Chemotherapy and Immunotherapy as Treatment for MSS Metastatic Colorectal Cancer With High Immune Infiltrate

Inclusion Criteria:

• Age ≥ 18 years
• MSS and pMMR metastatic colorectal adenocarcinoma (metachronous or synchronousmetastases), histologically proven
• Patients who have had chemotherapy (neo-adjuvant or adjuvant) or radiotherapy (neo-adjuvant or adjuvant) for the treatment of primary tumor or metastatic resecteddisease R0 can be included if they have a recurrence more than 6 months after the endof this treatment.
• High immune response defined as the immune infiltration scores obtained on the primarytumour (resection of primary tumour containing at least 2 mm of tumour-free marginbetween the tumour and non-tumour area)
• Unresectable cancer with at least one measurable metastatic target according to RECISTv1.1 criteria
• WHO PS ≤ 1
• Life expectancy ≥ 3 months
• Adequate haematological function: neutrophils ≥ 1,500 /mm3, platelets ≥ 100,000/mm3,Hb > 9 g/dL
• Adequate liver function: AST/ALT ≤ 5xULN, total bilirubin ≤ 2xULN, alkalinephosphatase. ≤ 5xULN
• Creatinine clearance > 50 mL/min according to the MDRD formula
• Proteinuria <2+ (dipstick urinalysis) or ≤1g/24hour
• Patient who is a beneficiary of the social security system
• Information provided to patient and signature of the informed consent form

Exclusion Criteria:

• Active infection requiring intravenous antibiotics at day 1 of cycle 1
• Active or untreated central nervous system metastases
• Another concomitant cancer or history of cancer during the last 5 years, except forcarcinoma in situ of the uterine cervix or a basal cell or squamous cell skincarcinoma or any other carcinoma in situ considered as cured
• Previous bone marrow allogenic stem cell transplantation or previous organtransplantation
• History of idiopathic pulmonary fibrosis, medicinal product-related pneumonia or proofof active pneumonia or pneumonitis on a chest CT-scan prior to therapy
• HIV infection, active hepatitis B or C infection, active tuberculosis
• Colorectal cancer with microsatellite instability (dMMR and/or MSI)
• Patient eligible for curative treatment (resection and/or thermal ablation accordingto the opinion of the local multidisciplinary tumour meeting board)
• Patient with only primary tumour biopsies available or only a sample of a metastasis (no surgical resection of the primary tumour)
• Previous treatment with anti-PD1 or anti-PDL1 or another immunotherapy
• An auto-immune disease which may worsen during treatment with an immune-stimulatingagent (patients with type I diabetes, vitiligo, psoriasis, hypo or hyperthyroidism notrequiring immunosuppressant therapy are eligible)
• Long-term immunosuppressant therapy (patients requiring corticosteroid therapy areeligible if administration at a dose ≤ 10 mg prednisone equivalent dose per day,administration of steroids by a route of administration resulting in minimal systemicexposure (cutaneous, rectal, ocular or inhalation) is authorised)
• Known severe hypersensitivity to monoclonal antibodies, to one of the medicinalproducts used or to one of the excipients in the products used or a history ofanaphylactic shock or of uncontrolled asthma
• Vaccinations (live vaccine) within 30 days prior to start of treatment
• Dihydropyrimidine Dehydrogenase (DPD) deficiency defined by uracilemy level ≥ 16 ng/mL
• QT/QTc interval > 450 msec in men and > 470 msec in women
• One of the following disorders during the 6 months prior to inclusion: myocardialinfarction, unstable/severe angina pectoris, coronary artery bypass grafting, NYHAclass II, III or IV congestive heart failure, stroke or transient ischaemic attack
• All uncontrolled progressive disorders during the last 6 months: hepaticinsufficiency, renal insufficiency, respiratory insufficiency, arterial hypertension
• History of an inflammatory digestive disease, obstruction or sub-obstruction notresolved with symptomatic treatment
• Peptic ulcer disease not healed before the treatment
• Not controlled HTA
• Patient already enrolled in another therapeutic trial with an ongoing investigationaldrug or whose treatment ended less than 4 weeks before inclusion
• Absence of effective contraception in patients (male and/or female patients) ofchildbearing potential, a pregnant or breastfeeding woman, women of childbearingpotential and who have not had a pregnancy test
• Impossibility to submit to medical follow-up of the trial due to geographic, social orpsychological reasons