GLP-1 RA Plus SOC Treatment in First-line, Metastatic Pancreatic, Colorectal, or Hepatocellular Cancer

Inclusion Criteria: * Histological or cytological diagnosis of pancreatic adenocarcinoma or colorectal adenocarcinoma. Previous tumor tissue testing is acceptable. Please refer to the "additional HCC cohort criteria" below. * The subject has disease that is not amenable to curative-intent management (e.g., oligometastatic disease) * Measurable disease per RECIST v1.1 as determined by the investigator * Patients must be appropriate candidates for first-line, SOC treatment. * SOC treatment as defined by NCCN® guidelines or institutional standard is allowable, however, options restricted to: * Colorectal: FOLFOX or FOLIFIRI +/- bevacizumab * Pancreatic: mFOLFIRINOX * HCC: Tremelimumab/Durvalumab * Patients are eligible who received prior perioperative chemotherapy for curative intent treatment and recurred ≥ 6 months since last dose of chemotherapy. * ≥ 18 years old on day of consent * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Adequate archival frozen or fixed tissue available from primary or metastatic site for genotypic analysis (at least 15 unstained slides and/or tumor block) * Adequate hematologic and organ function laboratory values as follows: * The ANC ≥ 1500/mm3 without colony stimulating factor support; * Platelets ≥ 75,000/mm3; * Hemoglobin ≥ 9 g/dL; * Bilirubin ≤ 1.5 ´ the ULN. For subjects with known Gilbert's disease, bilirubin ≤ 3.0 mg/dL; * Serum albumin ≥ 2.8 g/dl; * ALT and AST ≤ 3.0 ´ ULN; * Serum creatinine ≤ 1.5 ´ ULN or creatinine clearance (CrCl) ≥ 40 mL/min. For creatinine clearance estimation, the Cockcroft and Gault equation should be used: * Male: CrCl (mL/min) = (140 - age) × wt (kg) / (serum creatinine × 72); * Female: Multiply above result by 0.85; * The subject is capable of understanding and complying with the protocol requirements and has signed the informed consent document * Sexually active subjects (men and women) must agree to use medically accepted barrier methods of contraception (eg, male or female condom) during the study and for 4 months after the last dose of study drug(s), even if oral contraceptives are also used. All subjects of reproductive potential must agree to use both a barrier method and a second method of birth control or practice abstinence during the study and for 4 months after the last dose of study drug(s); Additional Inclusion Criteria for HCC Cohort ONLY: * Histologically or radiologically confirmed hepatocellular carcinoma (per AASLD/EASL criteria) * Unresectable or advanced HCC not amenable to curative surgery or locoregional therapy. * Barcelona Clinic Liver Cancer (BCLC) stage B or C. * Child-Pugh Score Class A; or Child-Pugh Class B7 or B8 at discretion of treating physician * Patients with HBV infection, characterized by positive hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibodies (anti-HBcAb) with detectable HBV deoxyribonucleic acid (DNA) (≥10 IU/mL or above the limit of detection per local or central lab standard), must be treated with antiviral therapy, as per institutional practice to ensure adequate viral suppression (HBV DNA \<2000 IU/mL) before enrolment. Patients must remain on antiviral therapy for the duration of their participation in the EAP and for 6 months after the last dose of EAP medication. Patients who test positive for anti-hepatitis B core (HBc) with undetectable HBV DNA (\<10 IU/mL or under the limit of detection per local or central lab standard) do not require anti-viral therapy before enrolment. These participants will be tested at every cycle to monitor HBV DNA levels and initiate anti-viral therapy if HBV DNA is detected (≥10 IU/mL or above the limit of detection per local or central lab standard). HBV DNA detectable patients must initiate and remain on anti-viral therapy for time they are on the EAP and for 6 months after the last dose of EAP medication. o Note: Testing required for subjects with a known history otherwise not required. * Patients with HCV infection must have confirmed diagnosis of HCV characterized by the presence of detectable HCV ribonucleic acid (RNA) or anti-HCV antibody upon enrolment (management of this disease is per local institutional practice). Exclusion Criteria * The subject has received cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (eg, cytokines or antibodies) for metastatic and/or unresectable disease. * BMI \< 25 kg/m2 * For colorectal cancer only - Microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) tumors. * For colorectal cancer only - BRAF V600E mutant tumors. * A personal or family history of medullary thyroid cancer (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN2). * A prior hypersensitivity reaction to semaglutide or any of the excipients in WEGOVY®. Serious hypersensitivity reaction, including anaphylaxis and angioedema, have been reported with WEGOVY®. * Cachexia * Subjects on insulin. * Subjects with a history of diabetic retinopathy * Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before the first dose of study treatment. