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Mechanism of action: TS-ONE contains Tegafur (FT), Gimeracil (CDHP) and Oteracil Potassium (Oxo), and the antitumor activity of TS-ONE after oral administration is based on 5-FU that appears gradually in the body via the transformation of FT. CDHP increased the concentration of 5-FU, which is converted from FT, by selectively and reversibly inhibiting DPD, a catabolic enzyme of 5-FU, which is particularly distributed in the liver. 5-fluoronucleotides, phosphorylated metabolites of 5-FU, are highly maintained in tumor tissues, thereby enhancing the antitumor activity in proportion to the increase in the concentration of 5-FU in the body. Oxo selectively inhibits the production of 5-fluoronucleotides from 5-FU by distributing in the gastrointestinal tissue as a result of oral administration and selectively and reversibly inhibiting orotate phosphoribosyltransferase.
The main mechanisms of action of 5-FU is the inhibition of DNA synthesis resulting from the antagonistic effect of the active metabolite FdUMP acting upon dUMP to form Ternary complex with thymidylate synthase and the reduced folic acid. RNA function is also thought to be damaged by conversion of 5-FU to FUTP, and its incorporation into RNA molecule.
Clinical Studies: Summary of Clinical Studies (Based on CSR): For the treatment of adjuvant gastric cancer: In a randomized phase III study of postoperative adjuvant chemotherapy in patients with gastric cancer, the survival benefit of TS-ONE monotherapy (one year after surgery, 529 patients) was compared with surgery alone (530 patients) in patients with stage II or III gastric cancer after curative gastrectomy (median postoperative follow-up period: 3 years).
TS-ONE reduced the risk of death by 32% compared with surgery alone, with a hazard ratio for death of 0.675 (95% CI: 0.523-0.871, p=0.0024 by the log-rank test). The three-year survival rate after surgery was 80.5% in the TS-ONE group and 70.1% in the surgery alone group. (See Figure 1.)
Click on icon to see table/diagram/imageTS-ONE reduced the risk of relapse by 38% compared with surgery alone, with a hazard ratio for relapse or death of 0.622 (95% CI: 0.501-0.772, p<0.0001 by the log-rank test). The three-year relapse-free survival rate was 72.2% in the TS-ONE group and 60.1% in the surgery alone group. (See Figure 2.)
Click on icon to see table/diagram/imageFor the treatment of advanced non-small cell lung cancer: In a randomized phase III study in patients with non-small cell lung cancer who have received a platinum-based treatment, the survival benefit of TS-ONE monotherapy (577 patients) was compared to the docetaxel therapy (570 patients) in previously treated non-small cell lung cancer patients. The median survival time for TS-ONE group was 12.75 months (95% CI, 11.53-14.00) and 12.52 months for the docetaxel group (95% CI, 11.14-14.36). The estimated overall survival hazard ratio (TS-ONE/docetaxel) was 0.945 (95% CI, 0.833-1.073), which confirmed the non-inferiority of TS-ONE monotherapy to docetaxel therapy.
For the treatment of advanced pancreatic cancer: In a randomized phase III study (GEST) comparing Gemcitabine (GEM) Versus TS-ONE Versus Gemcitabine Plus TS-ONE, TS-ONE group successfully demonstrated its anti-cancer effect in locally advanced or metastatic pancreatic cancer patients by showing similar median OS of 9.66 months to gemcitabine monotherapy (MST=8.80 months; hazard ratio=0.957; p=0.6310), which was significantly lower than the margin 1.33 (p=0.0003), meaning that TS-ONE monotherapy could be stated as non-inferior to gemcitabine therapy. Moreover, despite that GEM + TS-ONE group has shown an averagely longer OS of 10.05, the overall survival did not differ significantly between the combination therapy group and GEM group (hazard ratio=0.875; p=0.1496). With regards to safety, TS-ONE monotherapy has fewer severe drug-related TEAEs in contrast to gemcitabine monotherapy and the combination therapy.
Summary of Clinical Studies (Based on Published Data): Information on the target population, efficacy, and safety should refer to the original articles or treatment guidelines.
For the treatment of adjuvant and advanced gastric cancer: Advanced Gastric Cancer: In a randomized phase III study (SPIRITS1) of TS-ONE alone versus TS-ONE plus cisplatin (CDDP), TS-ONE + CDDP arm showed significant superiority in overall survival compared to TS-ONE alone.
In a randomized Phase III study (G-SOX2) comparing TS-ONE plus oxaliplatin (SOX) with cisplatin plus TS-ONE (CS) in chemotherapy-naïve patients, SOX demonstrated noninferiority in progression-free survival compared with CS.
In a randomized phase III study (START3) comparing TS-ONE plus docetaxel with TS-ONE alone as first-line chemotherapy, addition of docetaxel to TS-ONE prolongs survival of patients.
