AtezoTRIBE2

FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab is, currently, included among first-line options in most clinical guidelines and recommendations worldwide in patients with metastatic colorectal cancer (mCRC).

Immune-checkpoint inhibitors (ICIs) entered the therapeutic algorithm of metastatic colorectal cancer for the subgroup of patients – about 5% – of patients bearing tumours with a deficient DNA mismatch repair (dMMR) system, leading to high microsatellite instability (MSI-H).

Howewer, the majority of metastatic colorectal cancers have a proficient mismatch repair (pMMR) system and are microsatellite stable (MSS) and intrinsically resistant to immune checkpoint inhibitors, showing an immune desert or immune-excluded microenvironment, with absent or inactive CD8+ TLs, and reduced expression of checkpoint proteins on tumour cells.

With the aim of increasing the immunogenicity of pMMR/MSS tumours and making checkpoint inhibitors efficacious, their combination with antitumoral agents with immunomodulatory properties is an appealing research strategy.

Preliminary evidence suggest that both cytotoxic agents and bevacizumab seem able to increase the immunogenicity of pMMR or MSS tumours. Indeed, active chemotherapy regimens, such as the triplet FOLFOXIRI, are able to induce immunogenic cell death and activate CD8 T lymphocytes, as the consequence of the release of tumour-associated neoantigens, while bevacizumab establishes an immune-permissive tumour microenvironment, by promoting dendritic cell maturation, increasing tumour infiltration by CD8 T lymphocytes through tumour vasculature normalization.

The phase II randomized trial AtezoTRIBE investigated whether the addition of atezolizumab to first-line FOLFOXIRI plus bevacizumab was beneficial in terms of Progression-Free Survival (PFS) in patients with mCRC. In details, this study demonstrated that the addition of atezolizumab to first-line FOLFOXIRI plus bevacizumab is safe and prolongs progression-free survival, as compared to FOLFOXIRI plus bevacizumab, in mCRC patients, unselected for mismatch repair (MMR) status. Notably, a limited benefit in favour of FOLFOXIRI plus bevacizumab and atezolizumab has also been reported in patients with pMMR tumours.

A growing amount of evidence suggests that the characterization of tumour immune microenvironment may help to identify biomarkers potentially of interest for predicting benefit from ICI-based approaches in different solid tumours, also within pMMR or MSS mCRC.

To this regard, AtezoTRIBE is the first randomized trial providing compelling evidence that a biomarker describing tumour immune microenvironment, Immunoscore-IC, could be a reliable predictor of the efficacy of a first-generation ICI in pMMR mCRC.

Among patients with pMMR tumour enrolled in the phase 2 AtezoTRIBE study, results from biomarkers post-hoc exploratory analyses showed that patients with Immunoscore IC-high tumours are more likely to benefit from the addition of atezolizumab to first-line FOLFOXIRI plus bevacizumab.

Based on these considerations, we designed the present phase III randomized study of FOLFOXIRI plus bev (arm A) versus FOLFOXIRI plus bev and atezolizumab (arm B) as first-line treatment of patients with pMMR and Immunoscore IC-high mCRC, in order to assess the efficacy of the combination of an immune checkpoint inhibitor with an intensified chemotherapy regimen – the triplet FOLFOXIRI – plus bevacizumab in a molecularly selected population.

Inclusion criteria

– Histologically proven diagnosis of colorectal cancer
– Initially unresectable metastatic colorectal cancer not previously treated with chemotherapy for metastatic disease
– Proficient mismatch repair (pMMR) status in tumour tissue (primary or metastatic), as determined by a local laboratory assay in a CLIA- or similarly certified
– Immunoscore IC-high status in tumour tissue (primary or metastatic), as determined by a sponsor-defined central laboratory (HEGP, AP-HP, INSERM, France)
– Previous adjuvant chemotherapy allowed only if with fluoropyrimidine monotherapy and more than 6 months elapsed between the end of adjuvant and first relapse

Exclusion criteria

– Radiotherapy to any site within 4 weeks before the study
– Previous adjuvant oxaliplatin-containing chemotherapy
– Previous treatment with bevacizumab
– Prior treatment with CD137 agonists, anti-CTLA4, anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway-targeting agents
– Complete dihydropyrimidine dehydrogenase (DPYD) deficiency
– Any controindication to immune checkpoint inhibitors

Primary objective

Primary objective of this study is to evaluate the efficacy of the addition of Atezolizumab to FOLFOXIRI plus bev as first line treatment of patients with pMMR and Immunoscore IC-high metastatic colorectal cancer in terms of Progression Free Survival (PFS).

Secondary objective

Secondary objectives of this study are to evaluate the safety, activity and efficacy of the addition of Atezolizumab to FOLFOXIRI plus bev in terms of:

• Incidence and severity of adverse events, graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0;
• Objective response rate according to RECIST version 1.1 criteria (ORR), by investigators;
• Immuno-related objective response rate according to modified RECIST criteria (irORR), by investigators;
• Early Objective Response Rate (EOR);
• Depth of response (DpR);
• R0 Resection Rate;
• Overall Survival (OS);
• Quality of Life (QoL) as measured by PROs questionnaires (EORTC QLQ-C30 and EORTC QLQ-CR29);
• Time To Deterioration in Quality of Life (TTD);
• Translational analyses including the evaluation of immunity-related parameters on tumour and blood samples collected both before and during the study treatment.