Approximately 20-50% of patients with colorectal cancer (CRC) develop distant metastasis after curative surgery, and those with early relapse within one year of completing adjuvant chemotherapy (XELOX or FOLFOX) have a particularly poor prognosis and limited treatment options. Standard second-line therapy with FOLFIRI plus targeted therapy (bevacizumab or cetuximab) often yields suboptimal outcomes in this population. Moreover, over 95% of these patients have pMMR/MSS tumors, which are inherently resistant to immune checkpoint inhibitor monotherapy.
This phase II, prospective, randomized trial aims to evaluate the efficacy and safety of adding serplulimab, a PD-1 inhibitor, to second-line chemotherapy plus targeted therapy in patients with early-relapse CRC after adjuvant chemotherapy. Eligible patients with pMMR/MSS or MSI-L tumors will be randomly assigned (1:1) to either the experimental arm (serplulimab plus FOLFIRI and targeted therapy) or the control arm (FOLFIRI plus targeted therapy alone). Randomization is stratified by primary tumor location (left vs. right colon), initial disease status (liver-only vs. extrahepatic metastasis), and RAS status (wild-type vs. mutant). A total of 40 patients (20 per arm) will be enrolled using a Pick-the-Winner design.
The primary endpoint is progression-free survival (PFS). Secondary endpoints include objective response rate (ORR), overall survival (OS), R0 resection rate, and safety (NCI-CTCAE v5.0). Exploratory biomarker analyses in tumor tissue and blood (e.g., PD-L1 expression, tumor mutational burden, lymphocyte subsets, cytokines, TCR sequencing, circulating tumor DNA, and gut microbiome) will be performed to identify potential predictors of response and resistance.
This is the first prospective randomized study specifically targeting early-relapse CRC after adjuvant chemotherapy. The findings will provide high-level evidence on whether adding PD-1 blockade to standard chemo-targeted therapy can improve outcomes in this high-risk, understudied population and may inform future phase III trials.
Neutrophils ≥1.5 × 10⁹/L; platelets ≥100 × 10⁹/L; hemoglobin ≥9 g/dL; serum albumin ≥3 g/dL.
Thyroid-stimulating hormone (TSH) ≤ upper limit of normal (ULN), with T3 and T4 within normal range.
Bilirubin ≤1.5 × ULN; ALT and AST ≤2 × ULN.
Serum creatinine ≤1.5 × ULN, creatinine clearance ≥60 mL/min.
None
Parallel
Serplulimab
DrugSerplulimab: 3 mg/kg intravenously on Day 1, repeated every 2 weeks
Second-Line Chemo/Targeted Therapy
DrugLeft-sided, RAS wild-type Treatment Regimen: Cetuximab 400 mg/m², intravenous infusion, first infusion over \>2 hours, then 250 mg/m² intravenous infusion over ≥60 minutes, repeated weekly; FOLFIRI: Irinotecan 180 mg/m², intravenous infusion over 90 minutes, Day 1; Leucovorin (LV) 400 mg/m², intravenous infusion over 2 hours, Day 1; 5-FU 400 mg/m², intravenous bolus, Day 1; followed by 2400 mg/m² infusion over 46-48 hours; Repeated every 2 weeks Right-sided, RAS mutant Treatment Regimen: Bevacizumab 5 mg/kg, intravenous infusion, Day 1, repeated every 2 weeks FOLFIRI: Irinotecan 180 mg/m², intravenous infusion over 90 minutes, Day 1; Leucovorin (LV) 400 mg/m², intravenous infusion over 2 hours, Day 1; 5-FU 400 mg/m², intravenous bolus, Day 1; followed by 2400 mg/m² infusion over 46-48 hours; Repeated every 2 weeks
Progression-free survival (PFS)
Progression-free survival (PFS) is defined as the time from randomization to the first documented tumor progression or death from any cause.
Objective response rate (ORR = CR + PR)
Objective response rate (ORR = CR + PR): The proportion of patients whose best overall response is complete response or partial response.
Disease control rate (DCR = CR + PR + SD)
Disease control rate (DCR = CR + PR + SD): The proportion of patients whose best overall response is complete response, partial response, or stable disease.
R0 resection rate
R0 resection rate: The proportion of tumors in which pathological examination confirms no residual cancer cells at the surgical margin (resection margin) after surgery.
Overall survival (OS)
Overall survival (OS): The time from randomization to death from any cause.
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