Immune chekpoints (ICI) are evaluated in many digestive cancers. Certain types of cancer
appear to be rather refractory to ICI such as colorectal cancers (CRC). However, the MSI CRC
representing approximately 15% of the CRCs exhibits a high mutational load which generates
many potentially immunogenic neoantigens. In addition, strong expression of PD-L1 was found
in the MSI CRCs relative to the CRC (MSS) stages. Localized MSI CRCs have a better prognosis
than MSS CRCs, probably due to immunogenic neoantigens associated with a CD8 + T-specific
immune response. On the oher hand, in metastatic CRC (mCRC) things are different because i)
the MSI frequency is only 4 to 7% and ii) the good prognosis conferred by the MSI status is
controversial.
Preliminary results suggest that patients with MSI mCRC are highly sensitive to ICI even
chemoresistant tumors receiving several lines of chemotherapy. Recently, another anti-PD1
alone or in combination with an anti-CTLA4 (antigen associated with cytotoxic T-lymphocyte 4)
was tested in the MSI CRCs and a selection of interesting results in heavily pretreated
patients with a disease control rate of 56% for monotherapy and 81% for combinated therapy.
Anti-PD1s now have marketing authorization for patients with melanoma and metastatic
pulmonary carcinoma , Which are known to have a high level of mutations . ICIs appear to be
as promising in MSI CRCs as in other tumors and therefore face the same major challenges.
Avalumab is an anti-PD-L1 antibody recently tested in several different types of tumors with
promising results and is currently being studied in phase III in gastric cancer. There is no
data on the effectiveness of this ICI in the MSI mCRCs. In addition, only anti-PD1 was used
in the MSI-mCRC and not the anti-PD-L1, and only in chemoresistance (3rd line or more). The
main objective of the SAMCO study is to test the efficacy and tolerance of avelumab in the
2nd line of treatment in patients with a MSI mCRC progression after standard 1st line
chemotherapy +/- targeted therapy.
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
