Perioperative Oxaliplatin With S-1 Demonstrates Significant Clinical Activity in Locally Advanced Gastric Cancer

For patients with locally advanced gastric cancer who have undergone D2 gastrectomy, perioperative S-1 and oxaliplatin (SOX) demonstrated meaningful clinically benefit when compared with adjuvant capecitabine and oxaliplatin (CapOx), according to data from the randomized phase 3 RESOLVE trial (NCT01534546) published in Lancet Oncology.

Investigators reported an estimated 3-year disease-free survival (DFS) of 51.1% in the modified intention-to-treat population (mITT; 95% CI, 45.5%-56.3%) for patients in the adjuvant-CapOx group, 56.5% (95% CI, 51.0%-61.7%) for patients in the adjuvant-SOX group, and 59.4% (95% CI, 53.8%-64.6%) for patients in the perioperative-SOX group. Additionally, investigators reported a hazard ratio (HR) of 0.77 when comparing perioperative SOX with adjuvant CapOX (95% CI,0.61-0.97; Wald P = .028) and 0.86 when comparing adjuvant SOX with adjuvant CapOX (95% CI, 0.68-1.07; Wald P = .17).

“In our superiority analysis, patients in the perioperative-SOX group had significantly longer 3-year [DFS] and a similarly lower number of complications compared with the adjuvant-CapOx group,” the investigators wrote. “In the non-inferiority analysis, [DFS] and adverse [effects (AEs)] were similar between the adjuvant-SOX group and the adjuvant-CapOx group, and the HR was within the prespecified margin.”

The study randomized 1094 patients to 3 treatment groups between August 15, 2012, to February 28, 2017, 1022 of whom were included in the mITT population (adjuvant-CapOx, n = 345; adjuvant-SOX, n = 340; and perioperative-SOX, n = 337). In total, 8%, 8%, and 23% of patients in the adjuvant-CapOx, adjuvant-SOX, and perioperative-SOX groups were excluded due to protocol violations, respectively. The median follow-up was 40.6 months (IQR, 18.2-53.1).

In the adjuvant-CapOx group, patients received adjuvant chemotherapy 4 to 8 weeks post-surgery for 8 21-day treatment cycles. Patients received a 2-hour intravenous infusion of 130 mg/m2 oxaliplatin on day 1 plus 1000 mg/m2 oral capecitabine twice a day for 2 weeks, followed by one week of rest during each cycle. In the adjuvant-SOX group, patients received the same adjuvant chemotherapy and oxaliplatin backbone, plus oral S-1 twice daily at a dose of 40 to 60 mg. In the perioperative-SOX group, patients received S-1 at a dose of 40 to 60 mg twice daily for 3 cycles preoperatively and 5 cycles postoperatively; this was followed by 3 cycles of single agent S-1.

Eligibility criteria required patients have histologically confirmed cT4a N+ M0 or cT4b Nany M0 gastric or gastroesophageal junction adenocarcinoma with measurable or evaluable lesions according to RECIST 1.0 criteria.

Findings from the post-hoc analysis highlighted an objective response rate (ORR) of 41.0% (95% CI, 32.1%-49.9%) among those treated with perioperative SOX. Moreover, evaluable patients within this group (n = 117) had a complete response rate of 1.7%, a partial response rate of 39%, and a stable disease stable disease rate of 54%.

Any grade AEs were reported in 62% of patients in the adjuvant-CapOx group, 50% of patients in the adjuvant-SOX group, and 68% of patients in the perioperative-SOX group. Grade 3 or higher AEs were reported in 17%, 19%, and 21% of patients from each of the cohorts, respectively. Neutropenia was the most common grade 3 or higher AE, which was observed in 12%, 8%, and 10% of patients, respectively.

Serious AEs were reported in 3% of patients in the adjuvant-CapOx group, 3% of patients in the adjuvant-SOX group, and 2% of patients in the perioperative-SOX group. Common serious AEs included hypoalbuminemia and neutropenia in the adjuvant-CapOx group; nausea, thrombocytopenia, and neutropenia in the perioperative-SOX group; and neutropenia and intestinal obstruction in the adjuvant-SOX group.

“Perioperative SOX should be considered a standard procedure for the management of [patients with] locally advanced gastric. In our non-inferiority analysis, adjuvant SOX was non-inferior to adjuvant CapOx,” the investigators concluded.

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): an open-label, superiority and non-inferiority, phase 3 randomised controlled trial. Lancet Oncol. 2021;22(8):1081-1092. doi:10.1016/S1470-2045(21)00297-7