Immunotherapy acquired resistance was observed in clinical practice. The investigators intended to add anlotinib to PD-1 inhibitors, hoping reverse the resistance.

Anti-angiogenesis seems have positive effects on tumor immune microenvironment. the combination of PD-1/PD-L1 inhibitors and TKIs exhibited favorable efficacy on gastrointestinal malignancies. Here the investigators want to examine the efficacy and survival benefit from the combination therapy to PD-1 acquired resistance patients, which turns out to be critical issues in recent years.

Inclusion Criteria:

• ECOG scored 0 or 1, ≥18 years old, expected OS≥3 months;

• Histology confirmed unresectable or metastatic gastric/gastroesophageal junction adenocarcinoma or colorectal cancer;

• ≥1 evaluable lesion based on RECIST 1.1;

• Patients received PD-1/PD-L1 in the last treatment line, and should meet following conditions:

  i) there was no severe immune-related adverse events, ii) the duration between tumor progression and screening should be 3-12 weeks, iii) the best evaluation results should be PR or CR when receiving PD-1/PD-L1 treatment but progression was confirmed in the latest evaluation, iv) patients were diagnosed with special pathology subtypes, that are sensitive to immunotherapy, such as dMMR, MSI-H tumors, or gastric cancer with PD-L1 CPS≥10, PFS≥6 months in the last treatment line;

• laboratory test should meet following standard: i) HB≥90g/l, neutrophils≥1.5*10^9/L, plt≥100*10^9, ii) ALT and AST<2.5xULN (5ULN for liver metastatic patients), TBIL≤2×ULN, Cr≤1.5×ULN, and Ccr>50μmol/L iii) APTT, INR and PT≤1.5×ULN iv) LVEF≥50%

• for female participants, Hcg should be negative and both male and female participants should have contraception measures

• participants should be informed consent, and voluntary.

Exclusion Criteria:

• received anlotinib or other TKIs previously;
• allergic to other monoclonal antibody before the treatment;
• diagnosed with other malignancy in last five years (cured skin basal carcinoma, prostate cancer or cervical caner in situ were excluded)
• concurrent with other active autoimmune disease;
• any condition that require immune suppressor, such as cortisol (>10mg/d prednisone equally), CTX;
• conditions affect oral absorption (eg: dysphagia, intestinal obstruction; chronic diarrhea);
• uncontrolled pleural effusion, hydropericardium and seroperitoneum;
• brain metastasis;
• received other anti-tumor treatment in past 3 weeks, eg: surgery, radiotherapy, target therapy, immunotherapy, and traditional Chinese therapy (target therapy less than 5 half-life period, 5-Fu less than 14 days were excluded);
• concurrent with uncontrolled other diseases, i) hypertension (>150/90mmHg) ii) unstable angina pectoris, ≥ level 2 heart failure, arrhythmia within last 6 months; iii) clinical meaningful liver disease, eg: active HBV/HCV hepatitis; iv) HIV positive; v) uncontrolled diabetes; vi) urine protein ≥++ or 24h urine protein >1g;
• injected vaccine in past 4 weeks, or administrated with antibiotics;
• investigator assumed improper conditions, such as mental disease, family or society factors.