Pre-operative Targeted Treatments in Molecularly Selected Resectable Colorectal Cancer (UNICORN)

Inclusion Criteria: General inclusion criteria * Provide a signed and dated informed consent document. * Age ≥ 18 years at time of informed consent. * ECOG PS of 0 and 1. * Histologically confirmed colorectal cancer adenocarcinoma that is judged as initially resectable with elective surgery aimed at radical intent with R0 margins as per multidisciplinary team assessment. * Radiological stage cT3-4, N0-2, M0 using computed tomography (CT) as in the pivotal FOxTROT study. * Patients with rectal cancer candidate for R0 resection, not requiring pre-operative radiotherapy based on multidisciplinary team assessment, with the following characteristics on high-resolution thin slice (3 mm) contrast-enhanced magnetic resonance imaging (MRI): * ≤ T3a defined at the MRI (perivisceral fat infiltration \<2 mm) and clinical N0 * Upper-medium, defined as tumors with distal margin ≥ 5 cm from the anal verge. * Absence of mesorectal fascia invasion, as defined as a distance ≥ 1 mm between tumor and the mesorectal fascia. * Able to provide enough archival FFPE tumor specimen that is already available from initial diagnostic procedures for the purpose of molecular pre-screening. * Presence of one of the selected molecular profile/alteration after central pre-screening and necessary for the assignment to a matching treatment cohort. * No prior systemic treatment for colorectal cancer or neoadjuvant radiation therapy for rectal cancer. * Adequate bone marrow function (absolute neutrophil count ≥ 1.5 × 109/L; platelet count ≥ 100 × 109/L; hemoglobin ≥ 9.0 g/dL) * Adequate renal function characterized by serum creatinine ≤ 1.5 × upper limit of normal (ULN) or calculated by Cockroft-Gault formula or directly measured creatinine clearance ≥ 50 mL/min at screening. * Adequate hepatic function (serum total bilirubin ≤ 1.5 × ULN and \< 2 mg/dL. Note: Patients who have a total bilirubin level 1.5 × ULN will be allowed if their indirect bilirubin level is ≤ 1.5 × ULN; Alanine aminotransferase and/or aspartate aminotransferase ≤ 2.5 × ULN). * Women of childbearing potential must have a negative blood pregnancy test at the baseline visit. For this trial, women of childbearing potential are defined as all women after puberty, unless they are postmenopausal for at least 12 months, are surgically sterile, or are sexually inactive. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. * Subjects and their partners must be willing to avoid pregnancy during the trial and until a specific time interval after the last trial treatment: 7 months for female and 4 for male patients after last dose of trastuzumab-deruxtecan, 3 months for durvalumab, botensilimab and balstilimab and 2 months for panitumumab. Male subjects with female partners of childbearing potential and female subjects of childbearing potential must, therefore, be willing to use adequate contraception as approved by the Investigator (barrier contraceptive measure or oral contraception). * Willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures. Specific inclusion criteria for each Cohort COHORT 1: pMMR/MSS status and HER2-positive status and LVEF ≥ 50% within 28 days before enrolment, international normalised ratio or Prothrombin time and either partial thromboplastin or activated partial thromboplastin time ≤ 1.5 × ULN COHORT 2: Proofread domain mutations in POLE or POLD1 associated with ultra-mutated status, i.e. tumor mutational burden \>100 Mut/Mb. COHORT 3: pMMR/MSS status and wild-type status for RAS and BRAF, absence of molecular predictors of resistance (PRESSING panel negative), Left-sided and rectal primary tumor location, according to the specific inclusion criterion regarding rectal tumors. COHORT 4: pMMR/MSS status and absence of HER2 overexpression/amplification, absence of POLE/D1 proof-read domain pathogenic mutation associated with ultra-mutated status and absence of KRAS G12C mutation. COHORT 5: pMMR/MSS status and absence of of HER2 overexpression/amplification, absence of POLE/D1 proof-read domain pathogenic mutation associated with ultra-mutated status. COHORT 6: dMMR/MSI-H status and absence of POLE/D1 proof-read domain pathogenic mutation associated with ultra-mutated status. COHORT 7: dMMR/MSI-H status and absence of POLE/D1 proof-read domain pathogenic mutation associated with ultra-mutated status. COHORT 8: pMMR/MSS status and KRAS G12C mutation, absence of HER2 overexpression/amplification and wild-type status for BRAF. COHORT 9: pMMR/MSS status and absence of of HER2 overexpression/amplification, absence of POLE/D1 proof-read domain pathogenic mutation associated with ultra-mutated status, absence of KRAS G12C mutation. COHORT 10: pMMR/MSS status and absence of of HER2 overexpression/amplification, absence of POLE/D1 proof-read domain pathogenic mutation associated with ultra-mutated status, absence of KRAS G12C mutation. COHORT 11: pMMR/MSS status and wild-type status for RAS and BRAF, absence of molecular predictors of resistance (PRESSING panel negative except for MET alterations - MET amplifications and mutations are allowed), Left-sided and rectal primary tumor location, according to the specific inclusion criterion regarding rectal tumors. COHORT 12: pMMR/MSS status and wild-type status for RAS and BRAF, absence of molecular predictors of resistance (PRESSING panel negative except for MET alterations - MET amplifications and mutations are allowed), Right-sided primary tumor location. COHORT 1 of UNICORN part 2 (to enroll sequentially after completion of cohort 10): pMMR/MSS status and absence of molecular characteristics allowing enrollment in cohorts 1,2 and 8 (i.e HER2 overexpression/amplification, POLE/D1 proof-read domain pathogenic mutation associated with ultra-mutated status, absence of KRAS G12C mutation. Patients with tumor characteristics of EGFR dependency (regardless of MET) will be eligible for