FOLFOXIRI Plus Bevacizumab With or Without Atezolizumab as 1st Line Treatment of pMMR and IS IC-High Metastatic Colorectal Cancer Patients.

Inclusion Criteria:

• Histologically proven diagnosis of colorectal cancer;

• Initially unresectable metastatic colorectal cancer not previously treated withchemotherapy for metastatic disease;

• Proficient mismatch repair (pMMR) status in tumour tissue (primary or metastatic),as determined by a local laboratory assay in a CLIA- or similarly certified;

• Immunoscore IC-high status in tumour tissue (primary or metastatic), as determinedby a sponsor-defined central laboratory (HEGP, AP-HP, INSERM, France).

• At least one measurable lesion according to RECIST criteria (version 1.1);

• Availability of adequate tumour specimen (primary or metastatic);

• Male or female of 18-75 years of age;

• ECOG PS ≤ 2 if aged < 71 years, ECOG PS = 0 if aged 71-75 years;

• Life expectancy of at least 12 weeks;

• Previous adjuvant chemotherapy allowed only if with fluoropyrimidine monotherapy andmore than 6 months elapsed between the end of adjuvant and first relapse;

• Neutrophils >1.5 x 109/L, Platelets >100 x 109/L, Hb >9 g/dl;

• Total bilirubin ≤1.5 times the upper-normal limits (UNL) of the normal values andAST (SGOT) and/or ALT (SGPT) <2.5 x UNL (or <5 x UNL in case of liver metastases)alkaline phosphatase <2.5 x UNL (or <5 x UNL in case of liver metastases);

• Creatinine clearance ≥50 mL/min or serum creatinine ≤1.5 x UNL;

• INR or aPTT ≤1.5 x ULN. This applies only to patients who are not receivingtherapeutic anticoagulation;

• Urine dipstick of proteinuria <2+. Patients discovered to have 2+ proteinuria ondipstick urinalysis at baseline, should undergo a 24-hour urine collection and mustdemonstrate ≤1 g of protein/24 h;

• Women of childbearing potential must have a negative blood pregnancy test at thebaseline visit. For this trial, women of childbearing potential are defined as allwomen following menarche and until becoming post-menopausal unless permanentlysterile. Permanent sterilization methods include hysterectomy, bilateralsalpingectomy and bilateral oophorectomy. A postmenopausal state is defined as nomenses for 12 months without an alternative medical cause. A high folliclestimulating hormone (FSH) level in the postmenopausal range may be used to confirm apost-menopausal state in women not using hormonal contraception or hormonalreplacement therapy. However, in the absence of 12 months of amenorrhea, a singleFSH measurement is insufficient;

• Male subjects with female partners of childbearing potential and female subjects ofchildbearing potential must, therefore, be willing to use adequate contraception asapproved by the investigator (barrier contraceptive measure or oral contraception)and outlined in "Section 6.5 - Contraception", starting with the first dose of studytherapy through 6 months after the last dose of bevacizumab and fluorouracil andwithin 5 months after the last dose of atezolizumab.

• Females of childbearing potential must have a negative blood pregnancy test at thebaseline visit (i.e., performed maximum 7 days before the treatment start);

• Will and ability to comply with the protocol;

• Written informed consent to study procedures.

Exclusion Criteria:

• Radiotherapy to any site within 4 weeks before the study;

• Previous adjuvant oxaliplatin-containing chemotherapy;

• Previous treatment with bevacizumab;

• Prior treatment with CD137 agonists, anti-CTLA4, anti-PD-1, or anti-PD-L1therapeutic antibody or pathway-targeting agents;

• Complete dihydropyrimidine dehydrogenase (DPYD) deficiency (homozygous of thefollowing DPYD polymorphisms: c1679GG, c1905+1AA, c2846TT);

• Untreated brain metastases or spinal cord compression or primary brain tumours;

• History or evidence upon physical examination of CNS disease unless adequatelytreated;

