Inclusion Criteria:
1. The patients voluntarily participated in the study, signed the informed consent form, and the compliance was good.
2. Age \>=18 years old, male or female;
3. Patients with histologically confirmed or clinically diagnosed HCC, and the disease is not suitable for radical surgery;
4. Patients with oligometastatic HCC who had failed previous target-immunotherapy combined with first-line therapy. Oligometastases are defined as the number of metastatic organs ≤2 and the total number of metastases \<=5, and oligometastases are suitable for SBRT treatment.
5. Child-Pugh liver function score \<=7;
6. ECOG score of 0-1;
7. Expected survival time before initiation of study drug \>=12 weeks;
8. At least one measurable lesion (the long diameter of the measurable lesion on enhanced spiral CT or enhanced MR Scan \>=10mm or the short diameter of the enlarged lymph node \>=15mm according to RECISTv1.1; a lesion that has been treated with previous radiotherapy can be considered as a target lesion after definite progression according to RECISTv1.1 criteria);
9. The following laboratory tests performed within 7 days before the first dose of medication confirmed that the patient's bone marrow, liver and kidney function met the following requirements for study participation: 1) hemoglobin \>=80 g/L (which can be maintained or exceeded by transfusion); 2) absolute neutrophil count (ANC) \>=1.5×10\^9; 3) platelet count \>=50×10\^9/mm3; 4) Total bilirubin \<=1.5 times upper limit of normal; 5) alanine aminotransferase and aspartate aminotransferase \<=2.5 times upper limit of normal (ULN); 6) creatinine \<=1.5 times upper limit of normal (ULN); And creatinine clearance \>=60ml/min; 7) international normalized ratio (INR) of prothrombin time \<=1.5 in patients without previous anticoagulant therapy; Partial thromboplastin time (APTT)\<=1.5 times the upper limit of normal; 8) if HBV-DNA is detectable, antiviral therapy should be started before enrollment; 9) If HCV-RNA is detectable, antiviral therapy should be started before enrollment.
10. Women of childbearing age: must agree to abstain from sexual intercourse (heterosexual intercourse) or use a reliable, effective method of contraception for at least 120 days from the time of written informed consent until the last dose of study drug is administered. A serum HCG test had to be negative within 7 days before starting study treatment; And they must be non-lactating. Women were considered to be fertile if they had menstruated, had not yet reached a postmenopausal state (\>=12 months of continuous absence of menses, with no cause other than menopause identified), and had not undergone sterilization procedures (e.g., hysterectomy, bilateral tubal ligation, or bilateral oophorectomy).
11. Male patients whose partner was a woman of reproductive age had to agree to abstain from sex or to use a reliable, effective method of contraception for at least 120 days from the time of written informed consent until the last dose of study drug was administered. Male patients also had to agree not to donate sperm during the same period. Male subjects whose partner was pregnant were required to use condoms.
Exclusion Criteria:
1. Known cholangiocarcinoma, sarcomatoid HCC, mixed cell carcinoma, and fibrolamellar cell carcinoma. Other active malignant tumors other than HCC within 5 years or at the same time. The cured localized tumors, such as skin basal cell carcinoma, skin squamous cell carcinoma, superficial bladder cancer, prostate cancer in situ, cervical cancer in situ, breast cancer in situ, etc., were excluded.
2. Prior receipt of anlotinib or a non-PD-1 monoclonal antibody immune checkpoint inhibitor;
3. The time interval between the last target-free drug use and enrollment was less than 3 weeks.
4. Patients who received previous local treatment (including TACE, ablation, HAIC, or radiotherapy) for the target lesion less than 1 month before enrollment.
5. Patients preparing for or previously receiving organ or allogeneic bone marrow transplantation;
6. Moderate or severe ascites with clinical symptoms, which required therapeutic puncture, drainage or Child-Pugh score \>2 (except for patients with small amount of ascites on imaging but without clinical symptoms); Uncontrolled or moderate or above amount of pleural effusion and pericardial effusion;
7. A history of gastrointestinal bleeding within 6 months before the initiation of study treatment or a definite tendency for gastrointestinal bleeding, such as: Patients with risk of bleeding or severe esophagogastric varices, local active gastrointestinal ulcer lesions, and persistent positive fecal occult blood were excluded (patients with positive fecal occult blood at baseline could be re-examined, and patients with positive fecal occult blood after re-examination required gastroduodenoscopy (EGD). Patients with esophagogastric varices with a risk of bleeding were excluded).
