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Results of the Phase III Clinical Study (GEST) of TS-1 in Patients with Advanced Pancreatic Cancer Published in the Online Version of the Journal of Clinical Oncology

 

Taiho Pharmaceutical Co., Ltd. (HQ: Tokyo, President: Masayuki Kobayashi) announced that the results of a Japanese Phase III Clinical Study (GEST*) of TS-1 on patients with advanced pancreatic cancer have been published in the online version of theJournal of Clinical Oncology, one of the leading medical journals in the field of cancer research. 
*GEST: Gemcitabine and TS-1 Trial

The GEST study was performed in Japan and Taiwan on 834 patients with unresectable advanced recurrent pancreatic cancer. The patients were divided into 3 groups: a group that received gemcitabine alone, a group that received TS-1 alone, and a group that was treated with a combination of TS-1 and gemcitabine. The primary endpoint was overall survival. The results did not demonstrate the statistical superiority of TS-1 + gemcitabine combination therapy (median survival time: 10.1 months) over gemcitabine monotherapy in terms of overall survival (hazard ratio = 0.88, p = 0.15), but it did indicate that TS-1 therapy (median survival time: 9.7 months) was not inferior to gemcitabine therapy (median survival time: 8.8 months) in terms of overall survival (hazard ratio = 0.96, p<0.001). The results of this Phase III clinical study were also presented at the 47th meeting of the American Society of Clinical Oncology (ASCO 2011).

About TS-1
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 in the liver; 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 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. TS-1 is also approved for patients with gastric cancer in South Korea, China, Singapore, Taiwan, Thailand, and Hong Kong in Asia, and in Sweden, Denmark, Norway, Finland, the U.K., Austria, Germany, Bulgaria, the Netherlands , and Ireland in Europe.

About the Journal of Clinical Oncology
This publication is one of the leading medical journals in the field of cancer research, with an impact factor of 18.372 (2011). 

For a summary of the results of the GEST study, see the news release dated June 8, 2011.
Japanese version:
http://www.taiho.co.jp/corporation/news/2011/20110608.html
English version:
http://www.taiho.co.jp/english/news/20110608.html
 

Summary of the Results of the GEST Study

Name of study
Randomized Phase III Study of Gemcitabine Plus S-1, S-1 Alone, or Gemcitabine Alone in Patients With Locally Advanced and Metastatic Pancreatic Cancer
Background
The prognosis for unresectable advanced pancreatic cancer is poor. With few effective drugs available, a more effective therapy is in great demand. Phase III clinical trials were conducted in order to investigate the non-inferiority of TS-1 monotherapy to the standard gemcitabine therapy in terms of overall survival and to investigate the superiority of gemcitabine + TS-1 combination therapy.
Methods
Randomized, comparative, multi-institution Phase III clinical trials were conducted between July 2007 and October 2009. The subjects were patients with unresectable advanced recurrent pancreatic cancer who were chemotherapy naive. 
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 and 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 14-day 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 7-day rest period. Administration of the curative agent(s) was repeated until stated criteria for termination were met.The primary endpoint of the study was overall survival. The secondary endpoints were progression-free survival, response rate, adverse event rate, adverse drug reaction rate, and QOL (EQ-5D). 
Results
The 834 patients were randomly assigned to the three groups as follows: 277 patients in the gemcitabine group, 280 patients in the TS-1 group, and 277 patients in the TS-1 + gemcitabine combination therapy group. 
Median overall survival was 8.8 months (95% confidence interval: 8.0-9.7 months) in the gemcitabine (control) group; 9.7 months (95% confidence interval: 7.6-10.8 months, hazard ratio compared to the gemcitabine group: 0.96, 97.5%, confidence interval: 0.78-1.18, p<0.001, non-inferior) in the TS-1 group; and 10.1 months in the TS-1 + gemcitabine combination therapy group (95% confidence interval: 9.0-11.2 months, hazard ratio compared to the gemcitabine group: 0.88, 97.5%, confidence interval: 0.71-1.08, p=0.15, superior). With respect to safety, all three treatments were tolerated, but the TS-1 + gemcitabine combination therapy showed strong tendencies toward gastrointestinal toxicity and hematotoxicity. 
Conclusions
TS-1 monotherapy was demonstrated to be non-inferior to gemcitabine monotherapy, which is the standard therapy for pancreatic cancer, in terms of overall survival, and its tolerance was shown to be satisfactory. TS-1 + gemcitabine combination therapy was not shown to be superior to gemcitabine monotherapy. 

This study has been listed in the clinical trials registry at ClinicalTrials.gov (NCT00498225).

Hideki Ueno, Tatsuya Ioka, Masafumi Ikeda, Shinichi Ohkawa, Hiroaki Yanagimoto, Narikazu Boku, Akira Fukutomi, Kazuya Sugimori, Hideo Baba, Kenji Yamao, Tomotaka Shimamura, Masayuki Sho, Masayuki Kitano, Ann-Lii Cheng, Kazuhiro Mizumoto, Jen-Shi Chen, Junji Furuse, Akihiro Funakoshi, Takashi Hatori, Taketo Yamaguchi, Shinichi Egawa, Atsushi Sato, Yasuo Ohashi, Takuji Okusaka, Masao Tanaka, for the GEST study Group.
Randomized Phase III Study of Gemcitabine Plus S-1, S-1 Alone, or Gemcitabine Alone in Patients With Locally Advanced and Metastatic Pancreatic Cancer in Japan and Taiwan: GEST Study
Journal of Clinical Oncology, doi: 10.1200/JCO.2012.43.3680.