• History of haemoptysis ≥ 2 grade NCIC-CTG criteria within one month prior toscreening;

• Active or untreated CNS metastases:

• Symptomatic peripheral neuropathy > 2 grade NCIC-CTG criteria;

• Serious, non-healing wound, ulcer, or bone fracture;

• Evidence of bleeding diathesis or coagulopathy;

• Uncontrolled hypertension (SBP>150 mmHg and/or DPB>100 mmHg), or prior history ofhypertensive crisis, or hypertensive encephalopathy ;

• Clinically significant (i.e., active) cardiovascular disease for examplecerebrovascular accidents (within 6 months prior to study enrollment), myocardialinfarction (within 6 months prior to study enrollment), unstable angina, New YorkHeart Association (NYHA) grade II or greater congestive heart failure, seriouscardiac arrhythmia requiring medication;

• Significant vascular disease (e.g. aortic aneurysm requiring surgical repair orrecent arterial thrombosis) within 6 months of study enrolment;

• Active infection requiring antibiotics at the time of initiation of study treatment;

• Any previous venous thromboembolism ≥ NCI CTCAE Grade 4;

• History of abdominal fistula, GI perforation, intra-abdominal abscess or active GIbleeding within 6 months prior to the first study treatment;

• Current or recent (within 10 days prior to study treatment start) ongoing treatmentwith full-dose anticoagulants for therapeutic purposes.

• Chronic, daily treatment with high-dose aspirin (>325 mg/day);

• Treatment with any investigational drug within 30 days prior to enrollment or 2investigational agent half-lives (whichever is longer);

• Other co-existing malignancies or malignancies diagnosed within the last 5 yearswith the exception of localized basal and squamous cell carcinoma or cervical cancerin situ;

• Major surgical procedure, open biopsy, or significant traumatic injury within 28days prior to study treatment start, or anticipation of the need for major surgicalprocedure during the course of the study;

• Core biopsy or other minor surgical procedure, excluding placement of a vascularaccess device, within 7 days prior to initiation of study treatment;

• Lack of physical integrity of the upper gastrointestinal tract, malabsorptionsyndrome, or inability to take oral medication;

• Pregnant or lactating women. Women of childbearing potential with either a positiveor no pregnancy test at baseline. Postmenopausal women must have been amenorrheicfor at least 12 months to be considered of non-childbearing potential. Sexuallyactive males and females (of childbearing potential) unwilling to practicecontraception (barrier contraceptive measure or oral contraception) during the studyand until 6 months after the last dose of bevacizumab, fluorouracil and within 5months after the last dose of atezolizumab;

• History of autoimmune disease;

• History of idiopathic pulmonary fibrosis (including pneumonitis), drug-inducedpneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenicorganizing pneumonia), or evidence of active pneumonitis on screening chest CT scan;

• Positive test for human immunodeficiency virus (HIV);

• Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg]test prior to randomization) or hepatitis C;

• Active tuberculosis;

• Prior allogenic bone marrow transplantation or solid organ transplant;

• Treatment with systemic corticosteroids or other systemic immunosuppressivemedications (including but not limited to prednisone, dexamethasone,cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumour necrosisfactor [TNF] agents) within 2 weeks prior to start of study treatment, orrequirement for systemic immunosuppressive medications during the trial. The use ofinhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) is allowed;

• Known hypersensitivity or allergy to Chinese hamster ovary cell products or anycomponent of the atezolizumab formulation;

• Administration of a live, attenuated vaccine within 4 weeks prior to start of studytreatment or anticipation that such a live attenuated vaccine will be requiredduring the study;

• Treatment with systemic immunostimulatory agents (including but not limited tointerferons or interleukin-2) within 4 weeks or five half-lives of the drug,whichever is longer, prior to start of study treatment; • If receiving a RANKLinhibitor (e.g. denosumab), unwilling to adopt alternative treatment such as (butnot limited to) bisphosphonates, while receiving atezolizumab.