SUMMARY: The American Cancer Society estimates that in the US, about 27,510 cases of Gastric Cancer will be diagnosed in 2019 and about 11,140 people will die of the disease. The average age at diagnosis is 68 years and Gastric Cancer is one of the leading causes of cancer-related deaths in the world. Patients with localized disease (Stage II and Stage III) are often treated with multimodality therapy and 40% of the patients may survive for 5 years or more. However, majority of the patients with Gastric and GastroEsophageal (GE) Adenocarcinoma have advanced disease at the time of initial presentation and have limited therapeutic options with little or no chance for cure. Following progression after first line treatment for metastatic disease, the median survival is approximately 3 months.
LONSURF® (TAS-102) is a combination of two agents – a novel oral nucleoside Trifluridine and a thymidine phosphorylase inhibitor, Tipiracil hydrochloride. This combination has a unique mechanism of action. Trifluridine, the active ingredient of LONSURF® incorporates into DNA resulting in DNA damage. Degradation of Trifluridine which occurs when taken orally is prevented by Tipiracil hydrochloride. In a previously published Phase II study, LONSURF® demonstrated promising efficacy and was well tolerated among pretreated patients with advanced Gastric cancer. TAGS study was conducted to confirm these findings.
The TAGS (TAS-102 Gastric Study) trial is a pivotal Phase III multinational, randomized, double-blind study evaluating LONSURF® (Trifluridine and Tipiracil) plus Best Supportive Care (BSC) versus placebo plus BSC, in patients with metastatic Gastric Cancer, refractory to standard treatments. Enrolled patients (N=507) with histologically confirmed, non-resectable metastatic Gastric cancer including GastroEesophageal junction cancer, who had received 2 or more prior chemotherapy regimens, were randomly assigned in a 2:1 ratio to receive LONSURF® 35 mg/m2 BID on days 1-5 and 8-12 of each 28-day cycle (N=337) or placebo plus Best Supportive Care (N=170). Prior treatments included Fluoropyrimidine, Platinum, Taxane, Irinotecan, or a HER2 inhibitor. Both treatment groups were well balanced and 63% of patients had received 3 or more lines of prior systemic therapy. The Primary endpoint was Overall Survival.
At a median follow-up was 10.7 months, the Primary endpoint was met with a median OS of 5.7 months with LONSURF&rg; versus 3.6 months for those in the placebo group (HR=0.69; P=0.0003). This suggested a 31% reduction in the risk of death when treated with LONSURF®. This benefit was noted across all prespecified subgroups. Treatment with LONSURF® was also associated with 43% lower risk of disease progression or death compared with placebo (HR=0.57; P<0.0001). This Progression Free Survival benefit was again noted in all subgroups. Further, patients in the LONSURF® group had a higher Disease Control Rate (44% versus 14%; P<0.0001) and lower risk of deterioration in Performance Status (HR=0.69; P=0.0005), compared to placebo.
The authors concluded that LONSURF® provided clinically meaningful and statistically significant prolongation in Overall Survival and was well tolerated in patients with heavily pretreated metastatic Gastric Carcinoma. TAGS: a phase 3, randomised, double-blind study of trifluridine/tipiracil (TAS-102) versus placebo in patients with refractory metastatic gastric cancer. Arkenau H-T, Tabernero J, Shitara K, et al. Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA25.