Standard Chemotherapy vs Immunotherapie in 2nd Line Treatment of MSI Colorectal Mestastatic Cancer

Prior treatment

• Patient immediately eligible for a curative therapy (surgical and/or percutaneous) after discussion in CPR
• Patient treated with FOLFIRINOX or FOLFOXIRI in 1st line
• Previous treatment with anti-PD1 or anti-PDL1
• Autoimmune disease that might be aggravated during treatment with an immuno-stimulating agent (patients with type I diabetes, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible)
• Immunosuppressive long-term treatment (patients necessitating a corticotherapy are eligible if they are administered in doses \< or = to the equivalent of 10 mg of prednisone daily, administration of steroids by a route resulting in minimal systemic exposure (local, intra-anal, intraocular or inhalation) are eligible).
• Persistence of toxicities related to 1st line chemotherapy grade \> 2 (NCI-CTC v4.0) (except alopecia and neuropathy sequelae of oxaliplatin)
• Following alterations in the 6 months prior to inclusion: myocardial infarction, angina, severe/unstable angina, coronary artery bypass surgery, congestive heart failure NYHA class II, III or IV, stroke or transient ischemic attack
• Patient already included in another clinical trial during treatment with an experimental molecule for L2

Other illness

• Transplant patients (including stem cell transplants), HIV positive or other immune deficiency syndromes
• Active infection by HBV or HCV
• Known severe hypersensitivity to monoclonal antibodies or history of anaphylactic shock, or uncontrolled asthma
• Any known specific contraindication or allergy to the treatments used in the study
• Any progressive pathology not stabilised over the past 6 months: hepatic failure, renal failure, respiratory failure
• Patient with interstitial pneumonitis or pulmonary fibrosis
• History of chronic diarrhea or inflammatory disease of the colon or rectum, or unresolved occlusion or sub-occlusion in symptomatic treatment
• History of malignant pathologies during the past 5 years except basocellular skin carcinoma or in situ cervical carcinoma, properly treated

Lab values

• QT/QTc interval \> 450 msec for men and \> 470 msec for women

Age

• Lack of effective contraception in patients (men and/or women) of childbearing age, pregnant or breastfeeding women, women of childbearing age not having had a pregnancy test

Other

• Cerebral metastasis
• Vaccination during the 4 weeks preceding the start of treatment
• Known deficit in DPD
• K+ \< LIN, Mg2+ \< LIN, Ca2+ \< LIN
• Persons deprived of liberty or under supervision
• Impossibility of undergoing medical monitoring during the trial for geographic, social or psychological reasons

• Histologically proven colorectal adenocarcinoma with metastasis(es) non-resectable
• MSI-H determined by immunohistochemistry (loss of expression of MLH1, MSH2, MSH6 and/or PMS2) or by molecular biology
• At least one measurable target (primary tumor or metastasis) according to RECIST v1.1
• Mutational status RAS and BRAF
• Age ≥ 18
• OMS ≤ 2
• Life expectancy \< 3 months
• Patient failure (progression or unacceptable toxicity) of chemotherapy containing fluoropyrimidine (capecitabine or 5FU) +/- irinotecan +/- oxaliplatin with or without cetuximab, bevacizumab and panitumumab (patients in progression during or within 3 months after discontinuation of adjuvant chemotherapy are eligible)
• PNN \> 1500/mm3, platelets \> 100 000/mm3, Hb \> 9 g/dL
• Total bilirubin \< 25 µmol/L, ASAT \< 5x LSN, ALAT \< 5 x LSN, PT \> 60%, , PAL\<2.5 x LSN ( \< 5 x LSN in case of hepatic metastasis)
• Creatinine clearance \> 50 ml/min according to MDRD formula (≥ 30 ml/min according to the Cockcroft-Gault formula)
• Patient belonging to a social security scheme
• Patient information and signature of the informed consent