西妥昔单抗联合FOLFOXIRI与西妥昔单抗联合FOLFOX作为初始无法切除的RAS/BRAF野生型结直肠癌肝转移患者的转化治疗方案(TRICE试验):一项随机对照试验OACSTPCD

Background It remains unclear whether intensification of the chemotherapy backbone in tandem with an anti-EGFR can confer superior clinical outcomes in a cohort of RAS/BRAF wild-type colorectal cancer(CRC)patients with ini-tially unresectable colorectal liver metastases(CRLM).To that end,we sought to comparatively evaluate the efficacy and safety of cetuximab plus FOLFOXIRI(triplet arm)versus cetuximab plus FOLFOX(doublet arm)as a conversion regimen(i.e.,unresectable to resectable)in CRC patients with unresectable CRLM.Methods and findings This open-label,random-ized clinical trial was conducted from April 2018 to December 2022 in 7 medical centers across China,enrolling 146 RAS/BRAF wild-type CRC patients with initially unresectable CRLM.A stratified blocked randomization method was uti-lized to assign patients(1∶1)to either the cetuximab plus FOLFOXIRI(n=72)or cetuximab plus FOLFOX(n=74)treat-ment arms.Stratification factors were tumor location(left versus right)and resectability(technically unresectable ver-sus ≥ 5 metastases).The primary outcome was the objective response rate(ORR).Secondary outcomes included the me-dian depth of tumor response(DpR),early tumor shrinkage(ETS),R0 resection rate,progression-free survival(PFS),overall survival(not mature at the time of analysis),and safety profile.Radiological tumor evaluations were conducted by radiologists blinded to the group allocation.Primary efficacy analyses were conducted based on the intention-to-treat population,while safety analyses were performed on patients who received at least 1 line of chemotherapy.A total of 14 patients(9.6％)were lost to follow-up(9 in the doublet arm and 5 in the triplet arm).The ORR was comparable follow-ing adjustment for stratification factors,with 84.7％versus 79.7％in the triplet and doublet arms,respectively[OR,0.70;95％confidence intervals(CI),0.30-1.67;Chi-square P=0.42].Moreover,the ETS rate showed no significant difference be-tween the triplet and doublet arms[80.6％(58/72)versus 77.0％(57/74);OR,0.82;95％CI 0.37-1.83,Chi-square P=0.63].Although median DpR was higher in the triplet therapy group[59.6％,interquartile range(IQR),(50.0-69.7)versus 55.0％,IQR,(42.8,63.8);Mann-Whitney P=0.039],the R0/R1 resection rate with or without radiofrequency abla-tion/stereotactic body radiation therapy was comparable with 54.2％(39/72)of patients in the triplet arm versus 52.7％(39/74)in the doublet arm.At a median follow-up of 26.2 months[IQR(12.8,40.5)],the median PFS was 11.8 months in the triplet arm versus 13.4 months in the doublet arm[hazard ratio(HR)0.74;95％CI,0.50-1.11;Log-rank P=0.14].Grade ≥ 3 events were reported in 47.2％(35/74)of patients in the doublet arm and 55.9％(38/68)of pa-tients in the triplet arm.The triplet arm was associated with a higher incidence of grade ≥ 3 neutropenia(44.1％versus 27.0％,P=0.03)and diarrhea(5.9％versus 0％,P=0.03).The primary limitations of the study encompass the inherent bias in subjective surgical decisions regarding resection feasibility,as well as the lack of a centralized assessment for ORR and resection.Conclusions The combination of cetuximab with FOLFOXIRI did not significantly improve ORR com-pared to cetuximab plus FOLFOX.Despite achieving an enhanced DpR,this improvement did not translate into improved R0 resection rates or PFS.Moreover,the triplet arm was associated with an increase in treatment-related toxicity.Clinical-Trials.gov registration:NCT03493048.