2111 - Phase III randomized study of neoadjuvant chemotherapy (CT) with docetaxel(D), oxaliplatin(O) and S-1(S) (DOS) followed by surgery and adjuvant S-1, vs surgery and adjuvant S-1, for resectable advanced gastric cancer (GC) (PRODIGY)

Background

Adjuvant CT after D2 gastrectomy is standard therapy for resectable advanced GC in Asia. We investigated whether added neoadjuvant (NA) CT can further improve outcomes.

Methods

530 pts with newly diagnosed locally advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma (cT2,3/N[+]M0 or cT4/N[any]M0, AJCC 7^th ed), ECOG PS 0-1, were randomized 1:1 to NA DOS then surgery and adjuvant S-1 (CSC; n = 266), or surgery and adjuvant S-1 (SC; n = 264). NA CT was D 50mg/m² iv and O 100mg/m² iv on day 1, S 40mg/m² twice po on days 1–14 every 3 weeks for 3 cycles. Standard surgery was D2 gastrectomy. Adjuvant CT was S 40mg/m² twice po on days 1–28 every 6 weeks for 8 cycles. Primary endpoint: 3-year progression free survival (PFS) in full analysis set (FAS).

Results

With 46 pts excluded due to ineligibility or consent withdrawal, FAS was 484 pts (238 in CSC, 246 in SC). Baseline characteristics were balanced. In CSC arm, 214 pts (90.0%) completed 3 cycles of NA DOS. Main ≥grade3 toxicities: neutropenia in 12.6%, febrile neutropenia 9.2%, diarrhea in 5.0%, 1 treatment related death. 222 CSC (93.3%) and 246 SC (100%) pts underwent surgery. R0 resection rates: 96.4% vs 85.8%, p < 0.0001; lower pathologic stage in CSC with pathologic CR 10.4% vs 0%, p < 0.0001. Major surgical complication rates: 6.3% vs 8.5% with 1 surgical mortality in CSC arm. 204 CSC pts started adjuvant S-1, 170 (83.3%) completed 8 cycles; SC arm: 187 started, with completion of 8 cycles in 157 (84.0%). Main ≥grade3 toxicities: neutropenia (6.4% CSC, 5.4% SC), diarrhea (2.9% CSC, 3.2% SC). With median follow up of 37.4 months and 37.8% of PFS events, 3-year PFS rate (FAS) was 66.3% for CSC, 60.2% for SC; hazard ratio (HR) 0.70 (95% CI 0.52–0.95), stratified log-rank p = 0.023. Sensitivity analyses (intent to treat set and landmark analysis) confirmed these results.

Conclusions

Addition of NA DOS to D2 gastrectomy and adjuvant S-1 led to significant tumour downstaging and improved PFS with acceptable safety in PRODIGY study. Neoadjuvant DOS chemotherapy followed by D2 gastrectomy and adjuvant S-1 should be considered as a treatment option for resectable advanced GC.

Clinical trial identification

NCT01515748.

Editorial acknowledgement

Legal entity responsible for the study

Sanofi Korea.

Funding

Sanofi Korea.

Disclosure

Y. Kang: Advisory / Consultancy: Ono; Advisory / Consultancy: BMS; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Merck Serono; Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Daehwa; Advisory / Consultancy: LSKBiopharma; Advisory / Consultancy: Taiho; Advisory / Consultancy: Blueprint; Advisory / Consultancy: Macrogenics; Advisory / Consultancy: Zymeworks; Advisory / Consultancy: Hengrui. G. Kim: Shareholder / Stockholder / Stock options, Full / Part-time employment: Sanofi. Y. Lee: Shareholder / Stockholder / Stock options, Full / Part-time employment: Sanofi. All other authors have declared no conflicts of interest.