Treatment of microstellite stable metastatic colorectal cancer presenting high immune infiltrate with chemotherapy (XELOX or FOLFOX Bevacizumab) and immunotherapy ( Pembrolizumab)

Prior treatment

• Previous bone marrow allogenic stem cell transplantation or previous organ transplantation
• Previous treatment with anti-PD1 or anti-PDL1 or another immunotherapy
• History of idiopathic pulmonary fibrosis, medicinal product-related pneumonia or proof of active pneumonia or pneumonitis on a chest CTscan prior to therapy
• Patient with only primary tumour biopsies available or only a sample of a metastasis (no surgical resection of the primary tumour)
• An auto-immune disease which may worsen during treatment with an immune-stimulating agent (patients with type I diabetes, vitiligo, psoriasis, hypo or hyperthyroidism not requiring immunosuppressant therapy are eligible)
• Long-term immunosuppressant therapy (patients requiring corticosteroid therapy are eligible if administration at a dose ≤ 10 mg prednisone equivalent dose per day, administration of steroids by a route of administration resulting in minimal systemic exposure (cutaneous, rectal, ocular or inhalation) is authorised)
• Vaccinations (live vaccine) within 30 days prior to start of treatment
• One of the following disorders during the 6 months prior to inclusion: myocardial infarction, unstable/severe angina pectoris, coronary artery bypass grafting, NYHA class II, III or IV congestive heart failure, stroke or transient ischaemic attack
• Concomitant treatment with brivudine or brivudine within 4 weeks before capecitabine or 5FU initiation
• Patient already enrolled in another therapeutic trial with an ongoing investigational drug or whose treatment ended less than 4 weeks before inclusion
• Patients who have had neo-adjuvant treatment (chemotherapy or radiotherapy) for the treatment of primary tumor can not be included

Other illness

• Active infection requiring intravenous antibiotics at day 1 of cycle 1
• Another concomitant cancer or history of cancer during the last 5 years, except for carcinoma in situ of the uterine cervix or a basal cell or squamous cell skin carcinoma or any other carcinoma in situ considered as cured
• HIV infection, active hepatitis B or C infection, active tuberculosis
• Colorectal cancer with microsatellite instability (dMMR and/or MSI)
• All uncontrolled progressive disorders during the last 6 months: hepatic insufficiency, renal insufficiency, respiratory insufficiency, arterial hypertension
• Known severe hypersensitivity to monoclonal antibodies, to one of the medicinal products used or to one of the excipients in the products used or a history of anaphylactic shock or of uncontrolled asthma
• History of an inflammatory digestive disease, obstruction or subobstruction not resolved with symptomatic treatment
• Peptic ulcer disease not healed before the treatment

Lab values

• Patient eligible for curative treatment (resection and/or thermal ablation according to the opinion of the local multidisciplinary tumour meeting board) and patient with RAS wild-type tumour for whom a tumour shrinkage with an anti-EGFR is necessary to perhaps obtain a XML File Identifier: IjpoCuOJiXEw1TRpi8rHlb0n7yE= Page 27/63 downstaging for a secondary surgery (according to the opinion of the local multidisciplinary tumour meeting board and/or at investigator's discretion)
• QT/QTc interval > 450 msec in men and > 470 msec in women

Other

• Dihydropyrimidine Dehydrogenase (DPD) deficiency defined by uracilemy level ≥ 16 ng/mL
• Poor nutritional status
• Active or untreated central nervous system metastases
• Absence of effective contraception in patients (male and/or female patients) of childbearing potential, a pregnant or breastfeeding woman, women of childbearing potential and who have not had a pregnancy test
• Impossibility to submit to medical follow-up of the trial due to geographic, social or psychological reasons

• ≥ 18 years
• Adequate liver function: AST/ALT ≤ 5xULN, total bilirubin ≤ 2xULN, Alkaline phosphatase ≤ 5xULN
• Creatinine clearance > 50 mL/min according to the CKD-EPI 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
• Both MSS and pMMR metastatic colorectal adenocarcinoma (metachronous or synchronous metastases), histologically proven
• Patients who have had adjuvant/post-operative chemotherapy and/or post-operative radiotherapy for the treatment of their primary tumor or R0 resected metastatic lesions can be included if they have a recurrence more than 6 months after the end of this treatment
• High immune response defined as the immune infiltration score obtained on the primary tumour (resection of primary tumour containing at least 2 mm of tumour-free margin between the tumour and nontumour area)
• Unresectable cancer with at least one measurable metastatic target according to RECIST v1.1 criteria
• WHO PS ≤ 1
• Absence severe neuropathy (≥ grade 2) (chemo-induced or not)
• Life expectancy > 3 months
• Adequate haematological function: neutrophils > 1,500 /mm3, platelets > 100,000/mm3, Hb > 9 g/dL