Background of the study

In the last few years, the immunotherapy has deeply changed the treatment of several solid tumors. Less evidence is currently available in metastatic colorectal cancer, where the benefit of this class of drugs is limited to a small subset of patients, approximately 3-5% of cases, with tumours bearing a specific molecular characteristic, known as microsatellite instability. Indeed, in the majority of colorectal cancers with microsatellite stability, the use of immunotherapy alone reported no signals of activity. The AVETRIC study has been conceived from the hypothesis of testing a therapeutic strategy potentially able to definitely modify tumour biology and to sensitize it to an immunotherapeutic agent, named avelumab. This innovative approach aims to extend the clinical benefit of this class of drugs even to those patients with an otherwise resistant disease. A growing amount of data suggests that both chemotherapy and targeted agents commonly used in the treatment of colorectal cancer are effective in stimulating the immune system against cancer cells. The modified schedule of the triplet FOLFOXIRI (5fluorouracil, oxaliplatin, irinotecan) in combination with an anti-EGFR agent (cetuximab or panitumumab) in patients with a molecularly selected metastatic colorectal cancer showed a manageable safety profile and an interesting activity, as reported in two previous clinical trials by our group (MACBETH and TRIP studies). The promising immunogenic property of both this intensified chemotherapy regimen and the anti-EGFR antibody cetuximab could enhance the efficacy of the immunotherapy with avelumab. Furthermore, a phase II clinical study recently showed encouraging results in terms of efficacy and safety of the combination of FOLFOX (5fluorouracil and oxaliplatin) with cetuximab and avelumab. The AVETRIC study will enroll patients with initially unresectable and previously untreated RAS wild-type metastatic colorectal cancer.

Aim of the study

To assess the safety and efficacy of the modified schedule of FOLFOXIRI in combination with cetuximab and avelumab in patients with initially unresectable RAS wild-type metastatic colorectal cancer in terms of progression-free survival.