Nivolumab and Ipilimumab in Anti-PD1-Resistant dMMR/MSI mCRC

Inclusion Criteria:

1. Signed and dated patient informed consent form and willingness to comply with allstudy procedures and availability for the study duration,

2. Age ≥ 18 years,

3. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, 1, and 2,

4. Histologically confirmed colorectal adenocarcinoma,

5. Documented metastatic disease not suitable for complete surgical resection,

6. Disease progression per iRECIST criteria (i.e., iCPD: immune confirmed PD) duringmonotherapy with anti-PD1 monoclonal antibody or less than 6 months after thediscontinuation of anti-PD1 monoclonal antibody

7. Disease progression during, after, or patients who are intolerant or havecontraindications to approved standard therapies for the metastatic disease, whichmust include at least: • Fluoropyrimidine, oxaliplatin, and irinotecan, • Anti-EGFRtherapy if wild-type RAS, • Anti-VEGF therapy,

8. At least one measurable lesion as assessed by CT-scan or magnetic resonance imaging (MRI) according to RECIST 1.1 and feasibility of repeated radiological assessments,

9. dMMR and/or MSI tumor status defined by: - Loss of MMR protein expression usingimmunohistochemistry with four (anti-MLH1, anti-MSH2, anti-MSH6, and anti-PMS2)antibodies, - and/or ≥ two unstable markers by pentaplex polymerase chain reaction (BAT-25, BAT-26, NR-21, NR-24, and NR-27), NB: In case of loss of expression of onlyone MMR protein immunohistochemistry, it is necessary to confirm the tumor is MSIusing pentaplex PCR. NB: In cases with two unstable markers, comparison with matching normal tissue isrequired. NB: Agreement of the Sponsor (GERCOR) is mandatory to include the patient (thepatient's file will be verified to confirm MSI/dMMR status before inclusion [ananonymized fax] and confirmation of a patient's allocation will be sent by mail tothe Investigator within 24h).

10. For all patients, a new biopsy must be performed to obtain fresh anti-PD1 resistanttumor tissue prior to study treatment initiation,

11. For all patients, archival formalin-fixed paraffin-embedded tissue (FFPE) blocksand/or FFPE unstained slides (minimum of 30 positively charged slides representativeof tumor tissue and non-tumor adjacent prior to anti-PD1 therapy (i.e., primary ormetastatic site naïve of immunotherapy) must be submitted to the central laboratory,

12. Adequate hematologic and end-organ function, defined by the following laboratorytest results, obtained within 7 days prior inclusion: - Adequate hematologicalstatus (White blood cell > 2000/μL; o Neutrophils > 1500/μL; Platelets > 100.000/μL;Hemoglobin > 10.0 g/dL; - Adequate renal function: Serum creatinine level < 120 μM;Clearance > 50 ml/min (Modification of the Diet in Renal Disease [MDRD] or Cockcroftand Gault, - Adequate liver function: Serum bilirubin ≤ 1.5 x upper normal limit (ULN); Alkaline phosphatase (ALP) ≤ 3.0 x ULN; Alanine aminotransferase (ALT) ≤ 3.0x ULN; Aspartate aminotransferase (AST) ≤ 3.0 x ULN; Hemostasis: Prothrombin time (PT)/International normalized ratio (INR) and activated partial PT (aPTT) ≤ 1.5 xULN unless participants are receiving anticoagulant therapy and their INR is stableand within the recommended range for the desired level of anticoagulation,

13. Females of childbearing potential must have negative serum pregnancy test within 7days before starting study treatment,

14. Women of childbearing potential should use effective contraception during treatmentand at least 5 months thereafter.

15. Registration in a national health care system (Protection Universelle Maladie [PUMa]included)

Exclusion Criteria:

1. Known brain metastases or leptomeningeal metastases,

2. Persistence of toxicities related to prior treatments (chemotherapies or anti-P1therapies) grade > 1 (NCI CTCAE v 5.0; except dysthyroidism, adrenal glanddeficiency, alopecia, fatigue or oxaliplatin-induced peripheral sensory neuropathywhich can be ≥ grade 2),

3. Discontinuation of anti-PD1 treatment due to treatment-related adverse event (AE)grade > 2 (NCI CTCAE v 5.0),

4. Prior treatment with an anti-LAG-3, anti-CTLA-4 antibody, or any other antibody ordrug specifically targeting T-cell co-stimulation or immune checkpoint pathways,including prior therapy with anti-tumor vaccines or other immuno-stimulatoryantitumor agents, except anti-PD1 antibodies,

5. Concomitant unplanned antitumor therapy (e.g. chemotherapy, molecular targetedtherapy, radiotherapy, immunotherapy),

6. Major surgical procedure within 4 weeks prior to initiation of study treatment,

7. Patients receiving any investigational drug, biological, immunological therapywithin the previous 21 days before study treatment,

8. Patients with an active, known, or suspected autoimmune disease. Patients with typeI diabetes mellitus, hypothyroidism only requiring hormone replacement, skindisorders (such as vitiligo, psoriasis, or alopecia) not requiring systemictreatment, or conditions not expected to recur in the absence of an external triggerare permitted to be enrolled,

9. History of interstitial lung disease or pneumonitis,

10. Patients with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone or equivalent) or other immunosuppressive medicationswithin 14 days of inclusion. NB : Exceptions to this criterion: - Inhaled or topical steroids, and adrenalreplacement steroid doses >10 mg daily prednisone or equivalent are permitted in theabsence of active autoimmune disease, - Systemic corticosteroids at physiologicdoses not exceeding strictly 10 mg/day of prednisone or its equivalent,

11. Prior malignancy active within the previous 3 years, except for: - Locally curablecancers that have been apparently cured (e.g. squamous cell skin cancer, superficialbladder cancer, or carcinoma in situ of the prostate, cervix, or breast), - Lynchsyndrome-related non-colorectal cancer in complete remission for > 1 year,

12. Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg]test prior to randomization) virus (HBV) or hepatitis C virus (HCV), or humanimmunodeficiency virus (HIV) infection. Patients with past HBV infection or resolvedHBV infection (defined as having a negative HBsAg test and a positive antibody tohepatitis B core antigen antibody test) are eligible. Patients positive for HCVantibody are eligible only if polymerase chain reaction testing is negative for HCVribonucleic acid.

13. Prior allogeneic bone marrow transplantation or prior solid organ transplantation,

14. Any serious or uncontrolled medical disorder that, in the opinion of Investigator,may increase the risk associated with study participation or study drugadministration, impair the ability of the participant to receive protocol therapy,or interfere with the interpretation of study results,

15. Known allergy/hypersensitivity to any component of study agents,

16. Administration of a (attenuated) live vaccine within 28 days of planned start ofstudy therapy of known need for this vaccine during treatment,

17. Patient under a legal protection regime (guardianship, curatorship, judicialsafeguard) or administrative decision or incapable of giving his/her consent,

18. Impossibility of submitting to the medical follow-up of the study for geographical,social, or psychiatric illness.