SBRT Followed by PD-1 Inhibitor, Bevacizumab and TAS-102 as Third-Line Therapy for Recurrent/Metastatic Colorectal Cancer

Lab values

• 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.

• 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.