Background: AtezoTRIBE (NCT03721653) is a phase II randomized trial in which unresectable mCRC pts were randomized 1:2 to 1^st-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. Methods: The study had 85% power to detect a HR for PFS (time from randomization to 1^st PD or death [PD1]) of .66 in favor of arm B with 1-sided α error of .10. Secondary endpoints included PFS2 (time from randomization to PD on any treatment given after PD1 or death [PD2]), 2^nd PFS (time from PD1 to PD2), and OS. MMR, TMB, IS IC were correlated to clinical outcome. Results: 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. PFS, PFS2, 2^nd PFS and OS results in the intention-to-treat (ITT) population and the pMMR group are listed in the Table. In the ITT population, significant interactions between treatment and MMR status (P_int .011), TMB (P_int .008), and IS IC (P_int .037) were reported in terms of PFS. Only IS IC was associated with a differential OS benefit (P_int .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 (P_int .016 and .051, respectively) and OS (P_int .043 and .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). Conclusions: 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. Clinical trial information: NCT03721653.

*assessed on 135 pts in ITT and 127 pts in pMMR populations.