Radiotherapy followed by CAPOX plus tislelizumab in microsatellite-stable rectal cancer with synchronous resectable metastases: Updated results of the MIRACLE-1 study.

Abstract

e15555 Background: Microsatellite-stable (MSS) tumors comprise ~95% of metastatic colorectal cancer cases and show low response to immunotherapy. Emerging evidence suggests combining radiotherapy with chemotherapy and PD-1 inhibitors may yield promising responses in locally advanced rectal cancer (RC). The MIRACLE-1 study evaluated this combination as upfront treatment for MSS RC with synchronous resectable metastases. Methods: MIRACLE-1 was a prospective, single-arm, phase II study. Inclusion criteria included MSS RC with primary tumor ≤10 cm from anal verge on MRI and limited liver/lung metastases deemed resectable. Patients received upfront radiotherapy: hypofractionated radiotherapy (HFRT) for primary lesion and HFRT or stereotactic body radiotherapy (SBRT) for metastases. Subsequently, six cycles of CAPOX plus Tislelizumab were administered. Tumor response was assessed after the third and sixth cycles. Further management included primary tumor resection and metastasectomy/local ablative therapies for metastases. For patients unable to preserve anal sphincter, a watch-and-wait (WW) strategy was considered if clinical complete response (cCR) of primary tumor was achieved. For patients achieving no evidence of disease (NED), adjuvant Tislelizumab was continued for up to 1 year postoperatively. Other patients received investigator-determined subsequent therapy. Primary endpoint: 1-year NED rate. Secondary endpoints: objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and safety. Results: As of December 31, 2025, efficacy data were available for 50 patients (37 males, 74.0%; median age 60 years, range 28-71). Among these, 62.0% had liver metastases, 20.0% lung metastases, and 18.0% both liver and lung metastases. RAS/BRAF mutations were detected in 62.0% of primary tumors. Upon reassessment, 38 patients (76.0%) achieved partial response (PR), 10 (20.0%) stable disease (SD), and 2 (4.0%) progressive disease (PD). ORR was 76.0%. Additionally, 54% (27/50) attained NED. Median follow-up duration was 18.7 months (95% CI: 15.5-21.9). Median PFS was 17 months (95% CI: 8.7-25.3), and 1-year PFS rate was 61.2%. Median OS was not reached, with 1-year OS rate of 83.5%. One treatment-related death occurred due to immunotherapy-induced hepatitis. All-grade treatment-related adverse events (TRAEs): thrombocytopenia (93.8%), lymphopenia (81.3%), and anemia (77.1%). Grade 3/4 TRAEs: thrombocytopenia (39.6%), lymphopenia (14.6%), and neutropenia (12.5%). Conclusions: In MSS RC patients with synchronous resectable metastases, radiotherapy combined with CAPOX plus Tislelizumab demonstrated promising antitumor efficacy and manageable safety profile. While initial findings are encouraging, longer follow-up is needed to assess durable outcomes. Clinical trial information: NCT05359393 .