Oral Chemotherapy, Targeted Therapy and Immunotherapy With/Without Radiotherapy as 3rd- or Later-line Therapy for Advanced MSS/pMMR Colorectal Cancer

Inclusion criteria

• patients with advanced colorectal adenocarcinoma of MSS/pMMR confirmed by histologic or cytologic diagnosis;
• aged 18 years and older;
• have a quality of life score of 0-1 according to the Eastern Cooperative Oncology Group (ECOG);
• can take oral medications;
• expected survival ≥ 3 months;
• progressed after standard second-line or more than second-line therapy (received oxaliplatin, irinotecan, and fluorouracil analogs);
• have a measurable target lesion according to RECIST v1.1 evaluation criteria;
• have a number of recurrent metastatic organs ≤ 2 for all measurable lesions, a maximum diameter of recurrent metastatic lesions ≤ 5 cm, and a total number of recurrent metastatic lesions ≤ 10;
• agree to provide previously stored tumor tissue specimens or perform biopsies to collect tumor lesion tissue for biomarker analysis
• have chest, abdomen and pelvis CT or whole body PET-CT results within 4 weeks before enrollment;
• no ascites;
• having adequate major organ function, electrocardiogram, blood, biochemistry and other basic tests to exclude contraindications to chemotherapy and radiotherapy;
• hemoglobin \>8g/L, platelets ≥100×10\^9/L, neutrophils ≥1.5×10\^9/L
• for patients with liver metastases, aminotransferases and bilirubin \< 5 times the upper limit of normal;
• for patients without liver metastases, aminotransferases and bilirubin should be \<2.5 times the upper limit of normal.
• women of childbearing age must have a negative pregnancy test and conscientiously observe contraceptive measures;
• prior systemic systemic therapy and radiation therapy for other lesions are allowed;
• in case of discomfort such as obstruction, bleeding, compression and pain caused by the tumor, the clinical situation that local treatment may benefit the patient may be discussed between the doctor and the patient as to whether radiation therapy is to be taken;
• if radiotherapy is required, the patient can be kept in a fixed position during radiotherapy;
• If SABR treatment is required, the patient can tolerate the physical restraint of the immobilization device;
• good control of the primary site: at least 3 months from radical treatment of the primary tumor, with no disease progression at the site of the primary site; or the primary tumor is not radically treated but, in the judgment of the investigator, there is no current disease progression and no threat to the patient's survival, and there is no indication for local therapy.

Exclusion criteria

• prior application of trefluridine tepidopyrimidine;
• prior application of PD-1 or PD-L1 monoclonal antibody;
• extensive bone metastases;
• extensive peritoneal metastases;
• malignant hydrothorax and ascites;
• clinical or imaging signs of spinal cord compression, or dural sac tumor visible on MRI within 2 mm of the spinal cord. If surgically resectable, it may be enrolled, but a maximum of 3 surgical sites are allowed;
• unstable brain metastases with clinical signs or imaging evidence that require surgical decompression;
• brainstem metastases;
• metastatic lesions invading any of the following structures: gastrointestinal tract (including esophagus, stomach, small intestine, large intestine), skin. Includes extensive/poppy metastatic disease (e.g., brain, bone, lung, liver), or other sites where an adequate dose of irradiation could not be given (e.g., lymphovascular dissemination, malignant pleural and abdominal fluid, molluscum contagiosum metastases);
• multiple intracranial metastases only;
• pregnant or lactating females;
• no reliable contraception during the reproductive period
• patients with a known history of hypersensitivity to any of the study drugs, analogs, or excipients;
• patients at risk of gastrointestinal hemorrhage or gastrointestinal obstruction;
• patients with a history of thromboembolism, with the exception of thrombosis caused by PICCs or infusion ports
• patients with difficult-to-control hypertension (systolic blood pressure ≥160 mmHg and diastolic blood pressure ≥90 mmHg after optimal antihypertensive treatment);
• patients with contraindications to treatment such as other chronic diseases;
• Patients with active infections;
• patients with a pre-existing condition of immunotherapy-associated myocarditis, pneumonia, colitis, hepatitis, or nephritis who, in the judgment of the investigator, are at greater risk for reuse of immunotherapy;
• patients with existing toxic side effects ≥ grade 2 due to prior therapy according to NCI CTCAE version 5.0 (except for alopecia, hyperpigmentation, etc.);
• severe medical comorbidities that preclude radiotherapy, including interstitial lung disease with current metastases requiring radiotherapy to the lungs, Crohn's disease requiring radiotherapy to the gastrointestinal tract, or connective tissue disease such as lupus erythematosus or scleroderma;
• there is an overlap between the current radiation field and the field of prior radiotherapy. It may be permissible to have had prior radiation therapy as long as the fusion cumulative dose meets the dose limits. For this case, request that the dose be accrued in accordance with the BED and discuss with the PI whether this can be performed;
• prior systemic nuclide therapy, such as Radium-223 or Lutetium-177);
• other circumstances that the investigator determines are not appropriate for inclusion in the study.