Phase II study of adjuvant nab-paclitaxel plus S-1 after D2 resection in stage III diffuse gastric cancer (NORDICA study).

Abstract

4085 Background: Stage III diffuse-type gastric cancer (DGC) is highly aggressive, with a substantial risk of postoperative recurrence. Adjuvant chemotherapy with nab-paclitaxel plus S-1 (AS regimen) has shown potential efficacy in early studies, but its safety and effectiveness in this high-risk population remain unclear. Methods: This single-center, prospective phase II trial enrolled patients with stage III DGC who underwent D2 gastrectomy between January 2020 and October 2023. All patients first received one cycle of S-1 monotherapy as a pre-screening tolerance test. Eligible patients then received adjuvant AS therapy: nab-paclitaxel 260 mg/m² on day 1 every 3 weeks (maximum 400 mg) plus S-1 80–120 mg/day on days 1–14 every 3 weeks for 6 cycles, followed by 8 cycles of S-1 monotherapy. The primary endpoint was 1-year disease-free survival (DFS); secondary endpoints included 3-year DFS, overall survival (OS), and safety. To explore potential molecular correlates of treatment response, whole-exome sequencing was performed on tumor specimens obtained from surgical resection in 24 patients, including 12 patients who experienced recurrence within 2 years (resistant group) and 12 patients with DFS of 2 years or longer (sensitive group). Results: The 1-year DFS and OS rates were 84.9% (95% CI, 75.3–95.9%) and 100%, respectively. The 3-year DFS and OS rates were 45.2% (95% CI, 32.5–63.0%) and 62.5% (95% CI, 49.0–79.8%), with a median DFS of 27.7 months (95% CI, 16.5–NR). The most common ≥grade 3 treatment-related adverse events were neutropenia (29.2%), leukopenia (20.8%), rash (6.3%), febrile neutropenia (6.3%), and oral mucositis (4.2%). CDH1 and OBSCN mutations were more frequent in the resistant group, suggesting a potential link to early recurrence. Conclusions: Adjuvant AS therapy is feasible and demonstrates promising efficacy for stage III DGC, with an acceptable safety profile. Molecular findings may help identify patients at higher risk of recurrence, supporting further evaluation in larger, randomized phase III trials. Clinical trial information: NCT03977220 .