MIRACLE1: Phase II study of radiotherapy followed by CapeOx and tirelizumab as first-line treatment in MSS rectal cancer with synchronous resectable liver/lung metastases.

TPS3631 Background: Rectal cancer (RC) with synchronous resectable liver/lung metastases is commonly treated with surgery combined with systemic chemotherapy or local therapies. Prognosis remains poor. Microsatellite stable (MSS) are characterized by an immunosuppressive microenvironment and a low response rate to immunotherapy. Chemotherapy and Radiotherapy have been reported to potentially promote immunotherapy response. MIRACLE1 will investigate the safety and efficacy of Short-course radiotherapy (SCRT) combined with CapeOx and tirelizumab in MSS metastatic RC. Methods: We designed a single-arm, multicenter, phase II trial in MSS RC. MSS status is determined by normal immunohistochemical nuclear expression of all the mismatch repair genes MSH2, MSH6, MLH1 and PMS2. Additional inclusion criteria include RC with a distance of ≤ 10 cm from the anus by MRI evaluation and single or multiple measurable metastases in the liver and/or lungs (RECIST version 1.1) evaluated as resectable after MDT discussion. Exclusion criteria include patients with distant metastasis to parts other than the liver and lungs, including the brain, bone, ovary, peritoneum, and multiple retroperitoneal lymph node metastases.Patients are treated with radiotherapy including 25 Gy/5 fractions short-course hypofractionated radiotherapy (HFRT) for primary lesions and HFRT or stereotactic body radiotherapy (SBRT) for metastatic lesions. Afterward, six cycles of chemoimmunotherapy consisting of CapeOX and tislelizumab will be administered. Tislelizumab is administered intravenously (200 mg) along with each cycle of chemotherapy. Efficacy evaluations are conducted after the third and sixth cycles of chemoimmunotherapy and include radiological and serological evaluations. According to the efficacy evaluation results, a watch-and-wait nonoperative approach or surgical resection is performed. After surgery, postoperative treatment is to be determined by the investigators. Tislelizumab is to be maintained until one year after surgery. The primary endpoint of this study is the 1-year no-evidence of disease (NED) rate. The secondary endpoints include objective response rate (ORR), overall survival (OS), progression-free survival (PFS) and acute toxicity related to immunotherapy. 52 patients will be enrolled to ensure 47 evaluable. The design has 80% power to detected improvement in NED rate from 60 to 77% with significance level of 0.05. The first patient was recruited on 27th March 2023. To date, 15 patients have been enrolled. Full accrual is anticipated by late 2024. Correlative studies include genomic characterization of baseline tumors, assessment of immune infiltration of tumor microenvironment and serial circulating cell-free DNA and immune biomarkers. Clinical trial information: NCT05359393 .