Short-course radiotherapy followed by CAPOX combined with tislelizumab and bevacizumab or cetuximab for treatment-naive unresectable metastatic rectal cancer (UNION mRC).

e15553 Background: Doublet chemotherapy regimens based on oxaliplatin or irinotecan, combined with targeted agents such as bevacizumab or cetuximab, represent the standard first-line treatment for metastatic rectal cancer (mRC). Immunotherapy is primarily beneficial for a small subset of patients with deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) mRC. For patients with proficient mismatch repair (pMMR) or microsatellite-stable (MSS) mRC, optimal combination therapies are urgently needed to improve treatment efficacy and survival outcomes. The UNION Phase III trial (NCT04928807) demonstrated a high response rate with the UNION treatment strategy in locally advanced rectal cancer. This study evaluates the efficacy and safety of short-course radiotherapy followed by CAPOX combined with tislelizumab and bevacizumab or cetuximab in treatment-naive, unresectable pMMR/MSS mRC patients. Methods: All treatment-naive patients with unresectable pMMR/MSS mRC patients received short-course radiotherapy (a total of 25 Gy in 5 days) followed by CAPOX in combination with tislelizumab and either bevacizuma or cetuximab. Efficacy was assessed by overall response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Safety and clinical variables were also evaluated. Results: By December 2024, of the 21 patients enrolled, 17 patients were evaluable for efficacy. The median age was 57 years (range: 37-74), with 76.5% male.. The complete response (CR) rate was 5.9% (n = 1), the partial response (PR) rate was 76.5% (n = 13), and the stable disease (SD) rate was 17.6% (n = 3). The ORR was 82.4% (n = 14), and the DCR was 100% (n = 17). The 6-month PFS rate was 80% (95% confidence interval [CI]: 62.1–99.7%) and overall survival was immature. Subgroup analyses revealed an ORR of 100% (n = 4) in KNB wild-type patients, 76.9% (n = 10) in RAS or BRAF mutant patients, 90.9% (n = 10) in patients with liver metastases, and 66.7% (n = 4) in patients without liver metastases. Grade ≥3 bone marrow suppression was observed in 5.9% (n = 1) of patients, and grade ≥3 immune-related adverse events occurred in 17.6% (n = 3). Toxicity was manageable. Conclusions: Short-course radiotherapy followed by CAPOX combined with tislelizumab and bevacizumab or cetuximab showed encouraging efficacy and acceptable safety as first-line therapy for unresectable pMMR/MSS mRC. These results support further studies to confirm the benefits of this treatment strategy.