Updated results of TRIBE2, a phase III, randomized strategy study by GONO in the first- and second-line treatment of unresectable mCRC.
Authors: Chiara Cremolini, Carlotta Antoniotti, Sara Lonardi, Daniele Rossini, Filippo Pietrantonio, Stefano Sergio Cordio, Francesca Bergamo, Federica Marmorino, Evaristo Maiello, Alessandro Passardi, Gianluca Masi, Emiliano Tamburini, Daniele Santini, Roberta Grande, Alberto Zaniboni, Cristina Granetto, Sabina Murgioni, Giuseppe Aprile, Luca Boni, Alfredo Falcone
Journal: Journal of Clinical Oncology (2019)

3508 Background: In the phase III TRIBE study FOLFOXIRI/bev significantly improved Response Rate (RR), PFS and OS when compared with FOLFIRI/bev as initial treatment of mCRC. However, the actual advantage by the triplet could be lower when compared with a pre-planned sequential strategy of doublets (FOLFOX, FOLFIRI). TRIBE2 (NCT02339116) is a phase III trial in which unresectable mCRC pts were randomized 1:1 to FOLFOX/bev followed by FOLFIRI/bev after PD (arm A) or FOLFOXIRI/bev followed by the reintroduction of the same regimen after PD (arm B). A pre-planned interim analysis showed a significant advantage for arm B in terms of PFS2, primary endpoint of the study, defined as the time from randomization to PD on any treatment given after first PD or death (PD2). Methods: The study had 80% power to detect a HR for PFS2 of 0.77 in favor of arm B with an overall 2-sided-α error of 0.05 (0.0131 and 0.0455 for the interim and final analyses, planned at 303 and 466 PFS2 events, respectively). Secondary endpoints included RR, 1 st -PFS, i.e. the time from randomization to the first evidence of PD or death (PD1), 2 nd -PFS, i.e. the time from PD1 to PD2, and OS. Results: From February 2015 to May 2017, 679 pts (arm A/B: 340/339) were enrolled in 58 Italian sites. Main pts’ characteristics were (arm A/B): right side 38%/38%, synchronous mets 89%/89%, RAS mutant 65%/63%, BRAF mutant 10%/10%. 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 confirmed in terms of PFS2 (19.1 vs 16.4 mos, HR 0.74, 95%CI 0.62-0.88, p&lt;0.001), RR (62% vs 50%, OR 1.61, 95%CI 1.19-2.18, p=0.002) and 1 st -PFS (12.0 vs 9.8 mos, HR 0.75, 95%CI 0.63-0.88, p&lt;0.001). A significant OS benefit for pts in arm B was also observed (27.6 vs 22.6 mos, HR: 0.81, 95%CI: 0.67-0.98, p=0.033). Out of 594 pts with a PD1 event, 470 (79%, arm A/B: 251/219) received a treatment after PD. In the per-protocol analysis (N=323), pts in arm B showed significantly longer 2 nd -PFS (6.5 vs 5.8 mos, HR 0.76, 95%CI 0.59-0.97, p=0.024). Conclusion: Upfront FOLFOXIRI/bev followed by the pre-planned reintroduction of the same agents after PD provided a statistically significant and clinically relevant PFS2 and OS benefit when compared with the pre-planned sequential administration of FOLFOX/bev and FOLFIRI/bev in unresectable mCRC patients. A median OS of 27.6 mos was reached despite the high percentage of pts with poor prognostic features ( RAS and BRAF mutations, right side, synchronous mets). Clinical trial information: NCT02339116.