Updated results of TRIBE2, a phase III, randomized strategy study by GONO in the 1st- and 2nd-line treatment of unresectable mCRC

TRIBE2 (NCT02339116) is a phase III trial in which previously untreated pts with unresectable metastatic colorectal cancer (mCRC) were randomized 1:1 to FOLFOX/bev followed by FOLFIRI/bev after disease progression (PD) (arm A) or FOLFOXIRI/bev followed by the reintroduction of the same regimen after PD (arm B). The study was designed to demonstrate the actual advantage of the upfront exposure to the three cytotoxics when compared with a pre-planned sequential strategy of exposure to the same agents, in the frame of a sustained inhibition of angiogenesis. From February 2015 to May 2017, 679 pts (arm A/B: 340/339) were enrolled in 58 Italian sites.

The study was designed to detect an HR for PFS2 of 0.77 in favour of arm B with 80% power and an overall 2-sided-ɑ error of 0.05 (0.0131 and 0.0455 for the interim and final analyses, planned at 303 and 466 PFS2 events, respectively). Here we show updated results, including subgroup analyses for 1st-PFS and PFS2 according to the following clinical and molecular characteristics: ECOG PS, previous adjuvant therapy, time to metastases, surgery on primary tumor, liver-only disease, primary tumor site, RAS, BRAF and microsatellite status.

Main characteristics of the 679 enrolled pts were (arm A/B): ECOG PS 0 85%/86%, right-sided primary 38%/38%, RAS mutant 65%/63%, BRAF mutant 10%/10%, right-sided and/or RAS or BRAF mutant 79%/78%, MSI-high 4%/5%. At a median follow up of 30.6 mos, 514 (arm A/B: 272/242) PD2, 594 (arm A/B: 303/291) PD1 and 408 (arm A/B: 217/191) OS events were collected. A significant advantage by upfront FOLFOXIRI/bev was shown in terms of PFS2 (19.1 vs 17.5 mos; HR 0.74; 95% CI, 0.62-0.88; P < .001), 1st-PFS (12.0 vs 9.8 mos; HR 0.75; 95% CI, 0.63-0.88; P < .001) and OS (27.6 vs 22.6 mos; HR 0.81; 95% CI, 0.67-0.98, P = .033). Subgroup analyses for PFS2 and 1st-PFS did not reveal any significant interactions between treatment effect and key baseline clinical characteristics, with the exception of a higher PFS2 benefit in favour of arm B for pts with ECOG PS 0 compared to those with ECOG PS 1-2 (HR 0.70 vs 1.13; P-value of interaction = .05). However, in the absence of a significant interaction test, the subgroup of pts with a right-sided and/or RAS or BRAF mutant tumor and with ECOG PS 0 (n = 470) seemed to achieve a more relevant advantage from upfront FOLFOXIRI/bev (HRs for 1st-PFS and PFS2: 0.69 and 0.68, respectively), whereas for pts with left-sided and RAS/BRAF wild-type tumor and/or with ECOG PS 1-2 (n = 186) the magnitude of benefit is smaller (HR for 1st-PFS and PFS2: 0.90 and 0.87, respectively).

Upfront FOLFOXIRI/bev followed by the pre-planned reintroduction of the same agents after PD significantly prolonged PFS2 and OS when compared with the pre-planned sequential administration of FOLFOX/bev and FOLFIRI/bev in unresectable mCRC patients. Treatment effect is consistent across analysed clinical and molecular subgroups, with potentially increased benefit among patients with a right-sided and/or a RAS or BRAF mutant tumor and in particular with ECOG PS 0.