A Phase II Randomized Trial of Serplulimab With Second-Line Chemo/Targeted Therapy for Early Relapse Colorectal Cancer After Adjuvant Chemotherapy

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.