Longer survival with trifluridine/tipiracil in heavily pre-treated patients with metastatic gastric cancer
Trifluridine/tipiracil (FTD/TPI) is a novel oral therapy comprising the tymidine analog trifluridine, and tiparacil, an agent that prevents trifluridine degradation. During ESMO 2018, results of the phase III TAGS trial demonstrate that FTD/TPI induced a clinically meaningful and statistically significant improvement in both overall survival (OS) and progression-free survival (PFS) in heavily pre-treated patients with gastric or gastro-oesophageal junction (GEJ) cancer. Compared to placebo and best supportive care (BSC), FTD/TPI plus BSC reduced the risk of death by 31% and prolonged the median OS with more than 2 months. In addition, also the disease control rate (DCR) was higher with the experimental agent, while the risk of deterioration in performance status was lower compared to placebo. As such, FTD/TPI represents an effective new treatment option for heavily pre-treated patients with metastatic gastric, or GEJ cancer.
Patients with metastatic gastric, or GEJ cancer have a very poor prognosis, with a 5-year OS rate of only 4%. For patients who failed first- and second-line therapy, the treatment options are very limited. In a Japanese phase II trial, FTD/TPI demonstrated promising efficacy and was well tolerated in the treatment of pre-treated patients with advanced gastric cancer. The phase III TAGS trial was set up to confirm these findings. In this global phase III study, 507 patients with histologically confirmed, unresectable metastatic gastric, or GEJ cancer were randomised (2:1) to receive FTD/TPI (35 mg/m2 BID on days 1-5 and 8-12 of each 28-day cycle) or placebo, both in combination with BSC. In order to be eligible for the trial, patients had to have an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 and had to be pre-treated with 2 or more prior chemotherapy regimens.
The median age of patients in the study was 63 years, two-thirds had an ECOG PS of 1 and 70% had a gastric primary tumor (30 % GEJ). In 44% of the patients a prior gastrectomy was performed and 63% of patients received 3 or more prior lines of therapy. After a median follow-up of 10.7 months, the TAGS trial met its primary endpoint by demonstrating a significantly longer median OS with FTD/TPI than with placebo (median OS: 5.7 vs. 3.6 months). This translates into a 31% reduction in the risk of death with the experimental regimen, compared to placebo (HR[95%CI]: 0.69[0.56-0.85]; 2-sided p=0.0006). Further subgroup analyses for OS demonstrated that the benefit of FTD/TPI over placebo was maintained irrespective of age, ethnicity, ECOG PS, primary tumor site, the number and the location of the metastases and the number of prior therapy lines. In addition, FTD/TPI was also associated with a significantly lower risk of disease progression or death (HR[95%CI]: 0.57[0.47-0.70]; p<0.0001). This PFS advantage with FTD/TPI was seen in all investigated subgroups. The DCR with FTD/TPI was 44%, while this was only 14% with placebo (p<0.0001). Finally, the median time to deterioration of the ECOG PS to 2 or more was 4.3 months with FTD/TPI as compared to 2.3 months with placebo (HR[95%CI]: 0.69[0.56-0.85]; p=0.0005).
The clinical benefit of FTD/TPI did come at the cost of additional toxicity. The incidence of grade 3/4 treatment related adverse events was 53% in the experimental arm as compared to 13% with placebo. The most common grade 3/4 adverse events with FTD/TPI were neutropenia (34%), anemia (19%), leukopenia (9%), and a decreased appetite (9%). Of note, the incidence of grade 3/4 febrile neutropenia with FTD/TPI was low at 3%. Dose reductions as a result of toxicity were required in 11% of FTD/TPI treated patients.
In conclusion, FTD/TPI was associated with a clinically meaningful and statistically significant prolongation in OS (31% reduction in risk of death) in this heavily pre-treated cohort of metastatic gastric, or GEJ cancer patients. In general, the regimen was well tolerated. As such, FTD/TPI represents an effective new treatment option for metastatic gastric/GEJ cancer patients who failed two or more prior lines of therapy.
Arkenau H-T, Tabernero, 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 ESMO 2018; Abstract LBA25.