Inclusion Criteria:
1. Patient\* provide signed informed consent form.
2. Patient is ≥ 18 years at the time of given informed consent.
3. Patient has been diagnosed with histologically or cytologically proven microsatellite stable (MSS)/proficient mismatch repair (pMMR) metastatic adenocarcinoma of the colon or rectum, which is not amenable to potentially curative resection.
4. Known RAS (KRAS or NRAS) and BRAF V600E mutational status. Note: These mutations are mutually exclusive. Therefore, if one of the factors is mutated, it is not required to determine the mutation status of the others, as they are then assumed to be wildtype.
5. Patient without liver metastases (NLM) defined as subjects without active liver metastases at screening as determined on baseline imaging of the liver as performed by CT scan with contrast or MRI. Definitively treated liver metastases (which includes surgical resection, microwave or radiofrequency ablation, or stereotactic body radiation therapy, but not yttrium-90 or chemoembolization alone) that were treated at least 3 months prior to enrollment with no evidence of radiologic progression on subsequent imaging are considered to be non-active liver metastases.
6. Patient received at least one line of previous treatment with a fluoropyrimidine, oxaliplatin, irinotecan, VEGF(R) and if indicated EGFR and/or BRAF inhibitors in the advanced setting, or the patient has been intolerable or ineligible to those treatments.
7. Patient has an ECOG performance status ≤ 1.
8. Patient has a life expectancy \> 16 weeks.
9. Patient has adequate hematological, hepatic and renal function.
1. Absolute number of neutrophils (ANC) ≥ 1.5 x 109/L
2. Platelets ≥ 100 x 109/L
3. Total bilirubin ≤ 1.5 times the upper limit of normal (ULN) (or \< 2 x ULN in case of prior liver involvement or Gilbert's disease)
4. AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN, AP ≤ 5 x ULN
5. Serum creatinine ≤ 1.5 x ULN or creatinine clearance (measured by 24 h urine) ≥ 30 mL/min (i.e., if serum creatinine level is \> 1.5 x ULN, then a 24-hour urine test must be performed to check the creatinine clearance to be determined).
6. Urinary protein ≤2+ on dipstick or routine urinalysis (UA; if urine dipstick or routine analysis is ≥3+, a 24-hour urine collection for protein must demonstrate \<2000 mg of protein in 24 hours to allow participation in this protocol)
10. Adequate coagulation function as defined by International Normalized Ratio (INR) ≤ 1.5, and a partial thromboplastin time (PTT) ≤ 5 seconds above the ULN (unless receiving anticoagulation therapy).
11. Female patients of childbearing potential or male patients in Arm B with female partners of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of \<1% per year during the treatment period and for at least 6 months after the last trial treatment. Male patients in Arm B with a pregnant partner must agree to remain abstinent or to use a condom for the duration of the pregnancy. Female patients of child-bearing potential must have a negative pregnancy test within the last 7 days prior to the start of trial therapy.
12. Patient is willing and able to comply with the protocol (including contraceptive measures) for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
* There are no data that indicate special gender distribution. Therefore, patients will be enrolled in the trial gender-independently.
Exclusion Criteria:
1. Patient has known allergic / hypersensitive reactions to at least one of the treatment components
2. Patient had previous malignancy other than that under study within 3 years or concomitant malignancy, except: those with a 5-year overall survival rate of more than 90%, e.g. non-melanomatous skin cancer or adequately treated in situ cervical cancer
3. Patient received previous treatment with Fruquintinib, trifluridine/tipiracil, regorafenib or an anti-PD-1/anti-PD-L1 antibodies.
4. Patient receives current treatment with any anti-cancer therapy, such as systemic immunotherapy, chemotherapy, or hormone therapy within ≤ 2 weeks prior to study treatment start.
5. Patient receives simultaneous treatment with a different anti-cancer therapy other than that provided for in the trial (excluding palliative radiotherapy for symptom control).
6. Patient has known untreated or symptomatic CNS or leptomeningeal metastases.
7. Patient has impaired cardiac function or clinically significant cardiac disease including unstable angina within 6 months before the first dose of study treatment, acute myocardial infarction \< 6 months prior to the first dose of study treatment, New York Heart Association (NYHA) class II-IV congestive heart failure, uncontrolled hypertension (defined as an average systolic blood pressure \> 160 mmHg or diastolic \> 100 mmHg despite optimal treatment, uncontrolled cardiac arrhythmias requiring antiarrhythmic therapy other than beta blockers or digoxin, active coronary artery disease or corrected QT interval (QTc) ≥ 470.
8. Patient has history of uncontrolled infection with human deficiency virus (HIV) or chronic infection with hepatitis B or C virus (HBV, HCV).
9. Patient has evidence of bleeding diathesis.
10. Patient has history of gastrointestinal perforation or fistulae in past 6 months or risk factors for perforation.
11. Patient has grade 3-4 gastrointestinal bleeding within 3 months prior to first dose of trial therapy.
12. Use of strong inducers or inhibitors of CYP3A4 within 2 weeks (or 5 half-lives, whichever is longer) before the first dose of study drug (see Appendix 4 for examples).
13. Patient had a major surgery within 2 weeks prior to first dose of trial therapy.
14. Patient experienced severe, life-threatening, or recurrent (Grade 2 or higher) immune-mediated adverse events (AEs) or infusion-related reactions including those that led to permanent discontinuation while on treatment with immune-oncology agents.
15. Patient received prior immunosuppressive therapy: immunosuppressive doses of systemic medications of \> 10 mg/day of prednisone or equivalent must be discontinued ≥ 2 weeks before the first dose of study treatment. Short courses of high dose corticosteroids and/or continuous low dose of prednisone (\< 10 mg/day) are permitted. In addition, inhaled, intranasal, intraocular, and/or joint injections of corticosteroids are allowed.
16. Patient has active autoimmune disease that has required systemic treatment (except replacement therapy) within the past 2 years or any other diseases requiring immunosuppressive therapy while on study.
17. Patient has history of solid organ transplantation .
18. Patient has history of thromboembolic events (including deep vein thrombosis and pulmonary embolism) within the past 6 months or history of stroke and/or transient ischemic attack within the last 12 months.
19. Patients has evidence of any other serious concomitant or medical condition that, in the opinion of the investigator, presents a high risk of complications to the patient or reduces the likelihood of clinical effect.
20. Female patient is pregnant or breast feeding or planning to become pregnant within and up to 6 months after end of treatment.
