Safety and efficacy evaluation of neoadjuvant chemotherapy without radiotherapy combined with sintilimab for locally advanced rectal cancer: Short-term results of a single-arm phase 2 trial.

e15657 Background: Sequential total mesorectal excision (TME) and adjuvant chemotherapy following neoadjuvant chemoradiotherapy (nCRT) are currently the standard treatment strategies for locally advanced rectal cancer (LARC). However, this regimen has not significantly improved long-term survival or reduced distant metastasis rates, and radiation therapy may induce radiotherapy-related toxicities, increasing surgical complexity and complications. Tumor immunotherapy, particularly with PD-1 monoclonal antibodies, has demonstrated promising efficacy in advanced colorectal cancer. For LARC, neoadjuvant chemotherapy without radiotherapy, combined with sintilimab followed by TME, may offer better downstaging and reduce the risk of distant recurrence. Methods: This study evaluated the feasibility, efficacy, and safety of sintilimab combined with chemotherapy, without radiotherapy, as a neoadjuvant treatment for locally advanced rectal cancer (LARC). Patients with stage II (cT3-4N0M0 or cT1-3N1-3M0) or stage III (cT3-4aN1-3M0) LARC from three clinical centers in China were enrolled. Patients received sintilimab (200 mg, intravenous infusion, Day 1, every 3 weeks) combined with the XELOX chemotherapy regimen (capecitabine: 1000 mg/m², oral, twice daily, Days 1-14, every 3 weeks; oxaliplatin: 130 mg/m², intravenous infusion, Day 1, every 3 weeks) for three cycles. Imaging was conducted 3-4 weeks after the last treatment to evaluate the treatment response and plan for TME surgery. The primary endpoint was the pathological complete response (pCR) rate. Secondary endpoints included the major pathological response (MPR) rate, R0 resection rate, objective response rate (ORR), and disease control rate (DCR). Results: From May 2023 to January 2025, a total of 29 patients (all non-MSI-H/pMMR LARC) were enrolled. As of January 20, 2025, all 29 patients underwent curative surgery, achieving an R0 resection rate of 100%. The pCR rate was 24% (7/29), and the MPR rate was 48% (14/29). The ORR and DCR were 82.8% and 100%, respectively. During treatment, five immune-related adverse events occurred, with an incidence rate of 17.2% (5/29), including three cases of liver function abnormalities (Grade 1) and one case of immune-mediated colitis (Grade 3). Two patients experienced anastomotic leakage (6.9%), and one patient developed postoperative intestinal obstruction (3.4%). No treatment-related deaths were reported. Conclusions: Sintilimab combined with chemotherapy, without radiotherapy, followed by TME surgery for the treatment of LARC, demonstrated promising efficacy and safety. These results offer a potential new strategy for the neoadjuvant treatment of LARC, reducing complications associated with radiotherapy.