Colorectal Cancer Clinical Trials

• 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.

∙ 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 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 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