About 85% of cases of non-metastatic colorectal cancer (CRC) are related to chromosomal instability and have a proficient DNA Mismatch-Repair system (pMMR); which are also called CRC with microsatellite stability (MSS). Other CRC, i.e. 15%, are "microsatellite unstable" (MSI) with deficient DNA Mismatch-Repair system (dMMR). These latter are characterised by generation of many neo-antigens, which result in a high anti-tumour immune response and a high peri- and/or intra-tumour lymphocyte infiltration (TIL). Investigators recently showed, with a prospectively validated immune score, that 14% of localised MSS/pMMR CRC are also highly infiltrated by CD3+ lymphocytes. This same immune score has made it possible to measure high lymphocyte infiltration in hepatic metastases, in particular, in patients treated with XELOX/FOLFOX.

Pembrolizumab, an anti-PD1 monoclonal antibody (programmed death-1) is an immune checkpoint inhibitor (ICI) of PD1/PD-L1 axis, recently approved in many cancers. Anti-PD1 antibodies have recently been reported as being very effective in patients with dMMR metastatic CRC (mCRC). In the study by Le DT et al. pMMR mCRC did not seem to benefit from anti-PD1 antibodies. However, it is possible that 20% of pMMR mCRC with a high CD3+ infiltrate in the tumour may be a subgroup of pMMR mCRC sensitive to ICI, as is the case for dMMR mCRC. Lastly, immunogenic cell death induced by chemotherapy, such as oxaliplatin, can increase the efficacy of ICI.

The prognostic value of lymphocyte infiltrate has been demonstrated in CRC by several teams. However, no validated test is used in routine clinical practice. Previously, investigators described an automated and reproducible method for analysis of TIL and investigators validated it for clinical use. Automated tests evaluating TIL are performed on virtual slides and have showed that, out of 1,220 tumours tested, 20% were highly infiltrated by CD3+ T cells. Patients presenting with a pMMR CRC with a high immune infiltrate had a better progression-free survival (HR=0.70; p=0.02). An immunoscore® described by Galon et al. has also a high prognostic value in CRC and is based on CD3+ and CD8+ T cells infiltration in the center and periphery of the tumour. Finally, approximately 14% of tumours with a high immune infiltrate have been found in patients with metastatic CRC.

Investigators formulated the hypothesis that patients with a pMMR CRC with a high immune infiltrate can be sensitive to ICI . Therefore, blocks of resected primary tumour will be collected and analysed prospectively. For each patient, slides containing tumour tissue and adjacent non-tumour tissue will be analysed using two techniques : immunoscore® and TuLIS score.It consist in Immunohistochemistry with CD3 and CD8 staining. Slides will be scanned and analysed by image analysis as previously described . Tumours will then be classified as having a "high" or "low" immune response according to type of lymphocyte infiltrate, which is independent of pre-analytic conditions. Only patients with a high immune response will be eligible for the POCHI trial. Other biomarkers will be analysed like other immune populations or mutational load. If investigators identify an immune score which seems clinically relevant to predict sensitivity to ICI in pMMR mCRC, this will make it possible to plan a randomised phase III trial comparing chemotherapy and anti-angiogenic antibody versus chemotherapy and anti-angiogenic antibody plus pembrolizumab in patients with a pMMR mCRC with a high immune score and/or a hypermutated genotype.

Investigators choose PFS at 10 months as primary endpoint in POCHI trial because it is a surrogate marker of OS. Actually median PFS in first-line setting with a doublet plus a biological agent is range from 8 to 11 months in unresectable mCRC, corresponding to a PFS of 50% at 10 months. The alternative clinical hypothesis to obtain 70% of patients alive and without progression at 10 months is ambitious and currently not achieved with current chemotherapies plus a biological agent. Up until now there is no data concerning survivals outcomes of patients with a MSS mCRC with high immune infiltration score.

Inclusion Criteria:

• Age ≥ 18 years
• MSS and pMMR metastatic colorectal adenocarcinoma (metachronous or synchronous metastases), 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 resected disease R0 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 scores obtained on the primary tumour (resection of primary tumour containing at least 2 mm of tumour-free margin between the tumour and non-tumour area)
• Unresectable cancer with at least one measurable metastatic target according to RECIST v1.1 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, alkaline phosphatase. ≤ 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 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
• Previous bone marrow allogenic stem cell transplantation or previous organ transplantation
• History of idiopathic pulmonary fibrosis, medicinal product-related pneumonia or proof of 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 according to 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-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)
• 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
• 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: myocardial infarction, unstable/severe angina pectoris, coronary artery bypass grafting, NYHA class II, III or IV congestive heart failure, stroke or transient ischaemic attack
• All uncontrolled progressive disorders during the last 6 months: hepatic insufficiency, renal insufficiency, respiratory insufficiency, arterial hypertension
• History of an inflammatory digestive disease, obstruction or sub-obstruction not resolved with symptomatic treatment
• Peptic ulcer disease not healed before the treatment
• Not controlled HTA
• Patient already enrolled in another therapeutic trial with an ongoing investigational drug or whose treatment ended less than 4 weeks before inclusion
• 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