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It is reported here that, on June 7 (US time), Taiho Pharmaceutical Co., Ltd., made an oral presentation to the 47^th meeting of the American Society of Clinical Oncology (ASCO) about the results of a gemcitabine and TS-1 trial (GEST), which was a clinical study of TS-1 in patients with advanced pancreatic cancer (Abstract no. 4007).

In this study, TS-1, which is an orally administered anti-cancer agent, was shown to be not inferior to gemcitabine, which is the standard therapeutic agent for pancreatic cancer. The study did not demonstrate superiority of TS-1 + gemcitabine combination therapy.

The overall survival time, which was the primary endpoint, was approximately the same in the gemcitabine monotherapy and TS-1 monotherapy groups, at 8.8 and 9.7 months, respectively (hazard ratio = 0.957; p = 0.0003). With TS-1 + gemcitabine combination therapy, the overall survival time was 10.1 months, but the superiority in relation to gemcitabine monotherapy was not statistically significant (hazard ratio = 0.875; p = 0.1496).

The progression-free survival time was approximately the same in the gemcitabine monotherapy and TS-1 monotherapy groups, at 4.1 and 3.8 months, respectively (hazard ratio = 1.094; p = 0.237). The progression-free survival time with TS-1 + gemcitabine combination therapy was 5.7 months, which was statistically significantly superior to gemcitabine monotherapy (hazard ratio = 0.660; p < 0.0001).

The response rate with gemcitabine monotherapy was 13%, and the response rates with both TS-1 monotherapy and TS-1 + gemcitabine combination therapy were statistically significantly superior to this, at 21% (p = 0.242) and 29% (p < 0.0001). With respect to safety, all three treatments were tolerated.

In terms of characteristic safety-related findings in the three dose groups, the hematotoxicity findings at grade 3 or higher in the gemcitabine monotherapy, TS-1 monotherapy, and TS-1 + gemcitabine combination therapy groups, respectively, were decreased leukocyte count, at rates of 19%, 4% and 38%; neutropenia count, at 41%, 9% and 62%; and thrombocytopenia count, at 11%, 2% and 17%. The only non-hematotoxicity finding at grade 3 or higher was diarrhea, at 1%, 6% and 5%, respectively.

Quality of life (QOL) was evaluated on the basis of EQ-5D, using QOL questionnaires for cardinal valuation of changes in Euro-QOL-5D health standards. The results were that, in comparison with gemcitabine monotherapy, TS-1 monotherapy showed no difference (p = 0.61), whereas TS-1 + gemcitabine combination therapy showed statistically significant superiority (p = 0.003).

Tatsuya Ioka of the Osaka Medical Center for Cancer and Cardiovascular Diseases, who made the presentation at ASCO, made the following comment about the above results:

It is highly significant and important that TS-1, an oral formulation, showed no inferiority in comparison with gemcitabine monotherapy, which has been accepted as the standard treatment of pancreatic cancer. There is therefore now the potential for a standard treatment with an oral formulation.

Taiho Pharmaceutical considers that the above GEST results indicate a potentially major contribution to the treatment of pancreatic cancer, and intends to continue research, with development of treatment methods for pancreatic cancer.

A member of the fluoropyrimidine class of chemotherapeutic agents, TS-1 is a combination of three pharmacological compounds: tegafur, an antimetabolite agent that, after absorption, is converted into the anti-cancer agent fluorouracil (5-FU); gimeracil (5-chloro-2, 4-dihydroxypyridine, or CDHP), which decreases the degradation of 5-FU by the body; and oteracil (Oxo), which decreases 5-FU phosphorylation in the gastrointestinal tract. Developed as a gastric cancer treatment, TS-1 has become a standard of care for the treatment of gastric cancer in Japan since its initial approval there in 1999. TS-1 is also approved for patients with gastric cancer in South Korea, China, Singapore, and Taiwan. TS-1 was subsequently approved in Japan for six additional indications: for the treatment of colorectal, head and neck, non-small cell lung, unresectable or recurrent breast, pancreatic, and biliary tract cancers. To date, TS-1 has been used by more than 870,000 patients in Japan and Asia.

The trial was conducted jointly in Japan and Taiwan with the participation of more than 80 medical institutions, with 834 patients enrolled between July 2007 and October 2009. It compared subjects—patients with unresectable advanced pancreatic cancer—assigned to one of three groups: a group treated with gemcitabine alone, a group treated with the oral anticancer agent TS-1 alone, and a group treated with a combination of TS-1 and gemcitabine. Outcome measures included overall survival, progression-free survival, and safety. The group treated with gemcitabine alone followed a schedule in which one course lasted 28 days with gemcitabine administered by intravenous drip infusion at 1,000 mg/m² on days 1, 8, and 15 with day 22 being a day of rest. The group treated with TS-1 alone followed a schedule in which one course lasted 42 days with TS-1 administered orally at a dose prescribed in accordance with body surface area (80, 100 or 120 mg/day), twice daily for 28 days, followed by a two-week rest period. The group treated with a combination of TS-1 and gemcitabine followed a schedule in which one course lasted 21 days with gemcitabine administered by intravenous drip infusion at 1,000 mg/m² on days 1 and 8, and TS-1 co-administered orally at a dose prescribed according to body surface area (60, 80 or 100 mg/day), twice daily for 14 days, followed by a one-week rest period. In each treatment arm, administration of the curative agent(s) was repeated until stated criteria for termination were met.