S-1 and Oxaliplatin Show Long-Term Benefit Over CapOx in Gastric Cancer

Perioperative and adjuvant S-1 and oxaliplatin demonstrated consistent OS and DFS benefits over adjuvant capecitabine and oxaliplatin.

An extended 5-year analysis showed that overall survival (OS) continued to improve in patients with locally advanced gastric or gastroesophageal junction (GEJ) cancer who received perioperative and postoperative S-1 and oxaliplatin (SOX) compared with standard-of-care adjuvant capecitabine (Xeloda) and oxaliplatin (CapOx), according to the final report of the randomized, open-label phase 3 RESOLVE trial (NCT01534546) published in Lancet Oncology.

At the data cutoff of April 7, 2022, with a median duration of follow-up of 62.8 months (IQR, 52.0-75.1), the 5-year OS rate was 61.0% (95% CI, 55.3%-66.2%) in the adjuvant SOX group, 60.0% (95% CI, 54.2%-65.3%) in the perioperative SOX group, and 52.1% (95% CI, 46.3%-57.5%) in the adjuvant CapOx group. At data cutoff, 37.4% of the adjuvant SOX group, 38.6% of the perioperative SOX group, and 46.1% of the adjuvant CapOx group died.

Perioperative SOX improved OS compared with adjuvant CapOx (HR, 0.79; 95% CI, 0.62-1.00; Wald test P = .049); adjuvant SOX also prolonged OS vs adjuvant CapOx (HR, 0.77; 95% CI, 0.61-0.98; Wald test P = .033).

Additionally, a post hoc analysis demonstrated 5-year disease-free survival (DFS) rates of 50.8% (95% CI, 45.2%-56.2%) with adjuvant SOX, 53.2% (95% CI, 47.4%-58.6%) with perioperative SOX, and 45.8% (95% CI, 40.2%-51.2%) with adjuvant CapOx. At 5 years, DFS events occurred in 47.1% of the adjuvant SOX group, 44.8% of the perioperative SOX group, and 53.3% of the adjuvant CapOx group.

Significantly longer DFS was demonstrated with perioperative SOX vs adjuvant CapOx (HR, 0.79; 95% CI, 0.63-0.98; Wald test P = .034); adjuvant SOX was non-inferior to adjuvant CapOx, though superiority could not be established (HR, 0.86; 95% CI, 0.69-1.06; P = .16).

“This updated analysis of the RESOLVE trial shows that perioperative SOX and adjuvant SOX have [OS] benefits over adjuvant CapOx,” Jiafu Ji, MD, FACS, professor of gastrointestinal surgery at Peking University, president of Peking University Cancer Center Hospital and Institute, director of the Key Laboratory in “Malignancy Pathogenesis and Translational Research” in the Ministry of Education of the People’s Republic of China, and senior study author, wrote in the study with coauthors. “This updated analysis reinforces the trial’s initial findings and the [OS] benefit of perioperative chemotherapy in gastric and [GEJ] adenocarcinoma.”

A total of 1094 patients were enrolled in the RESOLVE trial and randomly assigned, in a 1:1:1 ratio, to receive either perioperative SOX (n = 337), adjuvant SOX (n = 340), and adjuvant CapOx (n = 345).

In the adjuvant CapOx group, chemotherapy began 4 to 8 weeks after D2 gastrectomy surgery and included 130 mg/m² of oxaliplatin over 2 hours on day 1 and 1000 mg/m² of capecitabine twice daily on days 1 to 14 for eight 21-day cycles. Adjuvant SOX substituted capecitabine for S-1 (40 mg twice daily for a body surface area [BSA] of less than 1.25 m², 50 mg for a BSA of 1.25 to 1.50 m², or 60 mg for a BSA of more than 1.50 m²) on days 1 to 14; and perioperative SOX was the same as the adjuvant SOX group, only given in 3 cycles at 3 to 6 weeks before surgery and then for 5 cycles beginning 4 to 8 weeks after surgery followed by 3 cycles of S-1 monotherapy.

Eligible patients were treatment-naïve and had histologically confirmed cT4a N+ M0 or cT4b Nany M0 gastric or GEJ adenocarcinoma that was D2 lymphadenectomy–feasible. Patients also had measurable or evaluable lesions per RECIST v1.0 criteria, a Karnofsky performance score of 70 or higher, and an age of 18 years or more.

The RESOLVE trial’s primary end point was 3-year DFS. Secondary end points included 5-year OS, R0 resection rate, and safety.

In female patients, those with gastric cancer, and those in non-intestinal disease subgroups, the perioperative SOX regimen prolonged OS; in patients younger than 65 years, those with non-intestinal disease, and in N+ and T4a disease subgroups, the adjuvant SOX regimen improved OS vs adjuvant CapOx.

Regarding DFS, for women, those with non-intestinal disease, and those in N+ disease subgroups, the perioperative SOX regimen reduced the risk of DFS events vs adjuvant CapOx; in all subgroups, DFS was similar between adjuvant SOX and adjuvant CapOx.

Reference

Zhang X, Liang H, Li Z, et al. Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): final report of a randomised, open-label, phase 3 trial. Lancet Oncol. Published online February 11, 2025. doi:10.1016/S1470-2045(24)00676-4