Adjuvant Gastric Cancer: In a randomized phase III study (ARTIST-24) comparing adjuvant single-agent TS-ONE, TS-ONE with oxaliplatin (SOX), and postoperative chemoradiation with TS-ONE and oxaliplatin (SOXRT) in patients with node-positive gastric cancer after D2 resection, adjuvant SOX was effective in prolonging disease-free survival when compared with TS-ONE monotherapy.
A randomized phase III study (START-25) demonstrated the superiority in 3-year relapse-free survival of postoperative TS-ONE plus docetaxel over TS-ONE alone for R0 resection of pathologic stage III gastric cancer.
For the treatment of advanced non-small cell lung cancer: In a randomized Phase III Study (LETS6) comparing oral TS-ONE plus carboplatin with Paclitaxel plus carboplatin in chemotherapy-naïve NSCLC patients, the study demonstrates noninferiority of TS-ONE plus carboplatin relative to carboplatin plus paclitaxel in terms of overall survival.
In a randomized phase III study (CATS7) of TS-ONE plus cisplatin versus docetaxel plus cisplatin in previously untreated advanced NSCLC patients, TS-ONE plus cisplatin is not inferior to docetaxel plus cisplatin in terms of overall survival.
For the treatment of colorectal cancer (locally advanced or unresectable or metastasis) when given in combination with oxaliplatin as first-line treatment, or in combination with irinotecan as second-line treatment: In a randomized phase II/III study (FIRIS8) of irinotecan plus TS-ONE (IRIS) versus fluorouracil and folinic acid plus irinotecan (FOLFIRI) as second-line chemotherapy for metastatic colorectal cancer, progression-free survival with IRIS is not inferior to that with FOLFIRI.
In a randomized Phase III Study (SOX versus CapeOX9) of TS-ONE plus oxaliplatin (SOX) versus Capecitabine plus oxaliplatin (CapeOX) for first-line treatment of patients with metastatic colorectal cancer, SOX is non-inferior to the CapeOX in terms of progression-free survival.
For the treatment of adjuvant pancreatic cancer: A randomized phase III study (JASPAC 0110) demonstrated that postoperative adjuvant chemotherapy with TS-ONE significantly extended both overall and relapse-free survival of Japanese patients with resected pancreatic cancer compared with gemcitabine.
For the treatment of HER-2 negative metastatic breast cancer when given as monotherapy: In a randomized phase III study (SELECT BC11) of taxanes versus TS-ONE as the first-line chemotherapy for metastatic breast cancer, TS-ONE is shown to be non-inferior to taxane with respect to overall survival.
For the treatment of adjuvant and advanced biliary tract cancer: Advanced biliary tract cancer: In a randomized phase III study (KHBO1401-MITSUBA12) of gemcitabine, cisplatin plus TS-ONE (GCS) versus gemcitabine, cisplatin (GC), GCS demonstrated superior overall survival over GC.
In a randomized phase III study (FUGA-BT13) of combination gemcitabine plus TS-ONE (GS) versus gemcitabine plus cisplatin (GC), GS demonstrated to be non-inferior to GC in terms of overall survival.
Adjuvant biliary tract cancer: When adjuvant TS-ONE is compared with observation in resected biliary tract cancer in a randomized phase III study, adjuvant therapy with TS-ONE led to significantly longer overall survival than observation in Japanese patients (JCOG1202, ASCOT14).
Time of occurrence of adverse reactions and period of recovery: The time of occurrence of adverse reactions considered noteworthy as a result of administration of TS-ONE was analyzed in 453 patients enrolled in late clinical phase II studies of TS-ONE for advanced or recurrent cancer in Japan. The results were as follows.
Among abnormal laboratory test results as follows any of the criteria including a WBC count of 3,000/mm3, a hemoglobin level of 8 g/dL, and a platelet count of 7.5 x 104/mm3, the median time to nadir in the cycle where the lowest level in a case was reached was 27 days for WBC count, 25 days for hemoglobin level, and 24 days for platelet count.
On the other hand, in patients who were confirmed to have recovered from the previously mentioned criteria, the median between the nadir of these values and recovery from them in the course were 7 days, 5.5 days and 6 days, respectively. (See Table 1.)
Click on icon to see table/diagram/imageWhen the time of occurrence of adverse reactions after the start of the first dose of TS-ONE was examined to assess the causality between them, the median until the occurrence of diarrhea, rash and stomatitis, which were judged adverse reactions, were 24.5 days, 21 days and 28 days, respectively.
On the other hand, the median between the highest grade of these adverse reactions and the improvement from them were 9 days for diarrhea, 14 days for rash, and 13.5 days for stomatitis. (See Table 2.)
