The trial also demonstrated improvements in progression-free survival (PFS) and disease control, with a predictable and manageable safety profile, said Hendrik-Tobias Arkenau, MD, PhD, at the 2018 European Society for Medical Oncology (ESMO) Congress.
FTD/TPI is already approved by the Food and Drug Administration (FDA) for the treatment of metastatic colorectal cancer in patients previously treated with chemotherapy and biologic therapy, on the basis of an improvement in overall survival (OS) compared with placebo. The thymidine phosphorylase inhibitor tipiracil prevents degradation of the thymide oral analog trifluridine, explained Arkenau, the Executive Medical Director of Sarah Cannon Research Institute UK.
“FTD/TPI showed a clinically meaningful and statistically significant improvement in OS and PFS compared with placebo in heavily pretreated patients with gastric or GEJ cancer,” he said. “The data presented today demonstrate that FTD/TPI represents an effective and new treatment option for patients who are heavily pretreated.”
TAGS was conducted to confirm findings from a phase II Japanese study in patients with metastatic gastric cancer in which FTD/TPI 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.1 Patients were randomized 2:1 to receive FTD/TPI (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 FTD/TPI compared with 3.6 months for patients randomized to placebo. The 2.1-month improvement in median OS with FTD/TPI over placebo translated into a hazard ratio for death of 0.69 (P = .0003). The 12-month OS rate for the FTD/TPI group was 21% versus 13% for the placebo group.
Multivariate analysis found 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 FTD/TPI was maintained (HR, 0.69; 95% CI, 0.56-0.85).
Median progression-free survival (PFS), a secondary endpoint, was also significantly improved with FTD/TPI 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 FTD/TPI 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 FTD/TPI 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 FTD/TPI 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 FTD/TPI versus 58% of those assigned to placebo. The FTD/TPI combination 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 FTD/TPI.
Dosing modification (dose delay or reduction) to manage adverse events was required in 58% of the FTD/TPI group, said Arkenau. 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 nivolumab3 (Opdivo; RECOURSE, 33% Japanese enrollment) and apatinib4 (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 FTD/TPI 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. FTD/TPI in combination with immunotherapy or antiangiogenic agents should be investigated, he added.
- 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.
- 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.
- Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015;372(20):1909-1919. doi: 10.1056/NEJMoa1414325.
- Xu J, Kim TW, Shen L, et al. Results of a randomized, double-blind, placebo-controlled, phase III trial of trifluridine/tipiracil (TAS-102) monotherapy in Asian patients with previously treated metastatic colorectal cancer: the TERRA study. J Clin Oncol. 2018;36(4):350-358. doi: 10.1200/JCO.2017.74.3245.