Tegafur/Leucovorin calcium/Gimeracil/Oteracil Potassium

A review.Practices are changing overtime,and geog. differences in the treatment of localised and metastatic gastric cancer are becoming increasingly less pronounced,even though some medications are not available or are not reimbursed equally in all countries.Regarding the use of fluoropyrimidines,capecitabine or S-1 can be used as an alternative to infusional fluorouracil in doublet regimens.In addition ciplatin or oxaliplatin are viewed as platinum agents with similar effectiveness when incorporated in doublet or triplet regimens although this aspect remains a matter of debate.S-1 plus cisplatin has been widely used in eastern Asia,whereas infusional fluorouracil (plus leucovorin) or capecitabine,combined with oxaliplatin or cisplatin,are standard practices in Europe and North America.As a conclusion to the SOLAR study,Kang and colleagues suggest that the combination of TAS-118 plus oxaliplatin could be a new first-line standard chemotherapy for advanced gastric cancer,in Asian patients.First,it would have been reasonable to the added value of leucovorin to S-1,by comparing TAS-118 (S-1 plus leucovorin) plus oxaliplatin with S-1 plus oxaliplatin (rather than S-1 plus cisplatin).Second,as the TAS-118 plus oxalipaltin combination appears effective in patients with Lauren's diffuse-type histol. and poor prognosis,we suggest clin. research should focus on this group.Third,TAS-118 plus oxaliplatin deserves to also be tested in non-Asian patients,although it is known that S-1 is not equally tolerated in non-Asian patients and Asian patients.Finally,ongoing phase 3 trials will elucidate the role of many promising compounds such as trifluridine-tipiracil,anti-CLDN18.2 monoclonal antibodies (zolbetuximab), or checkpoint inhibitors, in other clin. relevant subsets of patients with advanced HER2-neg. gastric cancer ,including frail or fit patients, with diffuse type histol., and CLDN18.2-pos. or microsatellite-unstable tumors.

S-1 plus leucovorin and oxaliplatin showed promising efficacy for treatment of advanced gastric cancer in a randomised phase 2 study. We aimed to evaluate the efficacy and safety of oral TAS-118 (S-1 plus leucovorin) and oxaliplatin versus S-1 plus cisplatin in patients with advanced gastric cancer.

We did a randomised, open-label, phase 3 trial in 62 centres across Japan and South Korea. Patients aged 20 years or older, with a histologically confirmed advanced gastric cancer with negative or unknown HER2 status, with Eastern Cooperative Oncology Group performance status of 0 or 1, measurable or evaluable metastatic lesions, and no previous treatment were randomly assigned (1:1) via an interactive web response system using the minimisation method, stratified by performance status, presence of a measurable lesion, and country, to receive TAS-118 (S-1 40-60 mg and leucovorin 25 mg orally twice daily for 7 days) plus oxaliplatin (85 mg/m² intravenously on day 1) every 2 weeks, or S-1 (40-60 mg orally twice daily) for 21 days plus cisplatin (60 mg/m² intravenously on day 1 or 8) every 5 weeks. The primary endpoint was overall survival in patients who had advanced gastric cancer with measurable or evaluable metastatic lesions and who received the study drug. Safety was assessed in all patients who received the study drug. This study was registered at ClinicalTrials.gov, NCT02322593.

Between Jan 28, 2015, and Dec 5, 2016, 711 patients were randomised to TAS-118 plus oxaliplatin (n=356) or S-1 plus cisplatin (n=355). 11 untreated patients and 19 ineligible patients were excluded from the primary analysis (TAS-118 plus oxaliplatin group n=347, S-1 plus cisplatin group n=334) following recommendation from the independent data monitoring committee. After median follow-up of 26·0 months (IQR 22·0-32·8), median overall survival was 16·0 months (95% CI 13·8-18·3) in the TAS-118 plus oxaliplatin group and 15·1 months (95% CI 13·6-16·4) in the S-1 plus cisplatin group (hazard ratio 0·83, 95% CI 0·69-0·99; p=0·039). The most common grade 3 or higher adverse events in the 352 patients in the TAS-118 plus oxaliplatin group and the 348 patients in the S-1 plus cisplatin group were anaemia (56 [16%] vs 64 [18%]), neutropenia (54 [15%] vs 88 [25%]), decreased appetite (53 [15%] vs 46 [13%]), diarrhoea (33 [9%] vs 15 [4%]), and peripheral sensory neuropathy (30 [9%] vs one [<1%]). Serious adverse events were observed in 155 (44%) of 352 patients in the TAS-118 plus oxaliplatin group and 159 (46%) of 348 patients in the S-1 plus cisplatin group. Two treatment-related deaths occurred in the TAS-118 plus oxaliplatin group (pulmonary tuberculosis and viral pneumonia).

TAS-118 plus oxaliplatin showed a clinically meaningful improvement in efficacy compared with S-1 plus cisplatin, and could be considered a new first-line treatment option for advanced gastric cancer in Asian patients.

Taiho Pharmaceutical and Yakult Honsha.