Click on icon to see table/diagram/imageAdverse reactions in the presence of renal disorder: In the post-marketing surveys of TS-ONE in patients with gastric cancer, the incidence of adverse reactions was tabulated by the range of creatinine clearance value (Ccr estimate), calculated from serum creatinine value, gender, age and weight using Cockcroft-Gault equation. The results were as follows. In the patients, as creatinine clearance value decreased, the incidence of adverse reactions increased and the severity of the adverse reactions also increased. Additionally, in the patients who were administrated initially at the lower dose (mostly, one stage lower than the standard), the incidence of adverse reactions was low, compared with the patients who were administrated initially at the standard dose. (See Table 3.)
Click on icon to see table/diagram/imagePharmacokinetics: Pharmacokinetic parameters obtained from the plasma concentrations of TS-ONE administered to 12 cancer patients in a single oral dose of 32-40 mg/m2 after a meal are shown in Table 4. The amount excreted in the urine within 72 hours after administration accounted for 52.8% of the CDHP, 7.8% of the FT, 2.2% of the Oxo, 11.4% of the metabolite cyanuric acid (CA) and 7.4% of the 5-FU. (See Table 4.)
Click on icon to see table/diagram/imageWhen TS-ONE was orally administered at a dose of 25-200 mg/body, the AUC and Cmax of FT, CDHP, Oxo and 5-FU increased in a dose-dependent manner. When the plasma concentration of TS-ONE was measured 1, 7, 14 and 28 days after administration of 32-40 mg/m2 of TS-ONE twice a day for 28 consecutive days, it rapidly reached a constant level. Endogenous uracil (Ura) rapidly decreased even after consecutive administration of TS-ONE, and the CDHP-induced DPD inhibition was reversible, and no enhancing effect was observed.
TS-ONE, alone or in combination with other fluoropyrimidine-group drugs, was orally administered to rats for 7 consecutive days, and the plasma concentration of 5-FU was measured 2 hours after the final dose. It was found to be 4.1, 8.1, 2.8, 6.9 and 2.3 times higher when combined with 5-FU, FT, FT·Ura, doxifluridine and flucytosine, respectively, than when administered alone. This suggests that the combined use of TS-ONE and other fluoropyrimidine-group drugs may enhance adverse reactions.
When TS-ONE was administered to a renal dysfunction rabbit, CDHP renal clearance was found to be decreased, and the blood concentration of 5-FU was markedly increased compared to control animal. These suggest that adverse reactions may be enhanced.
Creatinine clearance value (Ccr estimate) was calculated from serum creatinine value, gender, age, and weight using the Cockcroft-Gault equation*) for the clinical study patients for whom pharmacokinetics were examined in detail. The AUCs of two patient groups with normal and slightly impaired renal function were tabulated by range of creatinine clearance value (Ccr estimate). (See Table 5.)
Click on icon to see table/diagram/imagePhase I study of TS-ONE investigated the pharmacokinetics of its components and metabolites in patients with normal and impaired renal function. Patients with mild renal impairment (CrCl 51 to 80 mL/min) receiving the same monotherapy dose of 30 mg/m2 twice daily as patients with normal renal function (CrCl >80 mL/min) had an increase in mean 5-FU AUC0-inf relative to that of the normal patients. Patients with moderate renal impairment (CrCl 30 to 50 ml/min) who received a reduced dose of 20 mg/m2 twice daily showed no significant increase in mean 5-FU AUC0-inf relative to that of the normal group. Following a reduced dose of TS-ONE 20 mg/m2 administered once daily to the severe renal impairment group (CrCl <30 ml/min), the single-dose AUC0-inf and multiple-dose AUC0-τ values for 5-FU were approximately 2-fold higher in the severe renal impairment group compared to those observed in the normal renal function group receiving 30 mg/m2 twice daily. Therefore, the daily exposure to 5-FU would be expected to be comparable in these groups, since the daily exposure in patients in the severe renal impairment group is based on the administration of TS-ONE once a day, while the daily exposure to 5-FU in the patients with normal renal function is based on the administration of TS-ONE twice daily. However, it is to be noted that the exposure to 5-FU can be variable and unexpectedly higher in patients with severe renal impairment due to the impact of fluctuations in renal function in these patients.
*) Cockcroft-Gault equation: See equation.
Click on icon to see table/diagram/imageThere were no significant differences in AUCs of 5-FU, tegafur, gimeracil, or oteracil after either single or multiple dose administration of TS-ONE 30 mg/m2 twice daily in patients with mild, moderate, or severe hepatic impairment compared to those with normal hepatic function. After single dose administration, there was a statistically significant decrease in 5-FU and gimeracil Cmax for the severe hepatic impairment group relative to that of the normal group, but this difference was not observed after multiple dose administration.
Protein binding: The rates of protein binding of each component and 5-FU in human serum were 49-56% for FT, 32-33% for CDHP, 7-10% for Oxo and 17-20% for 5-FU (in vitro).
Metabolic enzyme: It has been reported that CYP2A6 is the major cytochrome P450 isoenzymes in human liver microsomes involved in the metabolic transformation of FT to 5-FU (in vitro).
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