5-fluorouracil Plus Panitumumab (Anti-EGFR) and Sotorasib (KRAS G12C Inhibitor) in First-line Treatment of Patients Non-eligible for a Doublet/Triplet Chemotherapy With Advanced Unresectab

• Age ≥ 18 years.
• Histologically proven advanced-stage unresectable locally advanced or metastatic colorectal adenocarcinoma.
• Proven KRAS G12C mutation as locally assessed by means of an IVDR-compliant test
• Agreement to participate to biological studies (blood samples for ctDNA and send tumour block).
• Patient with one these criteria:

Patient with WHO PS=2 Patient between 70 and 75 years old with WHO PS 1 Patient ≥ 75 years old

• Measurable lesion according to the Response Evaluation Criteria in Solid Tumours 1.1 (RECIST 1.1).
• No prior treatment for the metastatic disease. Prior adjuvant chemotherapy is allowed if there is more than 6 months between the end of adjuvant treatment and relapse.
• Adequate organ function: Hemoglobin > 9 g/dl, Absolute neutrophil count > 1500 /mm3, Platelets > 80 000/mm3, Creatinine clearance rate ≥50 mL/min as calculated using MDRD formula, ALT/AST ≤5×ULN and total bilirubin ≤1.5×ULN.
• Ability to understand and sign written informed consent to participate in the study.
• Provides written informed consent for the study.
• Life expectancy >6 months.
• Women of childbearing potential must agree to use contraception during the trial treatment and for at least 6 months after discontinuation of the experimental treatments. Men who have sexual relationship with women of childbearing potential must agree to use contraception during treatment and for at least 3 months after discontinuation of the experimental treatments.
• Patient affiliated to a social security scheme for France, or equivalent for other countries.

Exclusion Criteria:

- Patient with one of these criteria: Patient fit for doublet/triplet regimen Patient with WHO PS 3 or 4 Patient \< 75 years old with WHO PS 0 Patient \< 70 years old with WHO PS 0 or 1

• Uncontrolled intercurrent illness including liver (liver cirrhosis Child Pugh B or C) and lung (one second forced expiratory volume \<50%) severe insufficiency.
• Patients with high microsatellite instability (MSI-H) or a tumour with mismatched repair (dMMR).
• Clinically significant cardiac abnormalities including prior history of any of the following: severe cardiomyopathy, congestive heart failure of New York Heart Association grade ≥3, history of clinically significant (i.e., active) atherosclerotic cardiovascular disease (myocardial infarction, unstable angina, cerebrovascular accident within 6 months prior to the first dose of study treatments).
• Patients with Dihydropyrimidine Dehydrogenase (DPD) enzyme deficiencies (uracilemia ≥ 16 ng/mL).
• Immunotherapy within 3 months before the beginning of the treatment study.
• Patient under treatment by strong CYP3A4 inducers.
• Patients treated by brivudine within 4 weeks before the first dose of study treatment, or concomitant treatment with brivudine.
• Patient with potentially serious infection.
• Administration of live or live attenuated vaccine within 30 days prior to the first dose of study treatment start.
• Poor nutritional state (albuminemia \< 25 g/L or weight loss > 10% during the last month).
• Hereditary problems of galactose intolerance, total lactase deficiency or glucose galactose malabsorption.
• Other malignancy within 2 years prior to study enrolment, except for localized cancer in situ, basal or squamous cell skin cancer adequately treated.
• Less than 4 weeks from major surgeries and not recovered adequately from the procedure and/or any complications from the surgery.
• Patients with persistent toxicities related to prior treatment of grade greater than 1.Is c urrently participating in or has participated in a study of an investigational agent or has used an investigational device within 3 weeks or 5 half-lives (whichever longer) before study entry.
• Hypersensitivity to one of the active substances or to one of the excipients of the trial treatments.
• Patient with interstitial lung disease or pulmonary fibrosis.
• Patients with history of interstitial pneumonitis or pulmonary fibrosis.
• Has a known psychiatric or substance abuse disorder that would interfere with the patient's ability to cooperate with the requirements of the study.
• Patient who is under judicial protection and patient who is legally institutionalized or under guardianship or not able to give consent.
• Pregnant or breastfeeding woman.
• Inability to undergo the medical follow-up of the trial for geographical, social or psychological reasons.