PRODIGY: A Phase III Study of Neoadjuvant Docetaxel, Oxaliplatin, and S-1 Plus Surgery and Adjuvant S-1 Versus Surgery and Adjuvant S-1 for Resectable Advanced Gastric Cancer

Abstract

Purpose: Adjuvant chemotherapy after D2 gastrectomy is standard for resectable locally advanced gastric cancer (LAGC) in Asia. Based on positive findings for perioperative chemotherapy in European phase III studies, the phase III PRODIGY study (ClinicalTrials.gov identifier: NCT01515748) investigated whether neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) followed by surgery and adjuvant S-1 could improve outcomes versus standard treatment in Korean patients with resectable LAGC.

Patients and methods: Patients 20-75 years of age, with Eastern Cooperative Oncology Group performance status 0-1, and with histologically confirmed primary gastric or gastroesophageal junction adenocarcinoma (clinical TNM staging: T2-3N+ or T4Nany) were randomly assigned to D2 surgery followed by adjuvant S-1 (40-60 mg orally twice a day, days 1-28 every 6 weeks for eight cycles; SC group) or neoadjuvant DOS (docetaxel 50 mg/m2, oxaliplatin 100 mg/m2 intravenously day 1, S-1 40 mg/m2 orally twice a day, days 1-14 every 3 weeks for three cycles) before D2 surgery, followed by adjuvant S-1 (CSC group). The primary objective was progression-free survival (PFS) with CSC versus SC. Two sensitivity analyses were performed: intent-to-treat and landmark PFS analysis.

Results: Between January 18, 2012, and January 2, 2017, 266 patients were randomly assigned to CSC and 264 to SC at 18 Korean study sites; 238 and 246 patients, respectively, were treated (full analysis set). Follow-up was ongoing in 176 patients at data cutoff (January 21, 2019; median follow-up 38.6 months [interquartile range, 23.5-62.1]). CSC improved PFS versus SC (adjusted hazard ratio, 0.70; 95% CI, 0.52 to 0.95; stratified log-rank P = .023). Sensitivity analyses confirmed these findings. Treatments were well tolerated. Two grade 5 adverse events (febrile neutropenia and dyspnea) occurred during neoadjuvant treatment.

Conclusion: PRODIGY showed that neoadjuvant DOS chemotherapy, as part of perioperative chemotherapy, is effective and tolerable in Korean patients with LAGC.

Conflict of interest statement

Yoon-Koo KangConsulting or Advisory Role: DAEHWA Pharmaceutical, Bristol-Myers Squibb, Zymeworks, ALX Oncology, Amgen, Novartis, MacroGenics, Surface Oncology Min-Hee RyuHonoraria: DAEHWA Pharmaceutical, Bristol-Myers Squibb, Lilly, Ono Pharmaceutical, MSD, Taiho Pharmaceutical, Novartis, Daiichi Sankyo, AstraZenecaConsulting or Advisory Role: DAEHWA Pharmaceutical, Bristol-Myers Squibb, Lilly, Ono Pharmaceutical, MSD, Taiho Pharmaceutical, Novartis, Daiichi Sankyo, AstraZeneca Sun Young RhaConsulting or Advisory Role: MSD Oncology, Ipsen, Daiichi Sankyo, Eisai, Amgen, IndivumedSpeakers' Bureau: Lilly, EisaiResearch Funding: MSD Oncology, Bristol-Myers Squibb, Eisai, Roche/Genentech, MedPacto, ASLAN Pharmaceuticals, SillaJen, Bayer, Immunomet Gyunji KimEmployment: Sanofi, NovartisStock and Other Ownership Interests: Sanofi YeonJu LeeEmployment: SanofiStock and Other Ownership Interests: Sanofi Jee Hyun LeeEmployment: SanofiNo other potential conflicts of interest were reported.

Figures

FIG 1.

CONSORT diagram showing the study disposition. CSC, neoadjuvant chemotherapy plus surgery plus adjuvant chemotherapy; FAS, full analysis set; ITT, intent-to-treat; SC, surgery plus adjuvant chemotherapy.

FIG 2.

Kaplan-Meier survival estimates in the full analysis set: (A) progression-free survival and (B) preliminary overall survival. CSC, neoadjuvant chemotherapy plus surgery plus adjuvant chemotherapy; HR, hazard ratio; SC, surgery plus adjuvant chemotherapy.

FIG 3.

Progression-free survival analyses for subgroups in the full analysis set. CSC, neoadjuvant chemotherapy plus surgery plus adjuvant chemotherapy; GEJ, gastroesophageal junction; HR, hazard ratio; SC, surgery plus adjuvant chemotherapy.

FIG A1.

Design of the PRODIGY study. aAbdominopelvic CT every 6 months and esophagogastroduodenoscopy every 1 year after surgery. AJCC, American Joint Committee on Cancer; CSC, neoadjuvant chemotherapy plus surgery plus adjuvant chemotherapy; CT, computed tomography; DOS, docetaxel, oxaliplatin, and S-1; ECOG PS, Eastern Cooperative Oncology Group performance status; FAS, full analysis set; GEJ, gastroesophageal junction; LN, lymph node; OS, overall survival; PFS, progression-free survival; R, random assignment; SC, surgery plus adjuvant chemotherapy.

FIG A2.

Sensitivity analyses of progression-free survival (A) for the ITT population and (B) at the 6-month landmark analysis. CSC, neoadjuvant chemotherapy plus surgery plus adjuvant chemotherapy; HR, hazard ratio; ITT, intent-to-treat; SC, surgery plus adjuvant chemotherapy.

FIG A3.

Subgroup analyses for overall survival in the full analysis set. CSC, neoadjuvant chemotherapy plus surgery plus adjuvant chemotherapy; GEJ, gastroesophageal junction; HR, hazard ratio; SC, surgery plus adjuvant chemotherapy.