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

• FOLFOX regimen (Drug): A course of treatment every 14 days Oxaliplatin: 85 mg/m² IV over 2 hours Folinic acid: 400 mg/m² (or 200 mg/m² if Elvorine) IV over 2 hours 5FU bolus: 400 mg/m² IV bolus over 10 minutes in 100 ml 0.9% NaCl 5FU continuous: 2,400 mg/m² in NaCl 0.9% in IV over 46 hours
• FOLFIRI Protocol (Drug): A course of treatment every 14 days Irinotecan: 180 mg/m² IV over 1H30 Folinic acid: 400 mg/m² (or 200 mg/m² if Elvorine) IV over 2 hours 5FU bolus: 400 mg/m² IV bolus over 10 minutes in 100 ml 0.9% NaCl 5FU continuous: 2,400 mg/m² in NaCl 0.9% in IV over 46 hours
• Avelumab (Drug): A course of treatment every 14 days. Premedication obligatory with antihistamines and paracetamol (example: 25-50 mg diphenhydramine and 500-650 mg paracetamol) IV, approximately 30 to 60 minutes before each dose of avelumab. Then: Avelumab: 10 mg/kg IV in 1 hour diluted with 0.9% saline solution; alternatively a 0.45% saline solution can be used if needed
• Panitumumab (Drug): Administered at 6 mg/Kg
• Cetuximab (Drug): Administered at 500 mg/m²
• Bevacizumab (Drug): Administered at 5 mg/Kg
• Aflibercept (Drug): Administered at 4 mg/Kg

Primary outcomes

• Progression-free survival (PFS) according to the investigator [up to 12 months]: Progression is defined as RECIST v1.1 criteria. Death is also considered as an event

Secondary outcomes

• Overall Survival [up to 60 months]: Defined as death due to all causes

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* 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

Exclusion Criteria:

* Patient immediately eligible for a curative therapy (surgical and/or percutaneous) after discussion in CPR
* Patient treated with FOLFIRINOX or FOLFOXIRI in 1st line
* Cerebral metastasis
* 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).
* 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
* Persistence of toxicities related to 1st line chemotherapy grade > 2 (NCI-CTC v4.0) (except alopecia and neuropathy sequelae of oxaliplatin)
* Vaccination during the 4 weeks preceding the start of treatment
* Known deficit in DPD
* QT/QTc interval > 450 msec for men and > 470 msec for women
* K+ < LIN, Mg2+ < LIN, Ca2+ < LIN
* 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
* 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
* Patient already included in another clinical trial during treatment with an experimental molecule for L2
* 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
* Persons deprived of liberty or under supervision
* Impossibility of undergoing medical monitoring during the trial for geographic, social or psychological reasons

20 more sites not listed.

• Taieb J, Andre T, El Hajbi F, Barbier E, Toullec C, Kim S, Bouche O, Di Fiore F, Chauvenet M, Perrier H, Evesque L, Laurent-Puig P, Emile JF, Bez J, Lepage C, Tougeron D. Avelumab versus standard second line treatment chemotherapy in metastatic colorectal cancer patients with microsatellite instability: The SAMCO-PRODIGE 54 randomised phase II trial. Dig Liver Dis. 2021 Mar;53(3):318-323. doi: 10.1016/j.dld.2020.11.031. Epub 2020 Dec 25. PMID 33359404
• Results publication: Taieb J, Sullo FG, Lecanu A, Bourreau C, Barbier E, Gandini A, Bez J, Mulot C, Di Fiore F, Elhajbi F, Borg C, Bouche O, Aparicio T, Zaanan A, Andre T, Tougeron D, Taly V, Laurent-Puig P. Early ctDNA and Survival in Metastatic Colorectal Cancer Treated With Immune Checkpoint Inhibitors: A Secondary Analysis of the SAMCO-PRODIGE 54 Randomized Clinical Trial. JAMA Oncol. 2025 Aug 1;11(8):874-882. doi: 10.1001/jamaoncol.2025.1646. PMID 40531517
• Results publication: Taieb J, Bouche O, Andre T, Le Malicot K, Laurent-Puig P, Bez J, Toullec C, Borg C, Randrian V, Evesque L, Corbinais S, Perrier H, Buecher B, Di Fiore F, Gallois C, Emile JF, Lepage C, Elhajbi F, Tougeron D; SAMCO-PRODIGE 54 Investigators. Avelumab vs Standard Second-Line Chemotherapy in Patients With Metastatic Colorectal Cancer and Microsatellite Instability: A Randomized Clinical Trial. JAMA Oncol. 2023 Oct 1;9(10):1356-1363. doi: 10.1001/jamaoncol.2023.2761. PMID 37535388

• Julien Taieb, Pr, Principal investigator, HOPITAL EUROPEEN G. POMPIDOU