FOLFOXIRI plus bevacizumab and atezolizumab as upfront treatment of unresectable mCRC patients: Updated and overall survival results of the phase II randomized AtezoTRIBE study

AtezoTRIBE (NCT03721653) is a phase II randomized trial in which unresectable mCRC pts were randomized 1:2 to 1st-line FOLFOXIRI/bev [arm A] or FOLFOXIRI/bev/atezo [arm B]. Adding atezo to FOLFOXIRI/bev was safe and improved PFS (primary endpoint), with a modest benefit also among pts with pMMR tumors. Subgroup analyses suggest that TMB and Immunoscore IC® (IS IC) -an IHC biomarker measuring CD8 and PD-L1 cell densities and their proximity- may identify pts with pMMR tumors deriving benefit from adding atezo to FOLFOXIRI/bev.

The study had 85% power to detect a HR for PFS (time from randomization to 1st PD or death [PD1]) of 0.66 in favor of arm B with 1-sided α error of 0.10. Secondary endpoints included PFS2 (time from randomization to PD on any treatment given after PD1 or death [PD2]), 2nd PFS (time from PD1 to PD2), and OS. MMR, TMB, IS IC were correlated to clinical outcome.

218 pts (arm A/B:73/145) were enrolled. Main pts’ characteristics were right-sided 44%/45%, RAS mut 71%/74%, BRAF mut 14%/8%, dMMR 7%/6%, high TMB 10%/12%, high IS IC 32%/32%. At a median follow-up of 37.0 mos, 175 (80%, arm A/B: 64/111) PD1, 150 (69%, arm A/B: 53/97) PD2, and 118 (54%, arm A/B: 43/75) OS events were collected. Out of 175 pts with a PD1 event, 135 (77%, arm A/B:50/85) received a subsequent treatment; among them, 121 pts (arm A/B: 43/78) had a PD2 event. In the intention-to-treat (ITT) population, a significant advantage for arm B was confirmed in terms of PFS (HR:0.71, 80%CI 0.58-0.87, p=0.015), with a trend for a better outcome in terms of both PFS2 (HR:0.85, 80%CI 0.68-1.05, p=0.164) and OS (HR:0.81, 80% CI 0.63-1.04, p=0.136). No differences were observed in terms of 2nd PFS between arms (HR:1.15, 80%CI 0.90-1.48, p=0.228). Similar results were reported in the pMMR group. In the ITT population, significant interactions between treatment and MMR status (Pint 0.011), TMB (Pint 0.008), and IS IC (Pint 0.037) were reported in terms of PFS. Only IS IC was associated with a differential OS benefit (Pint 0.065), with pts bearing IS IC-high tumors deriving benefit from adding atezo (HR:0.43, 95%CI 0.19-1.00), differently than those with IS IC-low tumors (HR:1.09, 95%CI 0.65-1.83). In the pMMR group, significant interactions between treatment and TMB and IS IC were reported in terms of PFS (Pint 0.016 and 0.051, respectively) and OS (Pint 0.043 and 0.063, respectively). Pts bearing IS IC-high tumors derived higher OS benefit from adding atezo (HR:0.44, 95%CI 0.19-1.03), than those with IS IC-low tumors (HR:1.15, 95% CI 0.67-1.97).

Pts with IS IC-high and/or TMB high pMMR mCRC seem to derive a survival benefit from adding atezo to FOLFOXIRI/bev as upfront treatment. These findings deserve confirmation in a properly designed phase III trial.

NCT03721653.

The authors.

GONO Foundation. Roche.

D. Rossini: Honoraria (self): MSD Italy, AMGEN Italy. A. Catteau: Full / Part-time employment: Veracyte. J. Galon: Research grant / Funding (institution): Veracyte; Travel / Accommodation / Expenses: Veracyte; Shareholder / Stockholder / Stock options: Veracyte; Licensing / Royalties: INSERM, Veracyte; Full / Part-time employment: Veracyte. All other authors have declared no conflicts of interest.