8. Abdominal fistula, gastrointestinal perforation, or abdominal abscess within 6 months before study treatment;
9. Known inherited or acquired bleeding (e.g., coagulopathy) or thrombophilia, as in hemophilia patients;
10. Current or recent (within 10 days before initiation of study treatment) use of a full-dose oral or injectable anticoagulant or thrombolytic agent for therapeutic purposes (prophylactic use of low-dose aspirin and low-molecular-weight heparin was allowed);
11. Currently using or recently using (within 10 days before initiation of study treatment) aspirin (\> 325 mg/ day (maximum antiplatelet dose) or dipyridamole, ticlopidine, clopidogrel, and cilostazol; Thrombotic or embolic events, such as cerebrovascular accident (including transient ischemic attack, cerebral hemorrhage, cerebral infarction), pulmonary embolism, etc., occurred within 6 months before the initiation of study treatment;
12. There are not well controlled cardiac clinical symptoms or diseases, such as: (1) according to the New York Heart Association (NYHA) criteria (see Annex 5) grade II or higher cardiac dysfunction or cardiac ultrasound examination: Left ventricular ejection fraction (LVEF) \<50% (2) unstable heartache (3) myocardial infarction within 1 year before study treatment (4) clinically significant supraventricular or ventricular arrhythmia requiring treatment or intervention (5) QTc \> 450ms (male); QTc \> 470ms (female) (QTc interval was calculated with Fridericia's formula; if QTc was abnormal, three consecutive tests could be performed at a 2-minute interval, and the mean value was calculated);
13. Hypertension that is not well controlled with antihypertensive medication (systolic blood pressure \>=140 mmHg or diastolic blood pressure ≥90 mmHg) (based on the mean of \>=2 readings), and the use of antihypertensive treatment to achieve these parameters is permitted; A history of hypertensive crisis or hypertensive encephalopathy;
14. Major vascular disease within 6 months before starting study treatment (e.g., aortic aneurysm requiring manual repair or recent peripheral artery thrombosis);
15. Severe, unhealed or dehiscence wounds and active ulcers or untreated bone fractures;
16. Major surgery (other than diagnosis) within 4 weeks before the start of study treatment or anticipated need for major surgery during the study;
17. Inability to swallow tablets, malabsorption syndrome or any condition affecting gastrointestinal absorption;
18. Had intestinal obstruction and/or had clinical signs or symptoms of GI obstruction within 6 months before starting study treatment, including incomplete obstruction related to a preexisting disease or requiring routine parenteral hydration, parenteral nutrition, or tube feeding: Patients with incomplete obstruction/obstruction syndrome/intestinal obstruction signs/symptoms at initial diagnosis were allowed to enroll if definitive (surgical) treatment was given to resolve the symptoms;
19. Evidence of pneumoperitoneum that could not be explained by paracentesis or recent surgical procedures;
20. Metastatic disease involving a major airway or blood vessel (e.g., complete occlusion of the main portal vein or vena cava due to tumor invasion, which was defined as the confluence of the splenic vein and the superior mesenteric vein or the branch of the hepatic portal vein into left and right branches) or a centrally located large mediastinal tumor mass (\<30mm from the carinal crest) were excluded. The liver lesions were more than 50% occupied.
21. The patient presented with active symptomatic central nervous system metastases or hepatic encephalopathy;
22. Those who have had or are currently having interstitial pneumonia or interstitial lung disease, or a previous history of interstitial pneumonia or interstitial lung disease requiring steroid therapy, or other pulmonary fibrosis, organizing pneumonia (e.g., Bronchiolitis obliterans), pneumoconiosis, drug-related pneumonia, idiopathic pneumonia, or evidence of active pneumonia or severe impairment of lung function on chest computed tomography (CT) during the screening period were allowed to have radiation pneumonia in the radiation field. Active tuberculosis;
23. Have active autoimmune disease or a history of autoimmune disease with possible recurrence (including but not limited to: autoimmune hepatitis, interstitial pneumonia, uveitis, enteritis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism \[subjects controlled only with hormone replacement therapy are eligible\]); Subjects with skin diseases without systemic treatment such as vitiligo, psoriasis, alopecia, controlled type I diabetes treated with insulin, or asthma that had been completely relieved in childhood and without any intervention in adulthood were included. Patients with asthma who required medical intervention with bronchodilators were excluded.
24. Use of immunosuppressive or systemic hormonal therapy for immunosuppression within 14 days prior to initiation of study treatment (at a dose of \>10mg/ day of prednisone or other equivalent);
25. Use of strong CYP3A4/ CYP2C19 inducers including rifampicin (and its analogues) and St. John's ST. or strong CYP3A4/ CYP2C19 inhibitors within 14 days before starting study treatment;
26. Known to have a history of severe allergy to any monoclonal antibody or anti-angiogenesis targeted drugs;
27. Severe infection within 4 weeks before starting study treatment, including, but not limited to, hospitalization for infection, bacteremia, or complications of severe pneumonia; Therapeutic oral or intravenous antibiotics within 2 weeks before starting study treatment (patients receiving prophylactic antibiotics (e.g., to prevent urinary tract infection or exacerbations of chronic obstructive pulmonary disease were eligible);
28. Patients with congenital or acquired immune deficiency (such as HIV infection);
29. Patients who had received traditional Chinese medicine (TCM) with anti-tumor therapeutic effect less than two weeks before enrollment (TCM containing the following herbs, such as brucea javanica, Coix seed, lentinus edodes polysaccharide, cantharides, bui skin, Astragalus, Kushen, Wu Guteng, Chebulae, icaritin, etc.);
30. Received live attenuated vaccine within 28 days before starting study treatment;
31. Received other trial medication within 21 days before starting study treatment;
32. Pregnant or lactating women;
33. According to the investigator's judgment, the patient has other factors that may affect the study results or lead to the forced termination of the study, such as alcohol abuse, drug abuse, other serious diseases (including mental diseases) requiring combined treatment, serious laboratory test abnormalities, accompanied by family or social factors, which will affect the safety of the patient.
