, Humanized
  • Drug Combinations
  • Pyrrolidines
  • trifluridine tipiracil drug combination
  • Thymine
  • Trifluridine

Supplementary concepts

  • Adenocarcinoma Of Esophagus