Radiotherapy followed by CAPOX and tislelizumab in MSS locally advanced rectal cancer with resectable metastases: Results of the MIRACLE-1 study.

e15524 Background: MSS tumors account for 95% of metastatic colorectal cancer and are characterized by a low response rate to immunotherapy. Emerging evidence showed that radiotherapy combined with chemotherapy and PD-1 inhibitors led to promising tumor responses in patients (pts) with locally advanced rectal cancer (LARC). MIRACLE-1 aims to investigate the safety and efficacy of such approach as upfront treatment of MSS LARC with resectable metastases. Methods: MIRALCE-1 was a prospective, single arm, phase 2 study. The main inclusion criteria include MSS LARC with a distance of ≤10 cm from the anus by MRI evaluation and a limited number of metastases in the liver and/or lungs that were eligible for curable resection. Eligible patients were treated with upfront radiotherapy including hypofractionated radiotherapy (HFRT) for primary lesions and HFRT or stereotactic body radiotherapy (SBRT) for metastatic lesions. Afterwards, six cycles of systemic therapy consisted of CAPOX and Tislelizumab were administered. Then, reassessment was performed within 4 weeks afterwards by radiological and serological evaluations. Surgical resection, local ablative therapies or active surveillance was applied based on tumor response. For patients attained no-evidence of disease (NED), Tislelizumab was maintained until one year after surgery. Otherwise, the subsequent treatment was determined by the investigators. The primary endpoint is the 1-year NED rate. The secondary endpoints include objective response rate (ORR), overall survival (OS), progression-free survival (PFS) and toxicities. Results: From March 2023 to November 2024, 38 pts were enrolled and 20 were evaluable. At baseline, 60.0% of pts were male, median age was 57 years (range 34-71), 55.0% had liver metastases (mets), 15.0% had lung mets, and 30.0% had both liver and lung mets. 80.0% primary tumors had RAS/BRAF mutations. Upon reassessment, 18 (90.0%) pts had partial response (PR) and 2 (10.0%) had stable disease (SD). No patients showed progressive disease (PD). The ORR was 90.0%. 65% (13/20) pts attained NED. Median PFS and OS have not yet reached. No grade 5 adverse events occurred. The most common treatment-related adverse events (TRAEs) in all grades were fatigue (85.0%), thrombocytopenia (65.0%), leukopenia (50.0%) and anemia (40.0%). The most frequent grade 3/4 TRAEs were thrombocytopenia (30.0%) and neutropenia (20.0%). Conclusions: Combination treatment of upfront radiotherapy, immunochemotherapy demonstrated a promising efficacy and a manageable safety profile in MSS LARC with resectable metastases. Translational study to identify predictive biomarkers is ongoing. Clinical trial information: NCT05359393 .