Long-term survival and biomarker analysis of neoadjuvant chemoradiotherapy with or without PD-1 antibody sintilimab in pMMR locally advanced rectal cancer: A randomized clinical trial.

3610 Background: We previously reported that adding sintilimab to neoadjuvant chemoradiotherapy (NACRT) significantly improved the complete response (CR) rate compared to NACRT in mismatch repair-proficient (pMMR) locally advanced rectal cancer (LARC) patients (44.8% vs. 26.9%; P = 0.031). Here, we present the long-term survival outcomes and exploratory biomarker analyses from this randomized trial. Methods: Between June 2020 and July 2022, a total of 134 patients with pMMR LARC were randomly assigned (1:1) to the experimental arm (NACRT plus sintilimab, n = 67) or the control arm (NACRT, n = 67). The primary endpoint was CR rate. Secondary endpoints included disease-free survival (DFS) and overall survival (OS). Survival analysis was estimated using the Kaplan-Meier method and compared using the log-rank test. Hazard ratios (HR) were calculated using the Cox proportional hazards model. Baseline tumor and blood samples were collected for whole exome sequencing. Results: With a median follow-up of 48.5 months, the experimental arm exhibited significantly superior 3-year DFS compared to the control arm (91.0% vs. 77.6%; HR = 0.37, 95% CI: 0.14-0.94, log-rank P = 0.030). Analysis of failure patterns showed lower rates of both local recurrence (1.5% [1/67] vs 3.0% [2/67] and distant metastases (9.0% [6/67] vs. 19.4%[13/67]) in the experimental arm. Notably, liver metastases were more frequent in the control arm (1.5% [1/67] vs. 9.0% [6/67]). Subgroup analyses identified a pronounced DFS benefit from combination therapy in patients aged > 50 years (HR = 0.24, 95% CI: 0.07-0.86, P = 0.029) and those with extramural venous invasion (EMVI)-positive tumors (HR = 0.26, 95% CI: 0.09-0.81, P = 0.020). Notably, achieving a CR was consistently associated with a trend toward prolonged DFS in both the experimental (log-rank P = 0.129) and control arms (log-rank P = 0.145). In exploratory biomarker analysis, patients harboring MUC16 mutations in the experimental arm exhibited a trend toward improved DFS, although statistical significance was not reached (log-rank P = 0.318); conversely, no such trend was observed in the wild-type population (log-rank P = 0.496). The 3-year OS rates were 97.0% in both groups (log-rank P = 0.977). Conclusions: Adding PD-1 antibody to NACRT conferred a superior DFS benefit compared to NACRT in patients with pMMR LARC, particularly in older patients and those with EMVI-positive tumors, and potentially influenced the pattern of metastasis. MUC16 mutations warrant further investigation as a potential predictive biomarker for sensitivity to the combination therapy. Clinical trial information: NCT04304209 .