Radiotherapy followed by systemic therapy and tislelizumab in microsatellite-stable rectal cancer with synchronous unresectable metastases: Updated results of the MIRACLE-2 study.

Abstract

3578 Background: Microsatellite-stable (MSS) tumors comprise ~95% of metastatic colorectal cancer cases and exhibit intrinsic resistance to immunotherapy. Emerging evidence suggests systemic therapy may enhance immunotherapy responsiveness, while radiotherapy could improve efficacy by overcoming resistance and reducing tumor burden. The MIRACLE-2 study evaluated the safety and efficacy of combining radiotherapy with systemic therapy and tislelizumab as first-line treatment for unresectable metastatic MSS rectal cancer (RC). Methods: MIRACLE-2 was a prospective, single-arm, phase II study. Inclusion criteria: MSS RC with primary tumor ≤10 cm from anal verge on MRI and synchronous unresectable metastases. Patients received hypofractionated radiotherapy (HFRT) for primary lesions and HFRT or SBRT for metastases, followed by systemic therapy: FOLFOX-bevacizumab-tislelizumab for RAS/BRAF-mutant patients or FOLFIRI-cetuximab-tislelizumab for wild-type patients. Reassessment every 8 weeks. Patients achieving resectable disease underwent 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. Otherwise, systemic therapy continued until progression/intolerable toxicity. Primary endpoint: ETS rate (≥20% target lesion reduction at 8 weeks post systemic therapy initiation). Secondary endpoints: disease control rate (DCR), duration of response (DOR), overall survival (OS), progression-free survival (PFS), and safety. Results: As of December 31, 2025, efficacy data were available for 50 patients (38 males, 76.0%; median age 57 years, range 30-73). Among these, 52.0% had liver metastases, 8.0% lung metastases, and 40.0% both liver and lung metastases. RAS/BRAF mutations were detected in 56.0% of primary tumors. Median treatment courses: eight (range 3-12). Overall, 18% (9/50) attained no evidence of disease (NED). ETS rate: 76.0%; DCR: 88.0%. Median follow-up: 19.9 months (95% CI: 16.4-23.4). Among 34 patients with complete/partial response, median DOR: 8.0 months (95% CI: 5.2–10.8), with 1-year DOR rate of 20%. Median PFS: 9.3 months (95% CI: 7.1-11.5), with 1-year PFS rate of 33.4%. Median OS: 23.2 months (95% CI: 15.1-31.3), and 1-year OS rate: 93.3%. No grade 5 treatment-related adverse events (TRAEs) occurred. All-grade TRAEs: lymphopenia (95.9%), anemia (91.8%), and leukopenia (69.4%). Grade 3/4 TRAEs: lymphopenia (36.7%), neutropenia (26.5%), and leukopenia (20.4%). Conclusions: The combination of radiotherapy, systemic therapy, and tislelizumab showed a high ETS rate and manageable safety profile in first-line unresectable MSS RC. Long-term outcomes require further follow-up. Clinical trial information: NCT05359406 .