Cetuximab plus FOLFOXIRI versus cetuximab plus FOLFOX as conversion regimen in RAS/BRAF wild-type patients with initially unresectable colorectal liver metastases (TRICE trial): A randomized controlled trial.

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 initially 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, randomized 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 utilized to assign patients (1:1) to either the cetuximab plus FOLFOXIRI (n = 72) or cetuximab plus FOLFOX (n = 74) treatment arms. Stratification factors were tumor location (left versus right) and resectability (technically unresectable versus ≥5 metastases). The primary outcome was the objective response rate (ORR). Secondary outcomes included the median 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 following adjustment for stratification factors, with 84.7% versus 79.7% in the triplet and doublet arms, respectively (odds ratio [OR] 0.70; 95% confidence intervals [CI] [0.30, 1.67], Chi-square p = 0.42). Moreover, the ETS rate showed no significant difference between 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 ablation/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 patients 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 compared 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. Trial Registration: ClinicalTrials.gov Identifier: NCT03493048. De-Shen Wang and colleagues evaluate the efficacy and safety of cetuximab plus FOLFOXIRI versus cetuximab plus FOLFOX as a conversion regimen in CRC patients with initially unresectable colorectal liver metastases. Author summary: Why was this study done?: Liver metastasis is a common and significant challenge in colorectal cancer (CRC). Achieving resection through local treatments such as surgery, radiofrequency treatment, and stereotactic body radiation therapy is crucial for long-term survival. Therefore, identifying strategies to increase the conversion to resection rate in patients with initially unresectable colorectal liver metastases (CRLM) is paramount. Although the combination of an anti-EGFR with a doublet chemotherapy backbone has been established as the upfront conversion regimen in RAS/BRAF wild-type CRC patients with initially unresectable CRLM, several Phase II studies highlighted the substantial efficacy of a triplet chemotherapy backbone. Nevertheless, the added value of an intensified chemotherapy backbone in combination with cetuximab has not been explored in a randomized controlled trial at the time of this study. What did the researchers do and find?: This prospective, open-label, randomized clinical trial aimed to assess the efficacy of upfront cetuximab plus FOLFOXIRI versus cetuximab plus FOLFOX in a cohort consisting only of RAS/BRAF wild-type CRC patients with initially unresectable CRLM. The study findings reveal that the objective response rates (ORRs) were comparable between the 2 treatment arms. Although a superior depth of tumor response was achieved in the cetuximab plus FOLFOXIRI treatment arm, this did not translate to improved resection rates or progression-free survival (PFS). Instead, this regimen was associated with increased treatment toxicities. What do these findings mean?: Collectively, the TRICE study recommends selecting cetuximab plus FOLFOX as the first-line regimen for RAS/BRAF wild-type CRC patients with unresectable CRLM requiring conversion to resection. Major limitations of the study include the inherent bias in subjective surgical decisions regarding resection feasibility and the lack of centralized assessment for study endpoints. [ABSTRACT FROM AUTHOR]