KN 046 Plus Regorafenib in MSS Metastatic Colorectal Cancer

Inclusion Criteria: I01. Subjects are able to comprehend the informed consent form, voluntarily participate,and sign the informed consent form. I02. Subjects are ≥18 years old on the day of signing the informed consent form, with nogender restrictions. I03. Histologically confirmed colorectal adenocarcinoma, including signet ring cellcarcinoma and mucinous adenocarcinoma. I04. According to RECIST 1.1 criteria, there should be at least one measurable or evaluablelesion at baseline. If the subject has only one measurable or evaluable lesion at baseline,the lesion must not have been exposed to radiotherapy previously, or there must be evidenceof significant progression after radiotherapy treatment completion. I05. ECOG performance status of 0 or 1. I06. Expected survival ≥3 months. I07. Archivedtumor tissue samples or freshly obtained tumor tissue samples are available. I08. Female subjects of childbearing potential or male subjects with partners ofchildbearing potential agree to use highly effective contraception from 7 days before thefirst dose until 120 days after the last dose. Female subjects of childbearing potentialmust have a negative serum pregnancy test within 7 days before the first dose. I09. Subjects have the ability and willingness to comply with the study protocol's visits,treatment plan, laboratory tests, and other study-related procedures. I10. Within the first 7 days of initial dosing, subjects should have good organ function: HGB ≥ 80g/L NEU ≥ 1.010^9/L PLT ≥ 7510^9/L Cr≤1.5×ULN or CrCl≥50mL/min（ Cockcroft-Gaultmethod） TBiL ≤ 1.5×ULN ALT and AST ≤3 ×ULN； for patients with liver metastasis ALT and AST ≤5 ×ULN urine protein <2+；if urine protein ≥ 2+，24 hour urinary protein quantity <2g； INR，APTT，PT ≤ 1.5 ×ULN I11. For each cohort, the previous treatment history must meet the following conditions: Cohort A: pMMR/MSS mCRC with no BRAF V600E mutation, who failed fluoropyrimidine,oxaliplatin, and irinotecan treatments, and without definitive active liver metastases atenrollment (judged by the investigator based on medical history and imaging). Cohort B: pMMR/MSS mCRC with BRAF V600E mutation, who failed fluoropyrimidine, oxaliplatin,and irinotecan treatments. Cohort C: MSS mCRC that has not intolerant or unsuitable for or refuse to receive standardfirst-line or second-line chemotherapy.

Exclusion Criteria: E01. Subjects with untreated active brain metastases or meningeal metastases; if thesubject's brain metastases have been treated and the metastases are stable (brain imagingat least 4 weeks before the first dose shows stable lesions, and there is no evidence ofnew neurological symptoms or the neurological symptoms have returned to baseline), thenenrollment is allowed. E02. Subjects with a history of gastrointestinal perforation or fistula within 6 monthsbefore the first dose. If the perforation or fistula has been treated with resection orrepair, and the disease is judged to be recovered or improved by the investigator, thenenrollment is allowed. E03. Subjects who have received any other interventional clinical trial or any otherantitumor treatment within 28 days or 5 half-lives before the first dose (whichever isshorter). Palliative radiotherapy for bone metastases to relieve symptoms is permitted. E04. Subjects who have undergone major surgery within 28 days before the first dose (e.g.,major abdominal or thoracic surgery; excluding drainage, diagnostic puncture, or peripheralvascular access replacement). E05. Subjects who require systemic corticosteroids (≥10 mg/day prednisone or equivalent) orimmunosuppressive therapy for a continuous 7-day period within 14 days before the firstdose. Inhaled or locally applied steroids and physiological replacement doses of steroidsdue to adrenal insufficiency are allowed. Short-term (≤7 days) corticosteroids forprophylaxis (e.g., contrast dye allergy) or treatment of non-autoimmune diseases (e.g.,delayed hypersensitivity reaction caused by exposure to allergens) are allowed. E06. Subjects who have received live vaccines (including attenuated live vaccines) within 28 days before the first dose. E07. Subjects with interstitial lung disease or a history of non-infectious pneumoniarequiring oral or intravenous corticosteroid treatment. E08. Subjects with active autoimmune diseases requiring systemic treatment within 2 yearsbefore the start of the study or those considered at risk of recurrence or plannedtreatment for autoimmune diseases as judged by the investigator. Exclusions include a) skindiseases that do not require systemic treatment (e.g., vitiligo, alopecia, psoriasis, oreczema); b) hypothyroidism caused by autoimmune thyroiditis, requiring stable doses ofhormone replacement therapy; c) type 1 diabetes requiring stable doses of insulinreplacement therapy; d) childhood asthma fully resolved with no need for intervention inadulthood; e) the investigator judges that the disease will not relapse without externaltriggering factors. E09. Subjects with a history of other malignant tumors within 5 years, excluding cured skinsquamous cell carcinoma, basal cell carcinoma, non-invasive bladder carcinoma, localizedlow-risk prostate cancer (defined as stage ≤T2a, Gleason score ≤6, and prostate-specificantigen (PSA) ≤10 ng/mL (if measured) in patients who have undergone curative treatment andhave no biochemical recurrence of prostate-specific antigen (PSA)), in situ cervical/breastcarcinoma, or Lynch syndrome. E10. Subjects with uncontrolled comorbidities, including but not limited to: a) active HBVor HCV infection; b) subjects who are HBsAg positive and/or HCV antibody positive duringscreening must undergo HBV DNA and/or HCV RNA testing. Only subjects with HBV DNA ≤500IU/mL (or ≤2000 copies/mL) and/or HCV RNA negative can be enrolled; HBV DNA monitoring willbe at the discretion of the investigator based on the subject's condition during the trial;c) known HIV infection or AIDS history; d) active tuberculosis; e) active infection orsystemic use of anti-infective drugs for more than 1 week within 28 days before the firstdose; fever of unknown cause within 2 weeks before the first dose; f) uncontrolledhypertension (resting blood pressure ≥160/100 mmHg), symptomatic congestive heart failure (NYHA II-IV), unstable angina or myocardial infarction within 6 months, or the presence ofQTc prolongation or the risk of arrhythmia (baseline QTc >470 msec , difficult-to-correct hypokalemia, long QT syndrome, atrial fibrillation withresting heart rate >100 bpm, or severe valvular heart disease); g) active bleeding thatcannot be controlled after medical treatment. E11. Toxicity from previous antitumor treatments has not recovered to Grade ≤2 (NCI-CTCAEv5.0) or baseline, except for alopecia, skin pigmentation (allowed at any level), andimmune-related adverse reactions requiring physiological replacement (e.g., hypothyroidism,hypopituitarism, type 1 diabetes). E12. History of allogeneic bone marrow or organ transplantation. E13. Previous history ofallergic reactions, hypersensitivity reactions, or intolerance to antibody drugs (e.g.,severe allergic reactions, immune-mediated hepatotoxicity, immune-mediatedthrombocytopenia, or anemia). E14. Pregnant and/or lactating females. E15. Other conditions that, in the investigator'sopinion, may affect the safety or compliance of the study drug treatment, including but notlimited to moderate to large pleural/ascites/pericardial effusion, uncorrectablepleural/ascites/pericardial effusion, intestinal obstruction or subacute intestinalobstruction, psychiatric disorders, etc. E16. Previous treatment with any immune checkpoint inhibitors or T-cell co-stimulatorydrugs, including but not limited to PD-1/PD-L1, CTLA-4, LAG3, and other immune checkpointinhibitors, therapeutic vaccines, etc. E17. Previous treatment with regorafenib.