CHICAGO — Patients with unresectable, metastatic colorectal cancer derived significant PFS and OS benefits from upfront FOLFOXIRI chemotherapy and bevacizumab, followed by reintroduction of the regimen after progressive disease, compared with preplanned consecutive FOLFOX-bevacizumab and FOLFIRI-bevacizumab, according to updated results of the randomized phase 3 TRIBE2 study presented at ASCO Annual Meeting.
Previous results of the study showed the combination of FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin and irinotecan) and bevacizumab (Avastin, Genentech) was associated with a higher response rate and longer PFS and OS compared with FOLFIRI (fluorouracil, leucovorin and irinotecan) and bevacizumab in first-line treatment of metastatic colorectal cancer, according to Chiara Cremolini MD, of the department of translational research on new technologies in medicine and surgery at Universita di Pisa.
“Based on these results and other phase 2 randomized trials, FOLFOXIRI plus bevacizumab is recommended by major guidelines as a valuable option for the upfront treatment of selected patients [with metastatic colorectal cancer],” Cremolini said during a presentation.
Cremolini and colleagues tested whether FOLFOXIRI retained its advantage compared with a preplanned sequential strategy of the chemotherapy agents (FOLFOX and FOLFIRI), in combination with bevacizumab, among 679 patients with unresectable, metastatic colorectal cancer.
Researchers enrolled participants at 58 Italian sites between February 2015 and May 2017. They randomly assigned patients to as many as eight cycles of FOLFOX and bevacizumab, followed by FOLFIRI and bevacizumab after disease progression (arm A; n = 340; median age, 61 years; range, 30-75) or FOLFOXIRI and bevacizumab before and after progression (arm B; n = 339; median age, 60 years; range, 33-75).
Most patients in both arms had synchronous metastases (89%) and RAS-mutant disease (65% arm A; 63% arm B).
PFS2, defined as the time from randomization to progressive disease on any therapy administered after first sign of progressive disease or death (PD2), served as the primary endpoint.
The researchers designed the study to have 80% power to detect a HR for PFS2 of 0.77 in favor of arm B, with a total 2-sided-alpha error of .05 (.0131 for the interim analysis, planned at 303 PFS2 events, and .0455 for the final analysis, planned at 466 PFS2 events).
Response rate, first PFS (time from random assignment to the first sign of progressive disease or death [PD1]), second PFS (time from PD1 to PD2) and OS served as secondary endpoints.
At a median follow-up of 30.6 months, the researchers recorded 514 PD2 events (arm A, n = 272; arm B, n = 242), 594 PD1 events (arm A, n = 303; arm B, n = 291) and 408 OS events (arm A, n = 217; arm B, n = 191).
Upfront FOLFOXIRI conferred a significant benefit in terms of median PFS2 (19.1 months vs. 17.5 months; HR = 0.74; 95% CI, 0.62-0.88), response rate (62% vs. 50%; OR = 1.61; 95% CI, 1.19-2.18) and median first PFS (12 months vs. 9.8 months, HR =0.75; 95% CI, 0.63-0.88). Preliminary OS results also showed a significant benefit with FOLFOXIRI (median, 27.6 months vs. 22.6 months; HR = 0.81; 95% CI, 0.67-0.98).
Of the 594 patients who experienced a PD1 event, 470 (proceeded to second-line therapy, including 195 patients in arm A who received per-protocol FOLFIRI and bevacizumab and 129 patients in arm B who received per-protocol FOLFOXFIRI and bevacizumab . Results of the per-protocol analysis showed significantly longer second PFS in arm B vs. arm A (6.5 months vs. 5.8 months; HR = 0.76; 95% CI, 0.6- 0.97), as well as higher rates of response (19% vs. 12%) and disease control (77% vs. 64%).
FOLFIRINOX and bevacizumab appeared associated with higher rates of neutropenia (50% vs. 21%), diarrhea (17% vs. 5%) and febrile neutropenia (7% vs. 3%) vs. the FOLFOX regimen in the first line and higher rates of neurotoxicity (5% vs. 0%) vs. the FOLFIRI regimen in the second line.
“Efficacy, activity and safety results reported with FOLFOXIRI/bevacizumab are highly consistent with those from the previous phase 3 TRIBE study,” Cremolini said. “First-line treatment with FOLFOXIRI-bevacizumab does not impair the feasibility and efficacy of therapies after progression and may positively affect patients’ long-term outcome. These data support the use of FOLFOXIRI-bevacizumab as the best first-line option for most fit patients with right-sided and/or RAS/BRAF-mutated [metastatic colorectal cancer].” – by Jennifer Byrne
Cremolini C, et al. Abstract 3508. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
Disclosures: Cremolini reports honoraria from, consultant/advisory or speakers bureau roles with, or travel accommodations/expenses from Amgen, Bayer, Roche and Servier, as well as research funding from Merck. Please see the abstract for all other authors’ relevant financial disclosures.