Randomized phase III study of gemcitabine plus S-1 (GS) versus S-1 versus gemcitabine (GEM) in unresectable advanced pancreatic cancer (PC) in Japan and Taiwan: GEST study.

Abstract

4007 Background: S-1, an oral fluoropyrimidine, is one of the key drugs for PC in Japan. Phase II studies of S-1 alone as well as those of GS have shown high efficacy against the tumor as the first-line treatment of metastatic PC. Methods: The GEST study was a randomized, prospective, open-label, 3-arm, phase III study. Chemotherapy-naive patients with unresectable advanced PC, an ECOG PS of 0-1, with adequate organ functions were randomly assigned to receive GEM (1000 mg/m2, iv, d1, 8 and 15, q4w), S-1 (80/100/120 mg/day based on BSA, po, d1-28, q6w) or GS (GEM 1000 mg/m2, iv, d1 and 8 plus S-1 60/80/100 mg/day based on BSA po, d1-14, q3w). The primary endpoint was overall survival (OS) to assess the non-inferiority of S-1 alone and the superiority of GS to GEM, with a 90% power and a 1-sided alpha value of 0.0125 for each multiplicity-adjusted comparison. Secondary endpoints were progression-free survival (PFS), response rate (RR), safety, and quality of life (EQ-5D). Results: A total of 834 patients were enrolled from July 2007 to October 2009. We conducted this analysis after confirming over 680 events as expected. Demographic factors were well balanced. S-1 was confirmed to be non-inferior to GEM with respect to OS. There was no significant difference in OS between GEM and GS, while PFS differed significantly between these arms. (4.1M/5.7M, p value<0.0001) RR was 13.3%, 21.0%, and 29.3% in GEM, S-1, and GS respectively. Grade 3/4 toxicities (%) in GEM/S-1/GS were neutropenia 41.0/8.8/62.2, thrombocytopenia 11.0/1.5/17.2, anorexia 7.3/11.4/9.4, diarrhea 1.1/5.5/4.5. EQ-5D QOL score in S-1 was similar to GEM (p value=0.67), and that in GS was significantly better than that in GEM (p value=0.003). Conclusions: Without compromising QOL, oral S-1 provided similar efficacy and tolerable toxicity to GEM as the first-line treatment for PC. Our results suggested that GS contribute better QOL than GEM. Further clinical investigation might be needed to ensure the efficacy of GS. n MST HR (97.5%CI) P value GEM 277 8.8 M - - S-1 280 9.7 M 0.957 (0.780-1.175) 0.0003 (noninferiority) GS 275 10.1 M 0.875 (0.711-1.077) 0.1496 (superiority)