Regorafenib Alone or in Combination With Hypofractionated/Low-dose Radiotherapy Plus Toripalimab for Metastatic Colorectal Cancer

Control arm: regorafenib 120 mg orally once daily on days 1-21 of each 28 days cycle.

Experimental arm: regorafenib is administered 80 mg once daily on days 1-21 of each 28 days cycle with intravenous toripalimab 240 mg every 3 weeks. Radiotherapy regimes include hypofractionated radiotherapy (5 fractions of 4-12Gy) and low-dose radiotherapy (5 fractions of 0.5-2Gy).

Inclusion criteria

• Age ≥18 years old
• An Eastern Cooperative Oncology Group (ECOG) performance status ≤1
• Life expectancy of at least 3 months
• Histopathological confirmed MSS/pMMR adenocarcinoma of the colon or rectum
• At least one evaluable metastatic lesion for radiotherapy according to RECIST 1.1
• Progressed on or after the standard first-and second-line therapies or stopped standard therapy because of unacceptable toxic effects
• Previous radiotherapy completed at least 4 weeks before randomization
• Adequate bone-marrow, hepatic, and renal function: neutrophils ≥ 1.5 × 10^9/L, Hb ≥ 90 g/L, PLT ≥ 100 × 10^9/L, ALT/ AST≤2.5 ULN, Cr≤1 ULN
• Sign the informed consent and have good compliance

Exclusion criteria

• History of previous treatment with regorafenib and ICIs such as anti-PD-1 or anti-PD-L1 mAbs
• Current severe cardiovascular diseases such as unstable angina, congestive heart failure, or serious cardiac arrhythmia requiring medication
• Acute cardiac infarction or cerebral ischemic stroke occurred within 6 months before recruitment
• Active autoimmune diseases and immunodeficiencies, known history of organ transplantation, or systematic use of immunosuppressive agents
• Active Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection: HBsAg positive or HBV DNA positive, anti-HCV antibody testing positive and confirmatory HCV RNA positive
• Positive human immunodeficiency virus (HIV) infection, active syphilis infection, or active pulmonary tuberculosis infection
• Severe infections requiring systemic antibiotics, antifungal or antiviral therapy
• Uncontrollable pleural effusion, pericardial effusion, or ascites
• Other malignancies within 5 years before recruitment, except for non-melanoma skin cancer, superficial bladder cancer, cervical carcinoma in situ, or breast cancer in situ that had been effectively treated.
• Known history of severe neurological or mental illness such as schizophrenia, dementia, or epilepsy
• Known history of allergy to any component involved in this study.
• Pregnancy or breast-feeding women