FDA Grants Priority Review to TAS-102 for Gastric/GEJ Cancer

The FDA has granted a priority review to a supplemental new drug application for TAS-102 for use in previously treated patients with advanced or metastatic gastric adenocarcinoma, including cancer of the gastroesophageal junction.

The FDA has granted a priority review to a supplemental new drug application (sNDA) for TAS-102 (trifluridine/tipiracil; Lonsurf) for use in previously treated patients with advanced or metastatic gastric adenocarcinoma, including cancer of the gastroesophageal junction (GEJ).

UPDATE 2/25/2019: FDA Approves TAS-102 for Gastric/GEJ Cancer

The sNDA is based on data from the phase III TAGS trial, in which TAS-102 reduced the risk of death by about one-third compared with placebo in patients with heavily pretreated gastric or GEJ cancer.1 The TAGS trial also showed improvements in progression-free survival (PFS) and disease control, and demonstrated a predictable and manageable safety profile.

Under the Prescription Drug User Fee Act, the FDA is scheduled to make a decision on the sNDA by February 24, 2019.

"We look forward to working with the FDA as they consider the application for Lonsurf under priority review," Martin Birkhofer, MD, senior vice president and chief medical officer, Taiho Oncology, Inc, the manufacturer of TAS-102, said in a press release.

TAGS was conducted to confirm findings from a phase II Japanese study in patients with metastatic gastric cancer in which TAS-102 was evaluated after failure of standard chemotherapies (fluoropyrimidines, platinums, and taxanes) or irinotecan and found to lead to a median OS of 8.7 months and a disease control rate of 65.5%.2

The global phase III TAGS double-blind study enrolled 507 adults with histologically confirmed, nonresectable metastatic gastric/GEJ cancer and an ECOG performance status of 0 or 1 who received ≥2 prior chemotherapy regimens. Patients were randomized 2:1 to receive TAS-102 (35 mg/m2 twice daily on days 1 to 5 and 8 to 12 of each 28-day cycle) or placebo plus best supportive care, and were treated until progression, intolerability, or patient withdrawal.

The primary cancer site was gastric in 71% and GEJ in 29%. Fifty-five percent had ≥3 metastatic sites. Sixty-three percent in each arm had ≥3 prior treatments and 44% in each arm had prior gastrectomy. More than 90% received prior platinum, fluoropyridine, and taxane treatment. About one-third in each arm had prior ramucirumab.

Median OS, the primary endpoint, was 5.7 months for patients assigned to TAS-102 compared with 3.6 months for patients randomized to placebo. The 2.1-month improvement in median OS with TAS-102 over placebo translated into a hazard ratio for death of 0.69 (P = .0003). The 12-month OS rate for the TAS-102 group was 21% versus 13% for the placebo group.

Multivariate analysis the following factors to be prognostic for OS (P <.05): ECOG performance status of 1 (vs 0), 2 prior regimens (vs 33), age <65 years (vs ≥65 years), 1 or 2 metastatic sites (vs 3), and negative HER2 status (vs positive or undetermined). After adjusting for these factors, the treatment effect for TAS-102 was maintained (HR, 0.69; 95% CI, 0.56-0.85).

Median progression-free survival (PFS), a secondary endpoint, was also significantly improved with TAS-102 compared with placebo (2.0 vs 1.8 months; HR, 0.57; P < .0001). The 6-month PFS rates were 15% and 6%, respectively. The PFS advantage for TAS-102 was maintained when assessed by subgroups based on age, region, ethnicity, ECOG performance status, primary site, number of metastatic sites, and prior treatment with ramucirumab, among others.

The objective response rate with TAS-102 was 4% compared with 2% for placebo. In the active treatment group, there was 1 complete response (CR), 12 partial responses (PRs), and 115 patients with stable disease (SD), for a disease control rate of 44%. The disease control rate in the placebo group was 14% (0 CR, 3 PRs, 18 patients with SD). The absolute difference between groups in the disease control rate was 30% (P <.0001).

Time to deterioration of ECOG performance status to 2, a secondary endpoint, was longer in the TAS-102 group compared with the placebo group (median, 4.3 vs 2.3 months; HR, 0.69; P = .0005).

Grade ≥3 adverse events (AEs) of any cause occurred in 80% of patients on TAS-102 versus 58% of those assigned to placebo. TAS-102 was associated with more treatment-related AEs of any grade (81% vs 57%). There was 1 treatment-related death in each group. Grade ≥3 febrile neutropenia of any cause was reported in 6 (2%) patients treated with TAS-102.

Dosing modification (dose delay or reduction) to manage adverse events was required in 58% of the TAS-102 group. Treatment had to be discontinued due to adverse events in 13%. G-CSF treatment to manage neutropenia was necessary in 16%. The most common AEs leading to dosing modification were neutropenia and/or decreased neutrophil count (37%), anemia and/or decreased hemoglobin level (9%), and leukopenia and/or decreased white blood cell count (6%).

Yoon-Koo Kang, MD, PhD, a professor in the Department of Oncology at the Asan Medical Center of the University of Ulsan College of Medicine in Seoul, Korea, commented that although TAGS was a global trial, Asian patients were underrepresented, with Japanese patients constituting only 15% of the total patient population. Kang was not involved in the TAGS study.

Other agents explored in third or later lines of treatment include nivolumab (Opdivo; RECOURSE, 33% Japanese enrollment) and apatinib (YN968D1; TERRA, conducted in China, Korea, and Thailand). Those 2 therapies have HRs for OS relative to placebo similar to the 0.69 observed with TAS-102 as well as similar PFS, Kang noted.

The need for biomarkers to define the best third and later line of treatment for advanced gastric cancer is urgent, he said. Sequential use of these agents is possible if they are tolerated. TAS-102 in combination with immunotherapy or antiangiogenic agents should be investigated, he added.


  1. Arkenau H-T, Tabernero J, Shitara K, et al. TAGS: a phase 3, randomised, double-blind study of trifluridine/tipiracil (TAS-102) versus placebo in patients with refractory metastatic gastric cancer. Presented at: 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. LBA25.
  2. Bando H, Doi T, Muro K, et al. A multicenter phase II study of TAS-102 monotherapy in patients with pre-treated advanced gastric cancer (EPOC1201). Eur J Cancer. 2016;62:46-53. doi: 10.1016/j.ejca.2016.04.009.