The Intriguing Potential of S-1 in Pancreatic Cancer 

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The collective results of the GEST and JASPAC-01 trials suggest that further study of S-1 in Western patients is warranted.

—Eileen M. O’Reilly, MD

The results of the GEST study by Ueno and colleagues add to the intriguing potential role of the oral fluoropyrimidine S-1 in the treatment of pancreas adenocarcinoma. S-1 is a three-component drug consisting of tegafur (a prodrug of fluorouracil), gimeracil (5-chloro-2,4 dihydropyridine, or CDHP, a dihydropyrimidine dehydrogenase enzyme activity inhibitor), and oteracil (potassium oxonate). The drug has been extensively studied in Asia in gastrointestinal and other malignancies, and notable differences regarding pharmacogenomic and pharmacodynamic considerations have been inferred for Asian vs Western populations.

The results of the GEST study demonstrate noninferiority of S-1 to gemcitabine in advanced pancreatic cancer. However, overall survival superiority of a gemcitabine and S-1 combination over gemcitabine alone was not demonstrated. These results will lead to the use of S-1 as a single-agent instead of gemcitabine for front-line therapy for advanced pancreas adenocarcinoma in Asia for patients in whom single-agent therapy is an appropriate consideration.

An interim analysis of the results of the JASPAC-01 trial presented at the Gastrointestinal Cancers Symposium in early 2013 provided similar support for the notion that S-1 may have superior activity to gemcitabine. Specifically, in this latter trial, which was conducted in an adjuvant therapy population and was also designed with a noninferiority endpoint, preliminary results indicate superiority of S-1 over gemcitabine with a significant hazard ratio for survival for S-1 vs gemcitabine of 0.56 (95% confidence interval 0.42-0.74, P < .0001 for noninferiority, and P < .001 for superiority). Two-year survival was 70% with S-1 and 53% with gemcitabine.

Overall, S-1 adds to the therapeutic options available for front-line therapy for pancreas adenocarcinoma, and the results of the GEST study will likely lead to this drug’s further development in combination with other agents and provide an alternative nongemcitabine platform to build upon. The implications of the GEST results for treatment in the United States remain unclear, since there is no obvious pathway to regulatory approval and the benefits and risk/toxicity balance of S-1 in Western populations remain to be elucidated. Nevertheless, the collective results of the GEST and JASPAC-01 trials suggest that further study of S-1 in Western patients is warranted. ■

Dr. O’Reilly is a gastrointestinal medical oncologist at Memorial Sloan-Kettering Cancer Center and Weill Medical College of Cornell University, New York.

Disclosure: Dr. O'Reilly has received research funding from Clovis; honoraria from Celgene. She has served in a consultant or advisory role for Celgene and Clovis (uncompensated).

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