Background and Rationale Colorectal cancer (CRC) is the third most common malignancy worldwide. Approximately 40-50% of patients develop metastatic disease (mCRC). For patients who progress after first- and second-line systemic therapy (including fluoropyrimidines, oxaliplatin, irinotecan, and anti-VEGF or anti-EGFR antibodies where indicated), third-line treatment options remain limited. Currently approved agents such as regorafenib, fruquintinib, and trifluridine/tipiracil (TAS-102) provide modest benefit, with median progression-free survival (PFS) of approximately 2-3 months and objective response rates below 5%. Moreover, the vast majority (90-95%) of mCRC patients have microsatellite stable (MSS) or proficient mismatch repair (pMMR) tumors, which are largely unresponsive to immune checkpoint inhibitor monotherapy.
Preclinical and emerging clinical evidence suggests that stereotactic body radiotherapy (SBRT) can induce immunogenic cell death, remodel the tumor immune microenvironment, and synergize with immune checkpoint inhibitors. Additionally, bevacizumab (anti-VEGF) has immunomodulatory effects, including reducing regulatory T cells and M2-type tumor-associated macrophages, and promoting dendritic cell maturation. The phase III SUNLIGHT trial demonstrated that adding bevacizumab to TAS-102 significantly improved overall survival (10.8 vs. 7.5 months) and PFS (5.6 vs. 2.4 months) in refractory mCRC. Therefore, combining SBRT with PD-1 inhibitor, bevacizumab, and TAS-102 may further enhance antitumor immunity and improve clinical outcomes in MSS/pMMR mCRC patients.
Study Design This is a prospective, single-center, randomized, open-label, phase II trial. A total of 58 eligible patients will be randomized 1:1 to either the experimental arm or the control arm. Randomization will be performed using a computer-generated random sequence. No blinding is applied.
Interventions
* Experimental arm: Patients will first receive SBRT to metastatic lung or liver lesions. SBRT is delivered using image-guided radiotherapy. The fractionation schedule is tailored to tumor location, with a biologically effective dose (BED) ≥94 Gy, completed within 1-2 weeks. One week after completion of SBRT, patients start systemic therapy: sintilimab (200 mg intravenously every 2 weeks), bevacizumab (5 mg/kg intravenously every 2 weeks), and TAS-102 (35 mg/m² orally twice daily on days 1-5 of each 14-day cycle). Treatment continues until disease progression, unacceptable toxicity, patient withdrawal, or other protocol-specified discontinuation criteria.
* Control arm: Patients receive investigator's choice of standard-of-care third-line therapy for mCRC, which may include TAS-102 monotherapy, TAS-102 plus bevacizumab, regorafenib, or fruquintinib, according to local clinical practice and Chinese Society of Clinical Oncology (CSCO) guidelines.
Study Duration Enrollment period: 12 months. Total study duration: 24 months (12 months enrollment + 12 months follow-up).
Sample Size Justification Based on historical data, the control arm is expected to have a median PFS of 3 months. The experimental arm is expected to improve median PFS to 7 months. With a two-sided alpha of 0.05 and power of 80%, and accounting for 10% dropout, a total of 58 patients (29 per arm) is required.
Outcome Measures
Primary outcome measure:
• Progression-free survival (PFS), defined as time from randomization to first documented radiographic disease progression per RECIST v1.1 or death from any cause, whichever occurs first.
Secondary outcome measures:
* Overall survival (OS): time from randomization to death from any cause.
* Objective response rate (ORR): proportion of patients achieving complete response (CR) or partial response (PR) per RECIST v1.1.
* Local control rate (irradiated lesions) at 1 year.
* Abscopal response rate (non-irradiated lesions) at 1 year.
* Incidence and severity of adverse events graded according to CTCAE v5.0.
* Quality of life assessed by EORTC QLQ-C30 questionnaire.
Exploratory outcome measures:
• Biomarker analysis, including but not limited to circulating tumor DNA (ctDNA)/molecular residual disease (MRD), PD-L1 expression, tumor mutational burden (TMB), metabolites, and gut microbiota, to explore associations with disease status, radiotherapy resistance, and immunotherapy response.
Statistical Analysis Primary efficacy analysis will be performed on the full analysis set (FAS, intention-to-treat principle), with per-protocol analysis as supportive. PFS and OS will be estimated using the Kaplan-Meier method, and comparisons between arms will be performed using the log-rank test. Hazard ratios and 95% confidence intervals will be calculated using a Cox proportional hazards model. Sensitivity analysis using interval-censored Cox models will be conducted to account for potential bias from irregular imaging assessments. ORR will be compared using Pearson's chi-square test or Fisher's exact test. All statistical tests will be two-sided, with a significance level of 0.05. Statistical analyses will be performed using R software (version 4.1.1 or higher).
Safety Monitoring Adverse events will be collected from the time of informed consent until 30 days after the last dose of study treatment (or 90 days for serious adverse events considered related to study treatment). Safety will be assessed by the principal investigator and reported to the ethics committee according to Chinese regulations. No independent data monitoring committee (DMC) is established for this phase II trial; oversight is provided by the sponsor (Zhongshan Hospital) and the institutional ethics committee.
Ethics and Dissemination This study is approved by the Ethics Committee of Zhongshan Hospital, Fudan University (approval number and date to be inserted). The study will be conducted in accordance with the Declaration of Helsinki, Good Clinical Practice, and Chinese regulations. Written informed consent will be obtained from all participants. Results will be disseminated through peer-reviewed publications and presentations at scientific conferences.
