This phase II trial studies how well stereotactic body radiotherapy (SBRT) followed by a combination of an immune checkpoint inhibitor (sintilimab), bevacizumab, and trifluridine/tipiracil (TAS-102) works as third-line treatment for patients with recurrent or metastatic colorectal cancer (mCRC) that has progressed after at least two prior lines of systemic therapy.

The study will enroll 58 participants at Zhongshan Hospital, Fudan University. Participants will be randomly assigned (1:1) to either the experimental group or the control group. Those in the experimental group will receive SBRT to lung or liver metastases, followed one week later by sintilimab (200 mg every 2 weeks), bevacizumab (5 mg/kg every 2 weeks), and TAS-102 (35 mg/m² twice daily on days 1-5 every 2 weeks). Those in the control group will receive the investigator's choice of standard third-line therapy (such as TAS-102 alone or with bevacizumab, regorafenib, or fruquintinib).

The main purpose is to see whether the new combination extends the time without the cancer growing or spreading (progression-free survival, PFS). Other goals include measuring overall survival, tumor response rates, local control of treated tumors, abscopal (out-of-field) effects, safety, quality of life, and exploring biomarkers that might predict treatment response.

The study is expected to take 24 months to complete (12 months for enrollment and 12 months for follow-up). Results will help determine if adding SBRT and immunotherapy to standard chemotherapy and anti-angiogenic therapy is a beneficial option for patients with refractory mCRC.

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.

Inclusion Criteria:

• Age 18 to 75 years (inclusive).

Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

Histologically or cytologically confirmed colorectal cancer with unresectable metastatic or recurrent lesions.

Has received at least first- and second-line systemic anti-tumor therapy for metastatic colorectal cancer (chemotherapy regimens may include fluoropyrimidines, oxaliplatin, irinotecan, with or without targeted agents such as bevacizumab or cetuximab) and has progressed after second-line therapy.

Has evaluable lung or liver metastases amenable to stereotactic body radiotherapy (SBRT).

Has at least one measurable lesion according to RECIST v1.1.

Female patients of childbearing potential must have a negative urine or serum pregnancy test within ≤7 days before first dose of study drug. All fertile patients must agree to use highly effective contraception during the study and for ≥120 days after the last dose.

Willing and able to provide written informed consent.

Exclusion Criteria:

• Laboratory abnormalities: absolute neutrophil count <1.5×10⁹/L, platelet count <100×10⁹/L, hemoglobin <9 g/dL; total bilirubin >1.5× upper limit of normal (ULN) (>2.5× ULN for patients with liver metastases); AST/ALT >2.5× ULN (>5× ULN for patients with liver metastases); serum creatinine >1.5× ULN or creatinine clearance <60 mL/min; APTT or PT >1.5× ULN; albumin <30 g/L; clinically significant electrolyte abnormalities. Transfusion or growth factor support within 2 weeks before enrollment to meet eligibility is not permitted.

Prior evidence of deficient mismatch repair (dMMR), microsatellite instability-high (MSI-H), or BRAF mutation by histology or ctDNA testing.

Prior immunotherapy (anti-PD-1, anti-PD-L1, anti-CTLA-4, or any cellular immunotherapy).

Active or history of autoimmune disease that may relapse.

Requires systemic corticosteroids (>10 mg/day prednisone equivalent) or other immunosuppressive drugs within 14 days before first dose of study drug (exceptions allowed for low-dose steroids, topical/inhaled steroids, or short-term prophylaxis).

History of interstitial lung disease, non-infectious pneumonitis, pulmonary fibrosis, acute lung disease, or poorly controlled systemic disease (e.g., diabetes, hypertension).

Clinically uncontrolled diarrhea.

Severe chronic or active infection requiring systemic antimicrobial therapy, including tuberculosis.

Brain or leptomeningeal metastases.

Clinically significant pleural effusion, pericardial effusion, or ascites requiring repeated drainage within 2 weeks before first dose.

Presence of clinically detectable second primary malignancy or other malignancy within the past 5 years (except adequately treated basal cell carcinoma of the skin or cervical carcinoma in situ).

Poorly controlled diabetes or electrolyte disturbances despite standard medical management.

Known HIV infection.

Untreated chronic hepatitis B (HBV DNA >500 IU/mL) or detectable hepatitis C virus (HCV) RNA. Inactive HBsAg carriers, treated and stable hepatitis B (HBV DNA ≤500 IU/mL), and cured hepatitis C are allowed.

Major surgery within ≤28 days before first dose.

Prior allogeneic stem cell or organ transplantation.

Uncontrolled hypertension (systolic ≥140 mmHg or diastolic >90 mmHg on monotherapy).

Active gastrointestinal diseases (e.g., duodenal ulcer, ulcerative colitis, intestinal obstruction) or history of intestinal perforation/fistula not fully healed after surgery.

History of arterial or deep vein thrombosis within 6 months before enrollment, or bleeding tendency/bleeding history within 2 months before enrollment regardless of severity.

Stroke or transient ischemic attack within 12 months before enrollment; non-healing skin wound, surgical site, trauma, severe mucosal ulcer, or fracture; acute myocardial infarction, severe/unstable angina, or coronary artery bypass graft within 6 months; New York Heart Association (NYHA) class ≥2 heart failure.

Severe hypersensitivity to other monoclonal antibodies, trifluridine/tipiracil, or any excipient.

Received systemic chemotherapy within 28 days before first dose, or immunotherapy/hormonal therapy/targeted therapy/investigational therapy within 14 days or 5 half-lives (whichever is shorter).

Received Chinese herbal medicine or proprietary Chinese medicine for cancer control within 14 days before first dose.

Toxicities from prior anticancer therapy not recovered to baseline or stable level (except alopecia, neuropathy, and specific laboratory abnormalities deemed not a safety risk).

Received live vaccine within 4 weeks before first dose.

Any clinical or laboratory abnormality or compliance issue that, in the investigator's judgment, makes the patient unsuitable for the study.

Severe psychological or mental abnormalities.

No plan to share IPD due to the exploratory phase II design and lack of a pre-established data sharing agreement.