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of the start of study treatment * The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions: o Cardiovascular disorders including: * For patients being considered for bevacizumab (or bevacizumab biosimilar) only: * Concurrent uncontrolled hypertension defined as sustained blood pressure (BP) \> 150 mm Hg systolic or \> 100 mm Hg diastolic despite optimal antihypertensive treatment within 7 days of the first dose of study treatment; * thromboembolic event requiring therapeutic anticoagulation (Note: subjects with a venous filter (eg, vena cava filter) within 6 months before the first dose of study treatment. * Any of the following within 6 months before the first dose of study treatment: * unstable angina pectoris; * clinically-significant cardiac arrhythmias; * stroke (including transient ischemic attack (TIA), or other ischemic event); * myocardial infarction; * GI disorders particularly those associated with a high risk of perforation or fistula formation including: * Unresolved abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess. * Uncontrolled nausea, vomiting, or abdominal pain. * Other clinically significant disorders that would preclude safe study participation * Major surgery within 8 weeks before the first dose of study treatment. Subjects with clinically relevant ongoing complications from prior surgery are not eligible. * Females who are known or suspected to be pregnant or lactating. Women of childbearing potential must have a negative serum pregnancy test result within screening. * Female patients planning on becoming pregnant while on study. * Male subjects with a pregnant partner who are unwilling to practice abstinence or use a condom during treatment. * Male subjects unwilling to abstain from donating sperm during treatment. * Inability to comply with self-administration of GLP-1 RA subcutaneous injections. * Subject has known sensitivity to any of the products or components to be administered during dosing. * Concurrent use of other semaglutide containing products or any other GLP-1 receptor agonist. * Diagnosis of another malignancy within 2 years before the first dose of study treatment, except for superficial skin cancers, or localized, low grade tumors deemed cured and not treated with systemic therapy. * Subject likely to not be available to complete all protocol-required study visits or procedures and/or to comply with all required study procedures to the best of the subject and investigator's knowledge. * History or evidence of any other clinically significant disorder, condition or disease that in the opinion of the investigator, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion. Additional Exclusion Criteria for HCC Cohort ONLY: * Child-Pugh Score Class B9; or Child-Pugh Class C * Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 28 days of the first dose of EAP treatments. * History of allogenic organ transplantation (e.g., liver transplant). * History of hepatic encephalopathy within the past 12 months or requirement for medications to prevent or control encephalopathy (e.g., no lactulose, rifaximin, etc if used for purposes of hepatic encephalopathy. * Clinically meaningful ascites, defined as any ascites requiring non-pharmacologic intervention (e.g., paracentesis) to maintain symptomatic control, within 2 months before the first EAP treatment dose. Patients on stable doses of diuretics for ascites for ≥2 months are eligible. * Patients with main portal vein thrombosis (i.e., thrombosis in the main trunk of the portal vein, with or without blood flow) on baseline imaging. * Active or previously documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[e.g., colitis or Crohn's disease\], diverticulitis \[except for diverticulosis\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc\]). Patients without active disease in the last 5 years are excluded unless discussed with the Treating Physician and considered appropriate for EAP participation. The following are exceptions to this criterion: * Patients with vitiligo or alopecia * Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement * Any chronic skin condition that does not require systemic therapy * Patients with celiac disease controlled by diet alone * Patients co-infected with HBV and HCV, or co-infected with HBV and hepatitis D virus (HDV). HBV positive (presence of HbsAg and/or anti-HBcAb with detectable HBV DNA); HCV positive (presence of anti-HCV antibodies); HDV positive (presence of anti-HDV antibodies). o Note: Testing required for subjects with a known history otherwise not required. * Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC. * History of active primary immunodeficiency. * Current or prior use of immunosuppressive medication within 14 days before the first dose of EAP treatment. The following are exceptions to this criterion: * Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra-articular injection) * Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent * Steroids as pre-medication for hypersensitivity reactions (e.g., CT scan pre-medication) * Receipt of live attenuated vaccine within 30 days before first dose of treatment. Note: patients, if enrolled, should not receive live vaccine while receiving study treatment, and up to 30 days after the last dose of study treatment. * Previous randomization or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment. * Patients who have received anti-PD-1, anti-PD-L1, or anti-CTLA-4 before the first dose of EAP treatment.