cohort 1 of UNICORN part 2 only after completion of cohort 11 or 12 (depending on primary tumor sidedness) and upon discussion with the Sponsor Exclusion Criteria: General exclusion criteria * Distant metastases at any site, as defined by negativity of chest/abdomen/pelvis contrast-enhanced computed tomography (CT). * Risk criteria for obstructing disease at radiology or endoscopy as defined in the pivotal FOxTROT study. * Need to receive neoadjuvant radiation or chemoradiation in patients with rectal cancer. * Patients with known hypersensitivity to the study drug of the assigned cohort or to its excipients or to drugs belonging to the same drug class. * Previous or concurrent malignancy within 2 years of study entry. * Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following: history of acute myocardial infarction, acute coronary syndromes (including unstable angina, coronary artery bypass graft, coronary angioplasty or stenting) ≤ 6 months prior to start of study treatment; symptomatic congestive heart failure (i.e., Grade 2 or higher), history or current evidence of clinically significant cardiac arrhythmia and/or conduction abnormality ≤ 6 months prior to start of study treatment, except atrial fibrillation and paroxysmal supraventricular tachycardia. * Known history of HIV infection. * Active infection including tuberculosis, hepatitis B, hepatitis C. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody \[anti-HBc\] and absence of HBsAg) are eligible only in case of negativity of HBV DNA. Patients positive for hepatitis C (HCV) antibody are eligible only if PCR is negative for HCV RNA. * Other severe acute or chronic diseases that may increase the risk associated with study participation or study drug administration or that may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient an inappropriate candidate for the study. * Any psychiatric condition that would prohibit the understanding or rendering of informed consent and that would limit compliance with trial requirements. * Women in pregnancy or lactation condition. Women with child-bearing potential or sexually-active men not willing to use adequate contraception during whole study period. * Use of any disallowed drugs. Specific exclusion criteria for each Cohort: COHORT 1: * Previous treatment with a DXd-containing ADC or any anti-HER2 agent. * Has LVEF\< 50% within 28 days before enrolment. * Has a history of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening. (eg, pulmonary emboli within 3 months of the enrolment, severe asthma, severe chronic obstructive pulmonary disease \[COPD\], restrictive lung disease, pleural effusion, etc.). * Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (eg, pulmonary emboli within 3 months of the enrolment, severe asthma, severe chronic obstructive pulmonary disease \[COPD\], restrictive lung disease, pleural effusion, etc.). * Any autoimmune, connective tissue, or inflammatory disorders where there is documented, or a suspicion of, pulmonary involvement at the time of Screening. * Prior pneumonectomy. * Has substance abuse or any other medical conditions that may interfere with the subject's participation in the clinical study or evaluation of the clinical study results. * Patients with a medical history of myocardial infarction within 6 months before randomization/enrolment, symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV), subjects with troponin levels above ULN at screening (as defined by the manufacturer), and without any myocardial related symptoms, should have a cardiologic consultation before enrollment to rule out myocardial infarction. * Corrected QT interval (QTcF) prolongation to \> 470 msec (females) or \>450 msec (males) based on average of the screening triplicate12-lead ECG. * A pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy (CART). COHORT 2, 4, 5, 6, 7, 10 and Cohort 1 of UNICORN part 2: * History of autoimmune diseases or history of bone marrow or organ transplantation that requires immunosuppressive therapy. * History of active primary immunodeficiency. * Any condition requiring systemic treatment with corticosteroids at doses equal or superior to 10 mg daily of prednisone or equivalents, or other immunosuppressive drugs within 14 days from the inclusion in the study. * Administration of live vaccines within 4 weeks from the inclusion in the study. Note: patients, if enrolled, should not receive live vaccine while receiving study drug(s) and up to 30 days after the last dose of study drug(s). * Prior treatment with anti-CTLA4, anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway-targeting agents. COHORT 3 and 8 * History of interstitial lung disease (e.g. pneumonitis or pulmonary fibrosis) or evidence of interstitial lung disease on baseline chest CT scan. * Magnesium below the LNL. * Prior treatment with an EGFR inhibitor. COHORT 8: * Patients who are unable to take a drug by mouth or previous clinical conditions or surgical resection that may affect the absorption of the study drug. * Use of CYP3A4 or P-gp substrates with a narrow therapeutic window within 14 days or 5 half-lives of the drug or its major active metabolite, whichever is longer. * Use of any herbal medications/supplements. * Tumors with KRAS, NRAS, HRAS, BRAF or PTPN11 (SHP2) mutations, except KRAS G12C. * Prior treatment with a KRAS G12C inhibitor. COHORT 9 and 10: * Prior treatment with EP4 receptor antagonists. * Inability to swallow medications. * Presence of portal hypertension and/or oesophageal varices. * Known severe gastritis, duodenal or gastric ulcer, or any other condition that may lead to bleeding or perforation. COHORTS 11 and 12: * Prior treatment with an anti-EGFR and/or MET inhibitor. * History of interstitial lung disease (e.g. pneumonitis or pulmonary fibrosis) or evidence of interstitial lung disease on baseline chest CT scan * Clinically active infectious liver disease * Any ophthalmologic condition that is clinically unstable